A 57-year-old woman presented to the emergency department with left lower quadrant pain, which had started 1 week earlier and was constant, dull, aching, and nonradiating. There were no aggravating or alleviating factors. The pain was associated with low-grade fever and nausea. She reported no vomiting, no change in bowel habits, and no hematemesis, hematochezia, or melena. She did not have urinary urgency, frequency, or dysuria. She had no cardiac, respiratory, or neurologic symptoms.

Her medical history included hypothyroidism, type 2 diabetes mellitus, diverticulosis, and chronic obstructive pulmonary disease. Her medications included metformin, insulin, levothyroxine, and inhaled tiotropium. She had no allergies. She had never undergone surgery, including cesarean delivery. She was postmenopausal. She had two children, both of whom had been born vaginally at full term. She denied using alcohol, tobacco, and illicit drugs. Her family history was noncontributory.

On examination, she was not in acute distress. Her temperature was 36.7°C (98.1°F), blood pressure 130/90 mm Hg, heart rate 86 beats per minute and regular, respiratory rate 16 breaths per minute, and oxygen saturation 98% on ambient air. Examination of her head and neck was unremarkable. Cardiopulmonary examination was normal. Abdominal examination revealed normal bowel sounds, mild tenderness in the left lower quadrant with localized guarding, and rebound tenderness. Neurologic examination was unremarkable.

Initial laboratory data showed mild leukocytosis. Computed tomography with contrast of the abdomen and pelvis suggested acute diverticulitis.

ATRIAL FIBRILLATION, AND THEN A TURN FOR THE WORSE

The patient was admitted with an initial diagnosis of acute diverticulitis. She was started on antibiotics, hydration, and pain medications, and her abdominal pain gradually improved.

On the third hospital day, she suddenly experienced shortness of breath and palpitations. At the time of admission her electrocardiogram had been normal, but it now showed atrial fibrillation with a rapid ventricular response. She also developed elevated troponin levels, which were thought to represent type 2 non-ST-elevation myocardial infarction.

She was started on aspirin, clopidogrel, and anticoagulation with heparin bridged with warfarin for the new-onset atrial fibrillation. Her heart rate was controlled with metoprolol, and her shortness of breath improved. An echocardiogram was normal.

On the seventh hospital day, she developed severe right-sided lower abdominal pain and bruising. Her blood pressure was 90/60 mm Hg, heart rate 110 beats per minute and irregularly irregular, respiratory rate 22 breaths per minute, and oxygen saturation 97% on room air. Her abdomen was diffusely tender with a palpable mass in the right lower quadrant and hypoactive bowel sounds. Ecchymosis was noted (Figure 1).

DIFFERENTIAL DIAGNOSIS

1. What is the likely cause of her decompensation?

• Acute mesenteric ischemia
• Perforation of the gastrointestinal tract
• Rectus sheath hematoma
• Abdominal compartment syndrome due to acute pancreatitis

Acute mesenteric ischemia

Signs and symptoms of acute mesenteric ischemia can be vague. Moreover, when it leads to bowel necrosis the mortality rate is high, ranging from 30% to 65%.¹ Hence, one should suspect it and try to diagnose it early.

Most patients with this condition have comorbidities; risk factors include atherosclerotic disease, cardiac conditions (congestive heart failure, recent myocardial infarction, and atrial fibrillation), systemic illness, and inherited or acquired hypercoagulable states.²

The four major causes are:

• Acute thromboembolic occlusion of the superior mesenteric artery (the most common site of occlusion because of the acute angle of origin from the aorta)
• Acute thrombosis of the mesenteric vein
• Acute thrombosis of the mesenteric artery
• Nonocclusive disease affecting the mesenteric vessels²

Nonocclusive disease is seen in conditions in which the mesenteric vessels are already compromised due to background stenosis owing to atherosclerosis. Also, conditions such as septic and cardiogenic shock can compromise these arteries, leading to ischemia, which, if it persists, can lead to bowel infarction. Ischemic colitis falls under this category. It commonly involves the descending and sigmoid colon.³

The initial symptom of ischemia may be abdominal pain that is brought on by eating large meals (“postprandial intestinal angina.”² When the ischemia worsens to infarction, patients may have a diffusely tender abdomen and constant pain that does not vary with palpation. Surprisingly, patients do not exhibit peritoneal signs early on. This gives rise to the description of “pain out of proportion to the physical findings” traditionally associated with acute mesenteric ischemia.²

Diagnosis. Supportive laboratory data include marked leukocytosis, elevated hematocrit due to hemoconcentration, metabolic acidosis, and elevated lactate.⁴ Newer markers such as serum alpha-glutathione S-transferase (alpha-GST) and intestinal fatty acid-binding protein (I-FABP) may be used to support the diagnosis.

Elevated alpha-GST has 72% sensitivity and 77% specificity in the diagnosis of acute mesenteric ischemia.⁵ The caveat is that it cannot reliably differentiate ischemia from infarction. Its sensitivity can be improved to 97% to 100% by using the white blood cell count and lactate levels in combination.⁵

An I-FABP level higher than 100 ng/mL has 100% sensitivity for diagnosing mesenteric infarction but only 25% sensitivity for bowel strangulation.⁶

Early use of abdominal computed tomography with contrast can aid in recognizing this diagnosis.⁷ Thus, it should be ordered in suspected cases, even in patients who have elevated creatinine levels (which would normally preclude the use of contrast), since early diagnosis followed by endovascular therapy is associated with survival benefit, and the risk of contrast-induced nephropathy appears to be small.⁸ Computed tomography helps to determine the state of mesenteric vessels and bowel perfusion before ischemia progresses to infarction. It also helps to rule out other common diagnoses. Findings that suggest acute mesenteric ischemia include segmental bowel wall thickening, intestinal pneumatosis with gas in the portal vein, bowel dilation, mesenteric stranding, portomesenteric thrombosis, and solid-organ infarction.⁹

Treatment. If superior mesenteric artery occlusion is diagnosed on computed tomography, the next step is to determine if there is peritonitis.¹⁰ In patients who have evidence of peritonitis, exploratory laparotomy is performed. For emboli in such patients, open embolectomy followed by on-table angiography is carried out in combination with damage-control surgery. For patients with peritonitis and acute thrombosis, stenting along with damage-control surgery is preferred.¹⁰

On the other hand, if there is no peritonitis, the thrombosis may be amenable to endovascular intervention. For patients with acute embolic occlusion with no contraindications to thrombolysis, aspiration embolectomy in combination with local catheter-directed thrombolysis with recombinant tissue plasminogen activator can be performed. This can be combined with endovascular mechanical embolectomy for more complete management.¹⁰ Patients with contraindications to thrombolysis can be treated either with aspiration and mechanical embolectomy or with open embolectomy with angiography.¹⁰

During laparotomy, the surgeon carefully inspects the bowel for signs of necrosis. Signs that bowel is still viable include pink color, bleeding from cut surfaces, good peristalsis, and visible pulsations in the arterial arcade of the mesentery.

On day 7 she developed acute decompensation—what was the cause?

Acute mesenteric artery thrombosis arising from chronic atherosclerotic disease can be treated with stenting of the stenotic lesion.¹⁰ Patients with this condition would also benefit from aggressive management of atherosclerotic disease with statins along with antiplatelet agents.¹⁰

Mesenteric vein thrombosis requires prompt institution of anticoagulation. However, in advanced cases leading to bowel infarction, exploratory laparotomy with resection of the necrotic bowel may be required. Anticoagulation should be continued for at least 6 months, and further therapy should be determined by the underlying precipitating condition.¹⁰

Critically ill patients who develop mesenteric ischemia secondary to persistent hypotension usually respond to adequate volume resuscitation, cessation of vasopressors, and overall improvement in their hemodynamic status. These patients must be closely monitored for development of gangrene of the bowel because they may be intubated and not able to complain. Any sudden deterioration in their condition should prompt physicians to consider bowel necrosis developing in these patients. Elevation of lactate levels out of proportion to the degree of hypotension may be corroborative evidence.⁴

Our patient had risk factors for acute mesenteric ischemia that included atrial fibrillation and recent non-ST-elevation myocardial infarction. She could have had arterial emboli due to atrial fibrillation, in situ superior mesenteric arterial thrombosis, or splanchnic arterial vasoconstriction due to the myocardial infarction associated with transient hypotension.

Arguing against this diagnosis, although she had a grossly distended abdomen, abdominal bruising usually is not seen. Also, a palpable mass in the right lower quadrant is uncommon except when acute mesenteric ischemia occurs due to segmental intestinal strangulation, as with strangulated hernia or volvulus. She also had therapeutic international normalized ratio (INR) levels constantly while on anticoagulation. Nevertheless, acute mesenteric ischemia should be strongly considered in the initial differential diagnosis of this patient’s acute decompensation.

Perforation of the gastrointestinal tract

Diverticulitis is the acute inflammation of one or more diverticula, which are small pouches created by herniation of the mucosa into the wall of the colon. The condition is caused by microscopic or macroscopic perforation of the diverticula. Microscopic perforation is usually self-limited (uncomplicated diverticulitis) and responds to conservative treatment, whereas macroscopic perforation can be associated with fecal or purulent peritonitis, abscess, enteric fistula, bowel obstruction, and stricture (complicated diverticulitis), in which case surgery may be necessary.

Signs and symptoms of acute mesenteric ischemia can be vague

Patients with peritonitis due to free perforation present with generalized tenderness with rebound tenderness and guarding on abdominal examination. The abdomen may be distended and tympanic to percussion, with diminished or absent bowel sounds. Patients may have hemodynamic compromise.

Plain upright abdominal radiographs may show free air under the diaphragm. Computed tomography may show oral contrast outside the lumen and detect even small amounts of free intraperitoneal air (more clearly seen on a lung window setting).

Our patient initially presented with acute diverticulitis. She later developed diffuse abdominal tenderness with hypoactive bowel sounds. Bowel perforation is certainly a possibility at this stage, though it is usually not associated with abdominal bruising. She would need additional imaging to rule out this complication.

Other differential diagnoses to be considered in this patient with right lower-quadrant pain include acute appendicitis, incarcerated inguinal hernia, volvulus (particularly cecal volvulus), small-bowel obstruction, pyelonephritis, and gynecologic causes such as adnexal torsion, ruptured ovarian cyst, and tubo-ovarian abscess. Computed tomography helps to differentiate most of these causes.

Rectus sheath hematoma

Rectus sheath hematoma is relatively uncommon and often not considered in the initial differential diagnosis of an acute abdomen. This gives it the rightful term “a great masquerader.” It usually results from bleeding into the rectus sheath from damage to the superior (more common) or inferior epigastric arteries and occasionally from a direct tear of the rectus abdominis muscle. Predisposing factors include anticoagulant therapy (most common), advanced age, hypertension, previous abdominal surgery, trauma, paroxysmal coughing, medication injections, pregnancy, blood dyscrasias, severe vomiting, violent physical activity, and leukemia.¹¹

Clinical manifestations include acute abdominal pain, often associated with fever, nausea, and vomiting. Physical examination may reveal signs of hypovolemic shock, a palpable nonpulsatile abdominal mass, and signs of local peritoneal irritation. The Carnett sign¹¹ (tenderness within the abdominal wall that persists and does not improve with raising the head) and the Fothergill sign¹¹ (a tender abdominal mass that does not cross the midline and remains palpable with tensing of the rectus sheath) may be elicited.

Computed tomography is more sensitive than abdominal ultrasonography in differentiating rectus sheath hematoma from an intra-abdominal pathology.¹¹ In addition, computed tomography also helps to determine if the bleeding is active or not, which has therapeutic implications.

In our patient, rectus sheath hematoma is a possibility because of her ongoing anticoagulation, findings of localized abdominal bruising, and palpable right lower-quadrant mass, and it is high on the list of differential diagnoses. Rectus sheath hematoma should be considered in the differential diagnosis of lower abdominal pain particularly in elderly women who are on anticoagulation and in whom the onset of pain coincides with a paroxysm of cough.¹² Women are twice as likely as men to develop rectus sheath hematoma, owing to their different muscle mass.¹³ In addition, anterior abdominal wall muscles are stretched during pregnancy.¹³

Abdominal compartment syndrome

Abdominal compartment syndrome has been classically associated with surgical patients. However, it is being increasingly recognized in critically ill medical patients, in whom detecting and treating it early may result in significant reduction in rates of morbidity and death.¹⁴

Abdominal compartment syndrome is of three types: primary, secondary, and recurrent. Primary abdominal compartment syndrome refers to the classic surgical patients with evidence of direct injury to the abdominal or pelvic organs through major trauma or extensive abdominal surgeries. Secondary abdominal compartment syndrome refers to its development in critically ill intensive care patients in whom the pathology does not directly involve the abdominal or pelvic organs.

Various medical conditions can culminate in abdominal compartment syndrome and result in multiorgan failure. Recurrent abdominal compartment syndrome refers to its development after management of either primary or secondary intra-abdominal hypertension or abdominal compartment syndrome.¹⁵ Clinicians thus must be aware of secondary and recurrent abdominal compartment syndrome occurring in critically ill patients.

The normal intra-abdominal pressure is around 5 to 7 mm Hg, even in most critically ill patients. Persistent elevation, ie, higher than 12 mm Hg, is referred to as intra-abdominal hypertension.^16–18 Intra-abdominal hypertension is subdivided into four grades:

• Grade I: 12–15 mm Hg
• Grade II: 16–20 mm Hg
• Grade III: 21–25 mm Hg
• Grade IV: > 25 mm Hg.

The World Society of the Abdominal Compartment Syndrome (WSACS) defines abdominal compartment syndrome as pressure higher than 20 mm Hg along with organ damage.¹⁸ It may or may not be associated with an abdominal perfusion pressure less than 60 mm Hg.¹⁸

Risk factors associated with abdominal compartment syndrome include conditions causing decreased gut motility (gastroparesis, ileus, and colonic pseudo-obstruction), intra-abdominal or retroperitoneal masses or abscesses, ascites, hemoperitoneum, acute pancreatitis, third-spacing due to massive fluid resuscitation with transfusions, peritoneal dialysis, and shock.^18,19

Microscopic perforation is usually self-limited, whereas macroscopic perforation may need surgery

Physical examination has a sensitivity of only 40% to 60% in detecting intra-abdominal hypertension.²⁰ The gold-standard method of measuring the intra-abdominal pressure is the modified Kron technique,¹⁸ using a Foley catheter in the bladder connected to a pressure transducer. With the patient in the supine position, the transducer is zeroed at the mid-axillary line at the level of the iliac crest, and 25 mL of normal saline is instilled into the bladder and maintained for 30 to 60 seconds to let the detrusor muscle relax.¹⁵ Pressure tracings are then recorded at the end of expiration. Factors that are known to affect the transbladder pressure include patient position, respiratory movement, and body mass index, and should be taken into account when reading the pressure recordings.^15,21 Other techniques that can be used include intragastric, intra-inferior vena cava, and intrarectal approaches.¹⁵

The WSACS recommends that any patient admitted to a critical care unit or in whom new organ failure develops should be screened for risk factors for intra-abdominal hypertension and abdominal compartment syndrome. If a patient has at least two of the risk factors suggested by WSACS, a baseline intra-abdominal pressure measurement should be obtained. Patients at risk for intra-abdominal hypertension should have the intra-abdominal pressure measured every 4 to 6 hours. However, in the face of hemodynamic instability and worsening multiorgan failure, the pressure may need to be measured hourly.¹⁸

Clinicians managing patients in the intensive care unit should think of intra-abdominal pressure alongside blood pressure, urine output, and mental status when evaluating hemodynamic status. Clinical manifestations of abdominal compartment syndrome reflect the underlying organ dysfunction and include hypotension, refractory shock, decreased urine output, intracranial hypertension, progressive hypoxemia and hypercarbia, elevated pulmonary peak pressures, and worsening of metabolic acidosis.²²

Treatment. The standard treatment for primary abdominal compartment syndrome is surgical decompression. According to WSACS guidelines, insertion of a percutaneous drainage catheter should be advocated in patients with gross ascites and in whom decompressive surgery is not feasible. A damage-control resuscitation strategy used for patients undergoing damage-control laparotomy has been found to increase the 30-day survival rate.²³ A damage-control resuscitation strategy consists of increasing the use of plasma and platelet transfusions over packed red cell transfusions, limiting the use of crystalloid solutions in early fluid resuscitation, and allowing for permissive hypotension.

Rectus sheath hematoma is relatively uncommon and is not often considered in the initial differential diagnosis of an acute abdomen

Secondary abdominal compartment syndrome is treated conservatively in most cases, since patients with this condition are very poor surgical candidates owing to their comorbidities.¹⁸ However, in patients with progressive organ dysfunction in whom medical management has failed, surgical decompression should be considered.¹⁸ Medical management of secondary abdominal compartment syndrome depends on the underlying etiology. Strategies include nasogastric or colonic decompression, use of prokinetic agents, paracentesis in cases with gross ascites, and maintaining a cumulative negative fluid balance. The WSACS does not recommend routine use of diuretics, albumin infusion, or renal replacement strategies. Pain should be adequately controlled to improve abdominal wall compliance.^18,24 Neuromuscular blockade agents may be used to aid this process. Neostigmine may be used to treat colonic pseudo-obstruction when other conservative methods fail. Use of enteral nutrition should be minimized.¹⁸

Our patient might have abdominal compartment syndrome, but a definitive diagnosis cannot be made at this point without measuring the intra-abdominal pressure.

WHICH IMAGING TEST WOULD BE BEST?

2. Which imaging test would be best for establishing the diagnosis in this patient?

• Plain abdominal radiography
• Abdominal ultrasonography
• Computed tomography of the abdomen and pelvis with contrast
• Magnetic resonance imaging of the abdomen and pelvis

Plain abdominal radiography

Plain abdominal radiography can help to determine if there is free gas under the diaphragm (due to bowel perforation), obstructed bowel, sentinel loop, volvulus, or fecoliths causing the abdominal pain. It cannot diagnose rectus sheath hematoma or acute mesenteric ischemia.

Abdominal ultrasonography

Abdominal ultrasonography can be used as the first diagnostic test, as it is widely available, safe, effective, and tolerable. It does not expose the patient to radiation or intravenous contrast agents. It helps to diagnose rectus sheath hematoma and helps to follow its maturation and resolution once a diagnosis is made. It can provide a rapid assessment of the size, location, extent, and physical characteristics of the mass.

Ultrasonography is widely available, safe, effective, and tolerable

Rectus sheath hematoma appears spindle-shaped on sagittal sections and ovoid on coronal sections. It often appears sonolucent in the early stages and sonodense in the late stage, but the appearance may be heterogeneous depending on the combined presence of clot and fresh blood. These findings are sufficient to make the diagnosis.

Abdominal ultrasonography has 85% to 96% sensitivity in diagnosing rectus sheath hematoma.²⁵ It can help diagnose other causes of the abdominal pain, such as renal stones and cholecystitis. It is the preferred imaging test in pediatric patients, pregnant patients, and those with renal insufficiency.

Abdominal computed tomography

Abdominal computed tomography has a sensitivity and specificity of 100% for diagnosing acute rectus sheath hematoma with a duration of less than 5 days.²⁵ It not only helps to determine the precise location and extent, but also helps to determine if there is active extravasation. Even in patients with renal insufficiency, noncontrast computed tomography will help to confirm the diagnosis, although it may not show extravasation or it may miss certain abdominal pathologies because of the lack of contrast.

Acute rectus sheath hematoma appears as a hyperdense mass posterior to the rectus abdominis muscle with ipsilateral anterolateral muscular enlargement. Chronic rectus sheath hematoma appears isodense or hypodense relative to the surrounding muscle. Above the arcuate line, rectus sheath hematoma has a spindle shape; below the arcuate line, it is typically spherical.

In 1996, Berná et al²⁶ classified rectus sheath hematoma into three grades based on findings of computed tomography:

• Grade I is intramuscular and unilateral
• Grade II may involve bilateral rectus muscles without extension into the prevesicular space
• Grade III extends into the peritoneum and prevesicular space

Magnetic resonance imaging

Magnetic resonance imaging is useful to differentiate chronic rectus sheath hematoma (greater than 5-day duration) from an anterior abdominal wall mass. Chronic rectus sheath hematoma will have high signal intensity on both T1- and T2-weighted images up to 10 months after the onset of the hematoma.²⁷

Back to our patient

Since our patient’s symptoms are acute and of less than 5 days’ duration, computed tomography of the abdomen and pelvis would be the best diagnostic test, with therapeutic implications if there is ongoing extravasation.

Computed tomography of the abdomen with contrast showed a new hematoma, measuring 25 by 14 by 13.5 cm, in the right rectus sheath (Figure 2), with no other findings. The hematoma was grade I, since it was intramuscular and unilateral without extension elsewhere.

Laboratory workup showed that the patient’s hematocrit was falling, from 34% to 24%, and her INR was elevated at 2.5. She was resuscitated with fluids, blood transfusion, and fresh-frozen plasma. Anticoagulation was withheld. In spite of resuscitation, her hematocrit kept falling, though she remained hemodynamically stable.

THE WAY FORWARD

3. At this point, what would be the best approach to management in this patient?

• Serial clinical examinations and frequent monitoring of the complete blood cell count
• Urgent surgical consult for exploratory laparotomy with evaluation of the hematoma and ligation of the bleeding vessel
• Repeat computed tomographic angiography to identify a possible bleeding vessel; consideration of radiographically guided arterial embolization
• Measuring the intra-abdominal pressure using the intrabladder pressure for abdominal compartment syndrome and consideration of surgical drainage

The key clinical concern in a patient with a rectus sheath hematoma who is hemodynamically stable is whether the hematoma is expanding. This patient responded to initial resuscitation, but her falling hematocrit was evidence of ongoing bleeding leading to an expanding rectus sheath hematoma. Thus, serial clinical examinations and frequent monitoring of the complete blood cell count would not be enough, as it could miss fatal ongoing bleeding.

Radiographically guided embolization with Gelfoam, thrombin, or coils should be attempted first, as this is less invasive than exploratory laparotomy.²⁸ It can achieve hemostasis, decrease the size of the hematoma, limit the need for blood products, and prevent rupture into the abdomen. If this is unsuccessful, the next step is ligation of the bleeding vessel.²⁹

Surgical treatment includes evacuation of the hematoma, repair of the rectus sheath, ligation of bleeding vessels, and abdominal wall closure. Surgical evacuation or guided drainage of a rectus sheath hematoma on its own is not normally indicated and may indeed cause persistent bleeding by diminishing a potential tamponade effect. However, it may become necessary if the hematoma is very large or infected, if it causes marked respiratory impairment, or if abdominal compartment syndrome is suspected.

Abdominal compartment syndrome is very rare but is associated with a 50% mortality rate.³⁰ It should be suspected in patients with oliguria, low cardiac output, changes in minute ventilation, and altered splanchnic blood flow. The diagnosis is confirmed with indwelling catheter manometry of the bladder to measure intra-abdominal pressure. Intra-abominal pressure above 25 mm Hg should be treated with decompressive laparotomy.³⁰ However, the clinical suspicion of abdominal compartment syndrome was low in this patient.

The best choice at this point would be urgent computed tomographic angiography to identify a bleeding vessel, along with consideration of radiographically guided arterial embolization.

TREATMENT IS USUALLY CONSERVATIVE

Treatment of rectus sheath hematoma is conservative in most hemodynamically stable patients, with embolization or surgical intervention reserved for unstable patients or those in whom the hematoma is expanding.

Knowledge of the grading system of Berná et al²⁶ helps to assess the patient’s risk and to anticipate potential complications. Grade I hematomas are mild and do not necessitate admission. Patients with grade II hematoma can be admitted to the floor for 24 to 48 hours for observation. Grade III usually occurs in patients receiving anticoagulant therapy and frequently requires blood products. These patients have a prolonged hospital stay and more complications, including hypovolemic shock, myonecrosis, acute coronary syndrome, arrhythmias, acute renal failure, small-bowel infarction, and abdominal compartment syndrome—all of which increases the risk of morbidity and death. Thus, patients who are on anticoagulation who develop grade III rectus sheath hematoma should be admitted to the hospital, preferably to the intensive care unit, to ensure that the hematoma is not expanding and to plan reinstitution of anticoagulation as appropriate.

In most cases, rectus sheath hematomas resolve within 1 to 3 months. Resolution of large hematomas may be hastened with the use of pulsed ultrasound.³¹ However, this treatment should be used only after the acute phase is over, when there is evidence of an organized thrombus and coagulation measures have returned to the target range. This helps to reduce the risk of bleeding and to prevent symptoms from worsening.³¹

OUR PATIENT’S COURSE

Our patient underwent urgent computed tomographic angiography, which showed a modest increase in the size of the rectus sheath hematoma. However, no definitive blush of contrast was seen to suggest active arterial bleeding. Her hematocrit stabilized, and she remained hemodynamically stable without requiring additional intervention. Most likely her bleeding was self-contained. She had normal intra-abdominal pressure on serial monitoring. She was later transferred to acute inpatient rehabilitation in view of deconditioning and is currently doing well. The hematoma persisted, decreasing only slightly in size over the next 3 weeks.

A 57-year-old woman presented to the emergency department with left lower quadrant pain, which had started 1 week earlier and was constant, dull, aching, and nonradiating. There were no aggravating or alleviating factors. The pain was associated with low-grade fever and nausea. She reported no vomiting, no change in bowel habits, and no hematemesis, hematochezia, or melena. She did not have urinary urgency, frequency, or dysuria. She had no cardiac, respiratory, or neurologic symptoms.

Her medical history included hypothyroidism, type 2 diabetes mellitus, diverticulosis, and chronic obstructive pulmonary disease. Her medications included metformin, insulin, levothyroxine, and inhaled tiotropium. She had no allergies. She had never undergone surgery, including cesarean delivery. She was postmenopausal. She had two children, both of whom had been born vaginally at full term. She denied using alcohol, tobacco, and illicit drugs. Her family history was noncontributory.

On examination, she was not in acute distress. Her temperature was 36.7°C (98.1°F), blood pressure 130/90 mm Hg, heart rate 86 beats per minute and regular, respiratory rate 16 breaths per minute, and oxygen saturation 98% on ambient air. Examination of her head and neck was unremarkable. Cardiopulmonary examination was normal. Abdominal examination revealed normal bowel sounds, mild tenderness in the left lower quadrant with localized guarding, and rebound tenderness. Neurologic examination was unremarkable.

Initial laboratory data showed mild leukocytosis. Computed tomography with contrast of the abdomen and pelvis suggested acute diverticulitis.

ATRIAL FIBRILLATION, AND THEN A TURN FOR THE WORSE

The patient was admitted with an initial diagnosis of acute diverticulitis. She was started on antibiotics, hydration, and pain medications, and her abdominal pain gradually improved.

On the third hospital day, she suddenly experienced shortness of breath and palpitations. At the time of admission her electrocardiogram had been normal, but it now showed atrial fibrillation with a rapid ventricular response. She also developed elevated troponin levels, which were thought to represent type 2 non-ST-elevation myocardial infarction.

She was started on aspirin, clopidogrel, and anticoagulation with heparin bridged with warfarin for the new-onset atrial fibrillation. Her heart rate was controlled with metoprolol, and her shortness of breath improved. An echocardiogram was normal.

On the seventh hospital day, she developed severe right-sided lower abdominal pain and bruising. Her blood pressure was 90/60 mm Hg, heart rate 110 beats per minute and irregularly irregular, respiratory rate 22 breaths per minute, and oxygen saturation 97% on room air. Her abdomen was diffusely tender with a palpable mass in the right lower quadrant and hypoactive bowel sounds. Ecchymosis was noted (Figure 1).

DIFFERENTIAL DIAGNOSIS

1. What is the likely cause of her decompensation?

• Acute mesenteric ischemia
• Perforation of the gastrointestinal tract
• Rectus sheath hematoma
• Abdominal compartment syndrome due to acute pancreatitis

Acute mesenteric ischemia

Signs and symptoms of acute mesenteric ischemia can be vague. Moreover, when it leads to bowel necrosis the mortality rate is high, ranging from 30% to 65%.¹ Hence, one should suspect it and try to diagnose it early.

Most patients with this condition have comorbidities; risk factors include atherosclerotic disease, cardiac conditions (congestive heart failure, recent myocardial infarction, and atrial fibrillation), systemic illness, and inherited or acquired hypercoagulable states.²

The four major causes are:

• Acute thromboembolic occlusion of the superior mesenteric artery (the most common site of occlusion because of the acute angle of origin from the aorta)
• Acute thrombosis of the mesenteric vein
• Acute thrombosis of the mesenteric artery
• Nonocclusive disease affecting the mesenteric vessels²

Nonocclusive disease is seen in conditions in which the mesenteric vessels are already compromised due to background stenosis owing to atherosclerosis. Also, conditions such as septic and cardiogenic shock can compromise these arteries, leading to ischemia, which, if it persists, can lead to bowel infarction. Ischemic colitis falls under this category. It commonly involves the descending and sigmoid colon.³

The initial symptom of ischemia may be abdominal pain that is brought on by eating large meals (“postprandial intestinal angina.”² When the ischemia worsens to infarction, patients may have a diffusely tender abdomen and constant pain that does not vary with palpation. Surprisingly, patients do not exhibit peritoneal signs early on. This gives rise to the description of “pain out of proportion to the physical findings” traditionally associated with acute mesenteric ischemia.²

Diagnosis. Supportive laboratory data include marked leukocytosis, elevated hematocrit due to hemoconcentration, metabolic acidosis, and elevated lactate.⁴ Newer markers such as serum alpha-glutathione S-transferase (alpha-GST) and intestinal fatty acid-binding protein (I-FABP) may be used to support the diagnosis.

Elevated alpha-GST has 72% sensitivity and 77% specificity in the diagnosis of acute mesenteric ischemia.⁵ The caveat is that it cannot reliably differentiate ischemia from infarction. Its sensitivity can be improved to 97% to 100% by using the white blood cell count and lactate levels in combination.⁵

An I-FABP level higher than 100 ng/mL has 100% sensitivity for diagnosing mesenteric infarction but only 25% sensitivity for bowel strangulation.⁶

Early use of abdominal computed tomography with contrast can aid in recognizing this diagnosis.⁷ Thus, it should be ordered in suspected cases, even in patients who have elevated creatinine levels (which would normally preclude the use of contrast), since early diagnosis followed by endovascular therapy is associated with survival benefit, and the risk of contrast-induced nephropathy appears to be small.⁸ Computed tomography helps to determine the state of mesenteric vessels and bowel perfusion before ischemia progresses to infarction. It also helps to rule out other common diagnoses. Findings that suggest acute mesenteric ischemia include segmental bowel wall thickening, intestinal pneumatosis with gas in the portal vein, bowel dilation, mesenteric stranding, portomesenteric thrombosis, and solid-organ infarction.⁹

Treatment. If superior mesenteric artery occlusion is diagnosed on computed tomography, the next step is to determine if there is peritonitis.¹⁰ In patients who have evidence of peritonitis, exploratory laparotomy is performed. For emboli in such patients, open embolectomy followed by on-table angiography is carried out in combination with damage-control surgery. For patients with peritonitis and acute thrombosis, stenting along with damage-control surgery is preferred.¹⁰

On the other hand, if there is no peritonitis, the thrombosis may be amenable to endovascular intervention. For patients with acute embolic occlusion with no contraindications to thrombolysis, aspiration embolectomy in combination with local catheter-directed thrombolysis with recombinant tissue plasminogen activator can be performed. This can be combined with endovascular mechanical embolectomy for more complete management.¹⁰ Patients with contraindications to thrombolysis can be treated either with aspiration and mechanical embolectomy or with open embolectomy with angiography.¹⁰

During laparotomy, the surgeon carefully inspects the bowel for signs of necrosis. Signs that bowel is still viable include pink color, bleeding from cut surfaces, good peristalsis, and visible pulsations in the arterial arcade of the mesentery.

On day 7 she developed acute decompensation—what was the cause?

Acute mesenteric artery thrombosis arising from chronic atherosclerotic disease can be treated with stenting of the stenotic lesion.¹⁰ Patients with this condition would also benefit from aggressive management of atherosclerotic disease with statins along with antiplatelet agents.¹⁰

Mesenteric vein thrombosis requires prompt institution of anticoagulation. However, in advanced cases leading to bowel infarction, exploratory laparotomy with resection of the necrotic bowel may be required. Anticoagulation should be continued for at least 6 months, and further therapy should be determined by the underlying precipitating condition.¹⁰

Critically ill patients who develop mesenteric ischemia secondary to persistent hypotension usually respond to adequate volume resuscitation, cessation of vasopressors, and overall improvement in their hemodynamic status. These patients must be closely monitored for development of gangrene of the bowel because they may be intubated and not able to complain. Any sudden deterioration in their condition should prompt physicians to consider bowel necrosis developing in these patients. Elevation of lactate levels out of proportion to the degree of hypotension may be corroborative evidence.⁴

Our patient had risk factors for acute mesenteric ischemia that included atrial fibrillation and recent non-ST-elevation myocardial infarction. She could have had arterial emboli due to atrial fibrillation, in situ superior mesenteric arterial thrombosis, or splanchnic arterial vasoconstriction due to the myocardial infarction associated with transient hypotension.

Arguing against this diagnosis, although she had a grossly distended abdomen, abdominal bruising usually is not seen. Also, a palpable mass in the right lower quadrant is uncommon except when acute mesenteric ischemia occurs due to segmental intestinal strangulation, as with strangulated hernia or volvulus. She also had therapeutic international normalized ratio (INR) levels constantly while on anticoagulation. Nevertheless, acute mesenteric ischemia should be strongly considered in the initial differential diagnosis of this patient’s acute decompensation.

Perforation of the gastrointestinal tract

Diverticulitis is the acute inflammation of one or more diverticula, which are small pouches created by herniation of the mucosa into the wall of the colon. The condition is caused by microscopic or macroscopic perforation of the diverticula. Microscopic perforation is usually self-limited (uncomplicated diverticulitis) and responds to conservative treatment, whereas macroscopic perforation can be associated with fecal or purulent peritonitis, abscess, enteric fistula, bowel obstruction, and stricture (complicated diverticulitis), in which case surgery may be necessary.

Signs and symptoms of acute mesenteric ischemia can be vague

Patients with peritonitis due to free perforation present with generalized tenderness with rebound tenderness and guarding on abdominal examination. The abdomen may be distended and tympanic to percussion, with diminished or absent bowel sounds. Patients may have hemodynamic compromise.

Plain upright abdominal radiographs may show free air under the diaphragm. Computed tomography may show oral contrast outside the lumen and detect even small amounts of free intraperitoneal air (more clearly seen on a lung window setting).

Our patient initially presented with acute diverticulitis. She later developed diffuse abdominal tenderness with hypoactive bowel sounds. Bowel perforation is certainly a possibility at this stage, though it is usually not associated with abdominal bruising. She would need additional imaging to rule out this complication.

Other differential diagnoses to be considered in this patient with right lower-quadrant pain include acute appendicitis, incarcerated inguinal hernia, volvulus (particularly cecal volvulus), small-bowel obstruction, pyelonephritis, and gynecologic causes such as adnexal torsion, ruptured ovarian cyst, and tubo-ovarian abscess. Computed tomography helps to differentiate most of these causes.

Rectus sheath hematoma

Rectus sheath hematoma is relatively uncommon and often not considered in the initial differential diagnosis of an acute abdomen. This gives it the rightful term “a great masquerader.” It usually results from bleeding into the rectus sheath from damage to the superior (more common) or inferior epigastric arteries and occasionally from a direct tear of the rectus abdominis muscle. Predisposing factors include anticoagulant therapy (most common), advanced age, hypertension, previous abdominal surgery, trauma, paroxysmal coughing, medication injections, pregnancy, blood dyscrasias, severe vomiting, violent physical activity, and leukemia.¹¹

Clinical manifestations include acute abdominal pain, often associated with fever, nausea, and vomiting. Physical examination may reveal signs of hypovolemic shock, a palpable nonpulsatile abdominal mass, and signs of local peritoneal irritation. The Carnett sign¹¹ (tenderness within the abdominal wall that persists and does not improve with raising the head) and the Fothergill sign¹¹ (a tender abdominal mass that does not cross the midline and remains palpable with tensing of the rectus sheath) may be elicited.

Computed tomography is more sensitive than abdominal ultrasonography in differentiating rectus sheath hematoma from an intra-abdominal pathology.¹¹ In addition, computed tomography also helps to determine if the bleeding is active or not, which has therapeutic implications.

In our patient, rectus sheath hematoma is a possibility because of her ongoing anticoagulation, findings of localized abdominal bruising, and palpable right lower-quadrant mass, and it is high on the list of differential diagnoses. Rectus sheath hematoma should be considered in the differential diagnosis of lower abdominal pain particularly in elderly women who are on anticoagulation and in whom the onset of pain coincides with a paroxysm of cough.¹² Women are twice as likely as men to develop rectus sheath hematoma, owing to their different muscle mass.¹³ In addition, anterior abdominal wall muscles are stretched during pregnancy.¹³

Abdominal compartment syndrome

Abdominal compartment syndrome has been classically associated with surgical patients. However, it is being increasingly recognized in critically ill medical patients, in whom detecting and treating it early may result in significant reduction in rates of morbidity and death.¹⁴

Abdominal compartment syndrome is of three types: primary, secondary, and recurrent. Primary abdominal compartment syndrome refers to the classic surgical patients with evidence of direct injury to the abdominal or pelvic organs through major trauma or extensive abdominal surgeries. Secondary abdominal compartment syndrome refers to its development in critically ill intensive care patients in whom the pathology does not directly involve the abdominal or pelvic organs.

Various medical conditions can culminate in abdominal compartment syndrome and result in multiorgan failure. Recurrent abdominal compartment syndrome refers to its development after management of either primary or secondary intra-abdominal hypertension or abdominal compartment syndrome.¹⁵ Clinicians thus must be aware of secondary and recurrent abdominal compartment syndrome occurring in critically ill patients.

The normal intra-abdominal pressure is around 5 to 7 mm Hg, even in most critically ill patients. Persistent elevation, ie, higher than 12 mm Hg, is referred to as intra-abdominal hypertension.^16–18 Intra-abdominal hypertension is subdivided into four grades:

• Grade I: 12–15 mm Hg
• Grade II: 16–20 mm Hg
• Grade III: 21–25 mm Hg
• Grade IV: > 25 mm Hg.

The World Society of the Abdominal Compartment Syndrome (WSACS) defines abdominal compartment syndrome as pressure higher than 20 mm Hg along with organ damage.¹⁸ It may or may not be associated with an abdominal perfusion pressure less than 60 mm Hg.¹⁸

Risk factors associated with abdominal compartment syndrome include conditions causing decreased gut motility (gastroparesis, ileus, and colonic pseudo-obstruction), intra-abdominal or retroperitoneal masses or abscesses, ascites, hemoperitoneum, acute pancreatitis, third-spacing due to massive fluid resuscitation with transfusions, peritoneal dialysis, and shock.^18,19

Microscopic perforation is usually self-limited, whereas macroscopic perforation may need surgery

Physical examination has a sensitivity of only 40% to 60% in detecting intra-abdominal hypertension.²⁰ The gold-standard method of measuring the intra-abdominal pressure is the modified Kron technique,¹⁸ using a Foley catheter in the bladder connected to a pressure transducer. With the patient in the supine position, the transducer is zeroed at the mid-axillary line at the level of the iliac crest, and 25 mL of normal saline is instilled into the bladder and maintained for 30 to 60 seconds to let the detrusor muscle relax.¹⁵ Pressure tracings are then recorded at the end of expiration. Factors that are known to affect the transbladder pressure include patient position, respiratory movement, and body mass index, and should be taken into account when reading the pressure recordings.^15,21 Other techniques that can be used include intragastric, intra-inferior vena cava, and intrarectal approaches.¹⁵

The WSACS recommends that any patient admitted to a critical care unit or in whom new organ failure develops should be screened for risk factors for intra-abdominal hypertension and abdominal compartment syndrome. If a patient has at least two of the risk factors suggested by WSACS, a baseline intra-abdominal pressure measurement should be obtained. Patients at risk for intra-abdominal hypertension should have the intra-abdominal pressure measured every 4 to 6 hours. However, in the face of hemodynamic instability and worsening multiorgan failure, the pressure may need to be measured hourly.¹⁸

Clinicians managing patients in the intensive care unit should think of intra-abdominal pressure alongside blood pressure, urine output, and mental status when evaluating hemodynamic status. Clinical manifestations of abdominal compartment syndrome reflect the underlying organ dysfunction and include hypotension, refractory shock, decreased urine output, intracranial hypertension, progressive hypoxemia and hypercarbia, elevated pulmonary peak pressures, and worsening of metabolic acidosis.²²

Treatment. The standard treatment for primary abdominal compartment syndrome is surgical decompression. According to WSACS guidelines, insertion of a percutaneous drainage catheter should be advocated in patients with gross ascites and in whom decompressive surgery is not feasible. A damage-control resuscitation strategy used for patients undergoing damage-control laparotomy has been found to increase the 30-day survival rate.²³ A damage-control resuscitation strategy consists of increasing the use of plasma and platelet transfusions over packed red cell transfusions, limiting the use of crystalloid solutions in early fluid resuscitation, and allowing for permissive hypotension.

Rectus sheath hematoma is relatively uncommon and is not often considered in the initial differential diagnosis of an acute abdomen

Secondary abdominal compartment syndrome is treated conservatively in most cases, since patients with this condition are very poor surgical candidates owing to their comorbidities.¹⁸ However, in patients with progressive organ dysfunction in whom medical management has failed, surgical decompression should be considered.¹⁸ Medical management of secondary abdominal compartment syndrome depends on the underlying etiology. Strategies include nasogastric or colonic decompression, use of prokinetic agents, paracentesis in cases with gross ascites, and maintaining a cumulative negative fluid balance. The WSACS does not recommend routine use of diuretics, albumin infusion, or renal replacement strategies. Pain should be adequately controlled to improve abdominal wall compliance.^18,24 Neuromuscular blockade agents may be used to aid this process. Neostigmine may be used to treat colonic pseudo-obstruction when other conservative methods fail. Use of enteral nutrition should be minimized.¹⁸

Our patient might have abdominal compartment syndrome, but a definitive diagnosis cannot be made at this point without measuring the intra-abdominal pressure.

WHICH IMAGING TEST WOULD BE BEST?

2. Which imaging test would be best for establishing the diagnosis in this patient?

• Plain abdominal radiography
• Abdominal ultrasonography
• Computed tomography of the abdomen and pelvis with contrast
• Magnetic resonance imaging of the abdomen and pelvis

Plain abdominal radiography

Plain abdominal radiography can help to determine if there is free gas under the diaphragm (due to bowel perforation), obstructed bowel, sentinel loop, volvulus, or fecoliths causing the abdominal pain. It cannot diagnose rectus sheath hematoma or acute mesenteric ischemia.

Abdominal ultrasonography

Abdominal ultrasonography can be used as the first diagnostic test, as it is widely available, safe, effective, and tolerable. It does not expose the patient to radiation or intravenous contrast agents. It helps to diagnose rectus sheath hematoma and helps to follow its maturation and resolution once a diagnosis is made. It can provide a rapid assessment of the size, location, extent, and physical characteristics of the mass.

Ultrasonography is widely available, safe, effective, and tolerable

Rectus sheath hematoma appears spindle-shaped on sagittal sections and ovoid on coronal sections. It often appears sonolucent in the early stages and sonodense in the late stage, but the appearance may be heterogeneous depending on the combined presence of clot and fresh blood. These findings are sufficient to make the diagnosis.

Abdominal ultrasonography has 85% to 96% sensitivity in diagnosing rectus sheath hematoma.²⁵ It can help diagnose other causes of the abdominal pain, such as renal stones and cholecystitis. It is the preferred imaging test in pediatric patients, pregnant patients, and those with renal insufficiency.

Abdominal computed tomography

Abdominal computed tomography has a sensitivity and specificity of 100% for diagnosing acute rectus sheath hematoma with a duration of less than 5 days.²⁵ It not only helps to determine the precise location and extent, but also helps to determine if there is active extravasation. Even in patients with renal insufficiency, noncontrast computed tomography will help to confirm the diagnosis, although it may not show extravasation or it may miss certain abdominal pathologies because of the lack of contrast.

Acute rectus sheath hematoma appears as a hyperdense mass posterior to the rectus abdominis muscle with ipsilateral anterolateral muscular enlargement. Chronic rectus sheath hematoma appears isodense or hypodense relative to the surrounding muscle. Above the arcuate line, rectus sheath hematoma has a spindle shape; below the arcuate line, it is typically spherical.

In 1996, Berná et al²⁶ classified rectus sheath hematoma into three grades based on findings of computed tomography:

• Grade I is intramuscular and unilateral
• Grade II may involve bilateral rectus muscles without extension into the prevesicular space
• Grade III extends into the peritoneum and prevesicular space

Magnetic resonance imaging

Magnetic resonance imaging is useful to differentiate chronic rectus sheath hematoma (greater than 5-day duration) from an anterior abdominal wall mass. Chronic rectus sheath hematoma will have high signal intensity on both T1- and T2-weighted images up to 10 months after the onset of the hematoma.²⁷

Back to our patient

Since our patient’s symptoms are acute and of less than 5 days’ duration, computed tomography of the abdomen and pelvis would be the best diagnostic test, with therapeutic implications if there is ongoing extravasation.

Computed tomography of the abdomen with contrast showed a new hematoma, measuring 25 by 14 by 13.5 cm, in the right rectus sheath (Figure 2), with no other findings. The hematoma was grade I, since it was intramuscular and unilateral without extension elsewhere.

Laboratory workup showed that the patient’s hematocrit was falling, from 34% to 24%, and her INR was elevated at 2.5. She was resuscitated with fluids, blood transfusion, and fresh-frozen plasma. Anticoagulation was withheld. In spite of resuscitation, her hematocrit kept falling, though she remained hemodynamically stable.

THE WAY FORWARD

3. At this point, what would be the best approach to management in this patient?

• Serial clinical examinations and frequent monitoring of the complete blood cell count
• Urgent surgical consult for exploratory laparotomy with evaluation of the hematoma and ligation of the bleeding vessel
• Repeat computed tomographic angiography to identify a possible bleeding vessel; consideration of radiographically guided arterial embolization
• Measuring the intra-abdominal pressure using the intrabladder pressure for abdominal compartment syndrome and consideration of surgical drainage

The key clinical concern in a patient with a rectus sheath hematoma who is hemodynamically stable is whether the hematoma is expanding. This patient responded to initial resuscitation, but her falling hematocrit was evidence of ongoing bleeding leading to an expanding rectus sheath hematoma. Thus, serial clinical examinations and frequent monitoring of the complete blood cell count would not be enough, as it could miss fatal ongoing bleeding.

Radiographically guided embolization with Gelfoam, thrombin, or coils should be attempted first, as this is less invasive than exploratory laparotomy.²⁸ It can achieve hemostasis, decrease the size of the hematoma, limit the need for blood products, and prevent rupture into the abdomen. If this is unsuccessful, the next step is ligation of the bleeding vessel.²⁹

Surgical treatment includes evacuation of the hematoma, repair of the rectus sheath, ligation of bleeding vessels, and abdominal wall closure. Surgical evacuation or guided drainage of a rectus sheath hematoma on its own is not normally indicated and may indeed cause persistent bleeding by diminishing a potential tamponade effect. However, it may become necessary if the hematoma is very large or infected, if it causes marked respiratory impairment, or if abdominal compartment syndrome is suspected.

Abdominal compartment syndrome is very rare but is associated with a 50% mortality rate.³⁰ It should be suspected in patients with oliguria, low cardiac output, changes in minute ventilation, and altered splanchnic blood flow. The diagnosis is confirmed with indwelling catheter manometry of the bladder to measure intra-abdominal pressure. Intra-abominal pressure above 25 mm Hg should be treated with decompressive laparotomy.³⁰ However, the clinical suspicion of abdominal compartment syndrome was low in this patient.

The best choice at this point would be urgent computed tomographic angiography to identify a bleeding vessel, along with consideration of radiographically guided arterial embolization.

TREATMENT IS USUALLY CONSERVATIVE

Treatment of rectus sheath hematoma is conservative in most hemodynamically stable patients, with embolization or surgical intervention reserved for unstable patients or those in whom the hematoma is expanding.

Knowledge of the grading system of Berná et al²⁶ helps to assess the patient’s risk and to anticipate potential complications. Grade I hematomas are mild and do not necessitate admission. Patients with grade II hematoma can be admitted to the floor for 24 to 48 hours for observation. Grade III usually occurs in patients receiving anticoagulant therapy and frequently requires blood products. These patients have a prolonged hospital stay and more complications, including hypovolemic shock, myonecrosis, acute coronary syndrome, arrhythmias, acute renal failure, small-bowel infarction, and abdominal compartment syndrome—all of which increases the risk of morbidity and death. Thus, patients who are on anticoagulation who develop grade III rectus sheath hematoma should be admitted to the hospital, preferably to the intensive care unit, to ensure that the hematoma is not expanding and to plan reinstitution of anticoagulation as appropriate.

In most cases, rectus sheath hematomas resolve within 1 to 3 months. Resolution of large hematomas may be hastened with the use of pulsed ultrasound.³¹ However, this treatment should be used only after the acute phase is over, when there is evidence of an organized thrombus and coagulation measures have returned to the target range. This helps to reduce the risk of bleeding and to prevent symptoms from worsening.³¹

OUR PATIENT’S COURSE

Our patient underwent urgent computed tomographic angiography, which showed a modest increase in the size of the rectus sheath hematoma. However, no definitive blush of contrast was seen to suggest active arterial bleeding. Her hematocrit stabilized, and she remained hemodynamically stable without requiring additional intervention. Most likely her bleeding was self-contained. She had normal intra-abdominal pressure on serial monitoring. She was later transferred to acute inpatient rehabilitation in view of deconditioning and is currently doing well. The hematoma persisted, decreasing only slightly in size over the next 3 weeks.

A 57-year-old woman presented to the emergency department with left lower quadrant pain, which had started 1 week earlier and was constant, dull, aching, and nonradiating. There were no aggravating or alleviating factors. The pain was associated with low-grade fever and nausea. She reported no vomiting, no change in bowel habits, and no hematemesis, hematochezia, or melena. She did not have urinary urgency, frequency, or dysuria. She had no cardiac, respiratory, or neurologic symptoms.

Her medical history included hypothyroidism, type 2 diabetes mellitus, diverticulosis, and chronic obstructive pulmonary disease. Her medications included metformin, insulin, levothyroxine, and inhaled tiotropium. She had no allergies. She had never undergone surgery, including cesarean delivery. She was postmenopausal. She had two children, both of whom had been born vaginally at full term. She denied using alcohol, tobacco, and illicit drugs. Her family history was noncontributory.

On examination, she was not in acute distress. Her temperature was 36.7°C (98.1°F), blood pressure 130/90 mm Hg, heart rate 86 beats per minute and regular, respiratory rate 16 breaths per minute, and oxygen saturation 98% on ambient air. Examination of her head and neck was unremarkable. Cardiopulmonary examination was normal. Abdominal examination revealed normal bowel sounds, mild tenderness in the left lower quadrant with localized guarding, and rebound tenderness. Neurologic examination was unremarkable.

Initial laboratory data showed mild leukocytosis. Computed tomography with contrast of the abdomen and pelvis suggested acute diverticulitis.

ATRIAL FIBRILLATION, AND THEN A TURN FOR THE WORSE

The patient was admitted with an initial diagnosis of acute diverticulitis. She was started on antibiotics, hydration, and pain medications, and her abdominal pain gradually improved.

On the third hospital day, she suddenly experienced shortness of breath and palpitations. At the time of admission her electrocardiogram had been normal, but it now showed atrial fibrillation with a rapid ventricular response. She also developed elevated troponin levels, which were thought to represent type 2 non-ST-elevation myocardial infarction.

She was started on aspirin, clopidogrel, and anticoagulation with heparin bridged with warfarin for the new-onset atrial fibrillation. Her heart rate was controlled with metoprolol, and her shortness of breath improved. An echocardiogram was normal.

On the seventh hospital day, she developed severe right-sided lower abdominal pain and bruising. Her blood pressure was 90/60 mm Hg, heart rate 110 beats per minute and irregularly irregular, respiratory rate 22 breaths per minute, and oxygen saturation 97% on room air. Her abdomen was diffusely tender with a palpable mass in the right lower quadrant and hypoactive bowel sounds. Ecchymosis was noted (Figure 1).

DIFFERENTIAL DIAGNOSIS

1. What is the likely cause of her decompensation?

• Acute mesenteric ischemia
• Perforation of the gastrointestinal tract
• Rectus sheath hematoma
• Abdominal compartment syndrome due to acute pancreatitis

Acute mesenteric ischemia

Signs and symptoms of acute mesenteric ischemia can be vague. Moreover, when it leads to bowel necrosis the mortality rate is high, ranging from 30% to 65%.¹ Hence, one should suspect it and try to diagnose it early.

Most patients with this condition have comorbidities; risk factors include atherosclerotic disease, cardiac conditions (congestive heart failure, recent myocardial infarction, and atrial fibrillation), systemic illness, and inherited or acquired hypercoagulable states.²

The four major causes are:

• Acute thromboembolic occlusion of the superior mesenteric artery (the most common site of occlusion because of the acute angle of origin from the aorta)
• Acute thrombosis of the mesenteric vein
• Acute thrombosis of the mesenteric artery
• Nonocclusive disease affecting the mesenteric vessels²

Nonocclusive disease is seen in conditions in which the mesenteric vessels are already compromised due to background stenosis owing to atherosclerosis. Also, conditions such as septic and cardiogenic shock can compromise these arteries, leading to ischemia, which, if it persists, can lead to bowel infarction. Ischemic colitis falls under this category. It commonly involves the descending and sigmoid colon.³

The initial symptom of ischemia may be abdominal pain that is brought on by eating large meals (“postprandial intestinal angina.”² When the ischemia worsens to infarction, patients may have a diffusely tender abdomen and constant pain that does not vary with palpation. Surprisingly, patients do not exhibit peritoneal signs early on. This gives rise to the description of “pain out of proportion to the physical findings” traditionally associated with acute mesenteric ischemia.²

Diagnosis. Supportive laboratory data include marked leukocytosis, elevated hematocrit due to hemoconcentration, metabolic acidosis, and elevated lactate.⁴ Newer markers such as serum alpha-glutathione S-transferase (alpha-GST) and intestinal fatty acid-binding protein (I-FABP) may be used to support the diagnosis.

Elevated alpha-GST has 72% sensitivity and 77% specificity in the diagnosis of acute mesenteric ischemia.⁵ The caveat is that it cannot reliably differentiate ischemia from infarction. Its sensitivity can be improved to 97% to 100% by using the white blood cell count and lactate levels in combination.⁵

An I-FABP level higher than 100 ng/mL has 100% sensitivity for diagnosing mesenteric infarction but only 25% sensitivity for bowel strangulation.⁶

Early use of abdominal computed tomography with contrast can aid in recognizing this diagnosis.⁷ Thus, it should be ordered in suspected cases, even in patients who have elevated creatinine levels (which would normally preclude the use of contrast), since early diagnosis followed by endovascular therapy is associated with survival benefit, and the risk of contrast-induced nephropathy appears to be small.⁸ Computed tomography helps to determine the state of mesenteric vessels and bowel perfusion before ischemia progresses to infarction. It also helps to rule out other common diagnoses. Findings that suggest acute mesenteric ischemia include segmental bowel wall thickening, intestinal pneumatosis with gas in the portal vein, bowel dilation, mesenteric stranding, portomesenteric thrombosis, and solid-organ infarction.⁹

Treatment. If superior mesenteric artery occlusion is diagnosed on computed tomography, the next step is to determine if there is peritonitis.¹⁰ In patients who have evidence of peritonitis, exploratory laparotomy is performed. For emboli in such patients, open embolectomy followed by on-table angiography is carried out in combination with damage-control surgery. For patients with peritonitis and acute thrombosis, stenting along with damage-control surgery is preferred.¹⁰

On the other hand, if there is no peritonitis, the thrombosis may be amenable to endovascular intervention. For patients with acute embolic occlusion with no contraindications to thrombolysis, aspiration embolectomy in combination with local catheter-directed thrombolysis with recombinant tissue plasminogen activator can be performed. This can be combined with endovascular mechanical embolectomy for more complete management.¹⁰ Patients with contraindications to thrombolysis can be treated either with aspiration and mechanical embolectomy or with open embolectomy with angiography.¹⁰

During laparotomy, the surgeon carefully inspects the bowel for signs of necrosis. Signs that bowel is still viable include pink color, bleeding from cut surfaces, good peristalsis, and visible pulsations in the arterial arcade of the mesentery.

On day 7 she developed acute decompensation—what was the cause?

Acute mesenteric artery thrombosis arising from chronic atherosclerotic disease can be treated with stenting of the stenotic lesion.¹⁰ Patients with this condition would also benefit from aggressive management of atherosclerotic disease with statins along with antiplatelet agents.¹⁰

Mesenteric vein thrombosis requires prompt institution of anticoagulation. However, in advanced cases leading to bowel infarction, exploratory laparotomy with resection of the necrotic bowel may be required. Anticoagulation should be continued for at least 6 months, and further therapy should be determined by the underlying precipitating condition.¹⁰

Critically ill patients who develop mesenteric ischemia secondary to persistent hypotension usually respond to adequate volume resuscitation, cessation of vasopressors, and overall improvement in their hemodynamic status. These patients must be closely monitored for development of gangrene of the bowel because they may be intubated and not able to complain. Any sudden deterioration in their condition should prompt physicians to consider bowel necrosis developing in these patients. Elevation of lactate levels out of proportion to the degree of hypotension may be corroborative evidence.⁴

Our patient had risk factors for acute mesenteric ischemia that included atrial fibrillation and recent non-ST-elevation myocardial infarction. She could have had arterial emboli due to atrial fibrillation, in situ superior mesenteric arterial thrombosis, or splanchnic arterial vasoconstriction due to the myocardial infarction associated with transient hypotension.

Arguing against this diagnosis, although she had a grossly distended abdomen, abdominal bruising usually is not seen. Also, a palpable mass in the right lower quadrant is uncommon except when acute mesenteric ischemia occurs due to segmental intestinal strangulation, as with strangulated hernia or volvulus. She also had therapeutic international normalized ratio (INR) levels constantly while on anticoagulation. Nevertheless, acute mesenteric ischemia should be strongly considered in the initial differential diagnosis of this patient’s acute decompensation.

Perforation of the gastrointestinal tract

Diverticulitis is the acute inflammation of one or more diverticula, which are small pouches created by herniation of the mucosa into the wall of the colon. The condition is caused by microscopic or macroscopic perforation of the diverticula. Microscopic perforation is usually self-limited (uncomplicated diverticulitis) and responds to conservative treatment, whereas macroscopic perforation can be associated with fecal or purulent peritonitis, abscess, enteric fistula, bowel obstruction, and stricture (complicated diverticulitis), in which case surgery may be necessary.

Signs and symptoms of acute mesenteric ischemia can be vague

Patients with peritonitis due to free perforation present with generalized tenderness with rebound tenderness and guarding on abdominal examination. The abdomen may be distended and tympanic to percussion, with diminished or absent bowel sounds. Patients may have hemodynamic compromise.

Plain upright abdominal radiographs may show free air under the diaphragm. Computed tomography may show oral contrast outside the lumen and detect even small amounts of free intraperitoneal air (more clearly seen on a lung window setting).

Our patient initially presented with acute diverticulitis. She later developed diffuse abdominal tenderness with hypoactive bowel sounds. Bowel perforation is certainly a possibility at this stage, though it is usually not associated with abdominal bruising. She would need additional imaging to rule out this complication.

Other differential diagnoses to be considered in this patient with right lower-quadrant pain include acute appendicitis, incarcerated inguinal hernia, volvulus (particularly cecal volvulus), small-bowel obstruction, pyelonephritis, and gynecologic causes such as adnexal torsion, ruptured ovarian cyst, and tubo-ovarian abscess. Computed tomography helps to differentiate most of these causes.

Rectus sheath hematoma

Rectus sheath hematoma is relatively uncommon and often not considered in the initial differential diagnosis of an acute abdomen. This gives it the rightful term “a great masquerader.” It usually results from bleeding into the rectus sheath from damage to the superior (more common) or inferior epigastric arteries and occasionally from a direct tear of the rectus abdominis muscle. Predisposing factors include anticoagulant therapy (most common), advanced age, hypertension, previous abdominal surgery, trauma, paroxysmal coughing, medication injections, pregnancy, blood dyscrasias, severe vomiting, violent physical activity, and leukemia.¹¹

Clinical manifestations include acute abdominal pain, often associated with fever, nausea, and vomiting. Physical examination may reveal signs of hypovolemic shock, a palpable nonpulsatile abdominal mass, and signs of local peritoneal irritation. The Carnett sign¹¹ (tenderness within the abdominal wall that persists and does not improve with raising the head) and the Fothergill sign¹¹ (a tender abdominal mass that does not cross the midline and remains palpable with tensing of the rectus sheath) may be elicited.

Computed tomography is more sensitive than abdominal ultrasonography in differentiating rectus sheath hematoma from an intra-abdominal pathology.¹¹ In addition, computed tomography also helps to determine if the bleeding is active or not, which has therapeutic implications.

In our patient, rectus sheath hematoma is a possibility because of her ongoing anticoagulation, findings of localized abdominal bruising, and palpable right lower-quadrant mass, and it is high on the list of differential diagnoses. Rectus sheath hematoma should be considered in the differential diagnosis of lower abdominal pain particularly in elderly women who are on anticoagulation and in whom the onset of pain coincides with a paroxysm of cough.¹² Women are twice as likely as men to develop rectus sheath hematoma, owing to their different muscle mass.¹³ In addition, anterior abdominal wall muscles are stretched during pregnancy.¹³

Abdominal compartment syndrome

Abdominal compartment syndrome has been classically associated with surgical patients. However, it is being increasingly recognized in critically ill medical patients, in whom detecting and treating it early may result in significant reduction in rates of morbidity and death.¹⁴

Abdominal compartment syndrome is of three types: primary, secondary, and recurrent. Primary abdominal compartment syndrome refers to the classic surgical patients with evidence of direct injury to the abdominal or pelvic organs through major trauma or extensive abdominal surgeries. Secondary abdominal compartment syndrome refers to its development in critically ill intensive care patients in whom the pathology does not directly involve the abdominal or pelvic organs.

Various medical conditions can culminate in abdominal compartment syndrome and result in multiorgan failure. Recurrent abdominal compartment syndrome refers to its development after management of either primary or secondary intra-abdominal hypertension or abdominal compartment syndrome.¹⁵ Clinicians thus must be aware of secondary and recurrent abdominal compartment syndrome occurring in critically ill patients.

The normal intra-abdominal pressure is around 5 to 7 mm Hg, even in most critically ill patients. Persistent elevation, ie, higher than 12 mm Hg, is referred to as intra-abdominal hypertension.^16–18 Intra-abdominal hypertension is subdivided into four grades:

• Grade I: 12–15 mm Hg
• Grade II: 16–20 mm Hg
• Grade III: 21–25 mm Hg
• Grade IV: > 25 mm Hg.

The World Society of the Abdominal Compartment Syndrome (WSACS) defines abdominal compartment syndrome as pressure higher than 20 mm Hg along with organ damage.¹⁸ It may or may not be associated with an abdominal perfusion pressure less than 60 mm Hg.¹⁸

Risk factors associated with abdominal compartment syndrome include conditions causing decreased gut motility (gastroparesis, ileus, and colonic pseudo-obstruction), intra-abdominal or retroperitoneal masses or abscesses, ascites, hemoperitoneum, acute pancreatitis, third-spacing due to massive fluid resuscitation with transfusions, peritoneal dialysis, and shock.^18,19

Microscopic perforation is usually self-limited, whereas macroscopic perforation may need surgery

Physical examination has a sensitivity of only 40% to 60% in detecting intra-abdominal hypertension.²⁰ The gold-standard method of measuring the intra-abdominal pressure is the modified Kron technique,¹⁸ using a Foley catheter in the bladder connected to a pressure transducer. With the patient in the supine position, the transducer is zeroed at the mid-axillary line at the level of the iliac crest, and 25 mL of normal saline is instilled into the bladder and maintained for 30 to 60 seconds to let the detrusor muscle relax.¹⁵ Pressure tracings are then recorded at the end of expiration. Factors that are known to affect the transbladder pressure include patient position, respiratory movement, and body mass index, and should be taken into account when reading the pressure recordings.^15,21 Other techniques that can be used include intragastric, intra-inferior vena cava, and intrarectal approaches.¹⁵

The WSACS recommends that any patient admitted to a critical care unit or in whom new organ failure develops should be screened for risk factors for intra-abdominal hypertension and abdominal compartment syndrome. If a patient has at least two of the risk factors suggested by WSACS, a baseline intra-abdominal pressure measurement should be obtained. Patients at risk for intra-abdominal hypertension should have the intra-abdominal pressure measured every 4 to 6 hours. However, in the face of hemodynamic instability and worsening multiorgan failure, the pressure may need to be measured hourly.¹⁸

Clinicians managing patients in the intensive care unit should think of intra-abdominal pressure alongside blood pressure, urine output, and mental status when evaluating hemodynamic status. Clinical manifestations of abdominal compartment syndrome reflect the underlying organ dysfunction and include hypotension, refractory shock, decreased urine output, intracranial hypertension, progressive hypoxemia and hypercarbia, elevated pulmonary peak pressures, and worsening of metabolic acidosis.²²

Treatment. The standard treatment for primary abdominal compartment syndrome is surgical decompression. According to WSACS guidelines, insertion of a percutaneous drainage catheter should be advocated in patients with gross ascites and in whom decompressive surgery is not feasible. A damage-control resuscitation strategy used for patients undergoing damage-control laparotomy has been found to increase the 30-day survival rate.²³ A damage-control resuscitation strategy consists of increasing the use of plasma and platelet transfusions over packed red cell transfusions, limiting the use of crystalloid solutions in early fluid resuscitation, and allowing for permissive hypotension.

Rectus sheath hematoma is relatively uncommon and is not often considered in the initial differential diagnosis of an acute abdomen

Secondary abdominal compartment syndrome is treated conservatively in most cases, since patients with this condition are very poor surgical candidates owing to their comorbidities.¹⁸ However, in patients with progressive organ dysfunction in whom medical management has failed, surgical decompression should be considered.¹⁸ Medical management of secondary abdominal compartment syndrome depends on the underlying etiology. Strategies include nasogastric or colonic decompression, use of prokinetic agents, paracentesis in cases with gross ascites, and maintaining a cumulative negative fluid balance. The WSACS does not recommend routine use of diuretics, albumin infusion, or renal replacement strategies. Pain should be adequately controlled to improve abdominal wall compliance.^18,24 Neuromuscular blockade agents may be used to aid this process. Neostigmine may be used to treat colonic pseudo-obstruction when other conservative methods fail. Use of enteral nutrition should be minimized.¹⁸

Our patient might have abdominal compartment syndrome, but a definitive diagnosis cannot be made at this point without measuring the intra-abdominal pressure.

WHICH IMAGING TEST WOULD BE BEST?

2. Which imaging test would be best for establishing the diagnosis in this patient?

• Plain abdominal radiography
• Abdominal ultrasonography
• Computed tomography of the abdomen and pelvis with contrast
• Magnetic resonance imaging of the abdomen and pelvis

Plain abdominal radiography

Plain abdominal radiography can help to determine if there is free gas under the diaphragm (due to bowel perforation), obstructed bowel, sentinel loop, volvulus, or fecoliths causing the abdominal pain. It cannot diagnose rectus sheath hematoma or acute mesenteric ischemia.

Abdominal ultrasonography

Abdominal ultrasonography can be used as the first diagnostic test, as it is widely available, safe, effective, and tolerable. It does not expose the patient to radiation or intravenous contrast agents. It helps to diagnose rectus sheath hematoma and helps to follow its maturation and resolution once a diagnosis is made. It can provide a rapid assessment of the size, location, extent, and physical characteristics of the mass.

Ultrasonography is widely available, safe, effective, and tolerable

Rectus sheath hematoma appears spindle-shaped on sagittal sections and ovoid on coronal sections. It often appears sonolucent in the early stages and sonodense in the late stage, but the appearance may be heterogeneous depending on the combined presence of clot and fresh blood. These findings are sufficient to make the diagnosis.

Abdominal ultrasonography has 85% to 96% sensitivity in diagnosing rectus sheath hematoma.²⁵ It can help diagnose other causes of the abdominal pain, such as renal stones and cholecystitis. It is the preferred imaging test in pediatric patients, pregnant patients, and those with renal insufficiency.

Abdominal computed tomography

Abdominal computed tomography has a sensitivity and specificity of 100% for diagnosing acute rectus sheath hematoma with a duration of less than 5 days.²⁵ It not only helps to determine the precise location and extent, but also helps to determine if there is active extravasation. Even in patients with renal insufficiency, noncontrast computed tomography will help to confirm the diagnosis, although it may not show extravasation or it may miss certain abdominal pathologies because of the lack of contrast.

Acute rectus sheath hematoma appears as a hyperdense mass posterior to the rectus abdominis muscle with ipsilateral anterolateral muscular enlargement. Chronic rectus sheath hematoma appears isodense or hypodense relative to the surrounding muscle. Above the arcuate line, rectus sheath hematoma has a spindle shape; below the arcuate line, it is typically spherical.

In 1996, Berná et al²⁶ classified rectus sheath hematoma into three grades based on findings of computed tomography:

• Grade I is intramuscular and unilateral
• Grade II may involve bilateral rectus muscles without extension into the prevesicular space
• Grade III extends into the peritoneum and prevesicular space

Magnetic resonance imaging

Magnetic resonance imaging is useful to differentiate chronic rectus sheath hematoma (greater than 5-day duration) from an anterior abdominal wall mass. Chronic rectus sheath hematoma will have high signal intensity on both T1- and T2-weighted images up to 10 months after the onset of the hematoma.²⁷

Back to our patient

Since our patient’s symptoms are acute and of less than 5 days’ duration, computed tomography of the abdomen and pelvis would be the best diagnostic test, with therapeutic implications if there is ongoing extravasation.

Computed tomography of the abdomen with contrast showed a new hematoma, measuring 25 by 14 by 13.5 cm, in the right rectus sheath (Figure 2), with no other findings. The hematoma was grade I, since it was intramuscular and unilateral without extension elsewhere.

Laboratory workup showed that the patient’s hematocrit was falling, from 34% to 24%, and her INR was elevated at 2.5. She was resuscitated with fluids, blood transfusion, and fresh-frozen plasma. Anticoagulation was withheld. In spite of resuscitation, her hematocrit kept falling, though she remained hemodynamically stable.

THE WAY FORWARD

3. At this point, what would be the best approach to management in this patient?

• Serial clinical examinations and frequent monitoring of the complete blood cell count
• Urgent surgical consult for exploratory laparotomy with evaluation of the hematoma and ligation of the bleeding vessel
• Repeat computed tomographic angiography to identify a possible bleeding vessel; consideration of radiographically guided arterial embolization
• Measuring the intra-abdominal pressure using the intrabladder pressure for abdominal compartment syndrome and consideration of surgical drainage

The key clinical concern in a patient with a rectus sheath hematoma who is hemodynamically stable is whether the hematoma is expanding. This patient responded to initial resuscitation, but her falling hematocrit was evidence of ongoing bleeding leading to an expanding rectus sheath hematoma. Thus, serial clinical examinations and frequent monitoring of the complete blood cell count would not be enough, as it could miss fatal ongoing bleeding.

Radiographically guided embolization with Gelfoam, thrombin, or coils should be attempted first, as this is less invasive than exploratory laparotomy.²⁸ It can achieve hemostasis, decrease the size of the hematoma, limit the need for blood products, and prevent rupture into the abdomen. If this is unsuccessful, the next step is ligation of the bleeding vessel.²⁹

Surgical treatment includes evacuation of the hematoma, repair of the rectus sheath, ligation of bleeding vessels, and abdominal wall closure. Surgical evacuation or guided drainage of a rectus sheath hematoma on its own is not normally indicated and may indeed cause persistent bleeding by diminishing a potential tamponade effect. However, it may become necessary if the hematoma is very large or infected, if it causes marked respiratory impairment, or if abdominal compartment syndrome is suspected.

Abdominal compartment syndrome is very rare but is associated with a 50% mortality rate.³⁰ It should be suspected in patients with oliguria, low cardiac output, changes in minute ventilation, and altered splanchnic blood flow. The diagnosis is confirmed with indwelling catheter manometry of the bladder to measure intra-abdominal pressure. Intra-abominal pressure above 25 mm Hg should be treated with decompressive laparotomy.³⁰ However, the clinical suspicion of abdominal compartment syndrome was low in this patient.

The best choice at this point would be urgent computed tomographic angiography to identify a bleeding vessel, along with consideration of radiographically guided arterial embolization.

TREATMENT IS USUALLY CONSERVATIVE

Treatment of rectus sheath hematoma is conservative in most hemodynamically stable patients, with embolization or surgical intervention reserved for unstable patients or those in whom the hematoma is expanding.

Knowledge of the grading system of Berná et al²⁶ helps to assess the patient’s risk and to anticipate potential complications. Grade I hematomas are mild and do not necessitate admission. Patients with grade II hematoma can be admitted to the floor for 24 to 48 hours for observation. Grade III usually occurs in patients receiving anticoagulant therapy and frequently requires blood products. These patients have a prolonged hospital stay and more complications, including hypovolemic shock, myonecrosis, acute coronary syndrome, arrhythmias, acute renal failure, small-bowel infarction, and abdominal compartment syndrome—all of which increases the risk of morbidity and death. Thus, patients who are on anticoagulation who develop grade III rectus sheath hematoma should be admitted to the hospital, preferably to the intensive care unit, to ensure that the hematoma is not expanding and to plan reinstitution of anticoagulation as appropriate.

In most cases, rectus sheath hematomas resolve within 1 to 3 months. Resolution of large hematomas may be hastened with the use of pulsed ultrasound.³¹ However, this treatment should be used only after the acute phase is over, when there is evidence of an organized thrombus and coagulation measures have returned to the target range. This helps to reduce the risk of bleeding and to prevent symptoms from worsening.³¹

OUR PATIENT’S COURSE

Our patient underwent urgent computed tomographic angiography, which showed a modest increase in the size of the rectus sheath hematoma. However, no definitive blush of contrast was seen to suggest active arterial bleeding. Her hematocrit stabilized, and she remained hemodynamically stable without requiring additional intervention. Most likely her bleeding was self-contained. She had normal intra-abdominal pressure on serial monitoring. She was later transferred to acute inpatient rehabilitation in view of deconditioning and is currently doing well. The hematoma persisted, decreasing only slightly in size over the next 3 weeks.

Alcoholic hepatitis, a severe manifestation of alcoholic liver disease, is rising in incidence. Complete abstinence from alcohol remains the cornerstone of treatment, while other specific interventions aim to decrease short-term mortality rates.

Despite current treatments, about 25% of patients with severe alcoholic hepatitis eventually die of it. For those who survive hospitalization, measures need to be taken to prevent recidivism. Although liver transplantation seems to hold promise, early transplantation is still largely experimental in alcoholic hepatitis and will likely be available to only a small subset of patients, especially in view of ethical issues and the possible wider implications for transplant centers.

New treatments will largely depend on a better understanding of the disease’s pathophysiology, and future clinical trials should evaluate therapies that improve short-term as well as long-term outcomes.

ACUTE HEPATIC DECOMPENSATION IN A HEAVY DRINKER

Excessive alcohol consumption is very common worldwide, is a major risk factor for liver disease, and is a leading cause of preventable death. Alcoholic cirrhosis is the eighth most common cause of death in the United States and in 2010 was responsible for nearly half of cirrhosis-related deaths worldwide.¹

Alcoholic liver disease is a spectrum. Nearly all heavy drinkers (ie, those consuming 40 g or more of alcohol per day, Table 1) have fatty liver changes, 20% to 40% develop fibrosis, 10% to 20% progress to cirrhosis, and of those with cirrhosis, 1% to 2% are diagnosed with hepatocellular carcinoma every year.²

Within this spectrum, alcoholic hepatitis is a well-defined clinical syndrome characterized by acute hepatic decompensation that typically results from long-standing alcohol abuse. Binge drinkers may also be at risk for alcoholic hepatitis, but good data on the association between drinking patterns and the risk of alcoholic hepatitis are limited.

Alcoholic hepatitis varies in severity from mild to life-threatening.³ Although its exact incidence is unknown, its prevalence in alcoholics has been estimated at 20%.⁴ Nearly half of patients with alcoholic hepatitis have cirrhosis at the time of their acute presentation, and these patients generally have a poor prognosis, with a 28-day death rate as high as 50% in severe cases.^5,6 Moreover, although alcoholic hepatitis develops in only a subset of patients with alcoholic liver disease, hospitalizations for it are increasing in the United States.⁷

Women are at higher risk of developing alcoholic hepatitis, an observation attributed to the effect of estrogens on oxidative stress and inflammation, lower gastric alcohol dehydrogenase levels resulting in slower first-pass metabolism of alcohol, and higher body fat content causing a lower volume of distribution for alcohol than in men.⁸ The incidence of alcoholic hepatitis is also influenced by a number of demographic and genetic factors as well as nutritional status and coexistence of other liver diseases.⁹ Most patients diagnosed with alcoholic hepatitis are active drinkers, but it can develop even after significantly reducing or stopping alcohol consumption.

FATTY ACIDS, ENZYMES, CYTOKINES, INFLAMMATION

Alcohol consumption induces fatty acid synthesis and inhibits fatty acid oxidation, thereby promoting fat deposition in the liver.

The major enzymes involved in alcohol metabolism are cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase. CYP2E1 is inducible and is up-regulated when excess alcohol is ingested, while alcohol dehydrogen-
ase function is relatively stable. Oxidative degradation of alcohol by these enzymes generates reactive oxygen species and acetaldehyde, inducing liver injury.¹⁰ Interestingly, it has been proposed that variations in the genes for these enzymes influence alcohol consumption and dependency as well as alcohol-driven tissue damage.

In addition, alcohol disrupts the intestinal mucosal barrier, allowing lipopolysaccharides from gram-negative bacteria to travel to the liver via the portal vein. These lipopolysaccharides then bind to and activate sinusoidal Kupffer cells, leading to production of several cytokines such as tumor necrosis factor alpha, interleukin 1, and transforming growth factor beta. These cytokines promote hepatocyte inflammation, apoptosis, and necrosis (Figure 1).¹¹

Besides activating the innate immune system, the reactive oxygen species resulting from alcohol metabolism interact with cellular components, leading to production of protein adducts. These act as antigens that activate the adaptive immune response, followed by B- and T-lymphocyte infiltration, which in turn contribute to liver injury and inflammation.¹²

THE DIAGNOSIS IS MAINLY CLINICAL

The diagnosis of alcoholic hepatitis is mainly clinical. In its usual presentation, jaundice develops rapidly in a person with a known history of heavy alcohol use. Other symptoms and signs may include ascites, encephalopathy, and fever. On examination, the liver may be enlarged and tender, and a hepatic bruit has been reported.¹³

Other classic signs of liver disease such as parotid enlargement, Dupuytren contracture, dilated abdominal wall veins, and spider nevi can be present, but none is highly specific or sensitive for alcoholic hepatitis.

Elevated liver enzymes and other clues

Laboratory tests are important in evaluating potential alcoholic hepatitis, although no single laboratory marker can definitively establish alcohol as the cause of liver disease. To detect alcohol consumption, biochemical markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), mean corpuscular volume, carbohydrate-deficient transferrin, and, more commonly, gamma-glutamyl transpeptidase are used.

In the acute setting, typical biochemical derangements in alcoholic hepatitis include elevated AST (up to 2 to 6 times the upper limit of normal; usually less than 300 IU/L) and elevated ALT to a lesser extent,¹⁴ with an AST-to-ALT ratio greater than 2. Neutrophilia, anemia, hyperbilirubinemia, and coagulopathy with an elevated international normalized ratio are common.

Patients with alcoholic hepatitis are also prone to develop bacterial infections, and about 7% develop hepatorenal syndrome, itself an ominous sign.¹⁵

Imaging studies are valuable in excluding other causes of abnormal liver test results in patients who abuse alcohol, such as biliary obstruction, infiltrative liver diseases, and hepatocellular carcinoma.

Screen for alcohol intake

During the initial evaluation of suspected alcoholic hepatitis, one should screen for excessive drinking. In a US Centers for Disease Control and Prevention study, only one of six US adults, including binge drinkers, said they had ever discussed alcohol consumption with a health professional.¹⁶ Many patients with alcoholic liver disease in general and alcoholic hepatitis in particular deny alcohol abuse or underreport their intake.¹⁷

Screening tests such as the CAGE questionnaire and the Alcohol Use Disorders Identification Test can be used to assess alcohol dependence or abuse.^18,19 The CAGE questionnaire consists of four questions:

• Have you ever felt you should cut down on your drinking?
• Have people annoyed you by criticizing your drinking?
• Have you ever felt guilty about your drinking?
• Have you ever had a drink first thing in the morning (an eye-opener) to steady your nerves or to get rid of a hangover?

A yes answer to two or more questions is considered clinically significant.

Is liver biopsy always needed?

Although alcoholic hepatitis can be suspected on the basis of clinical and biochemical clues, liver biopsy remains the gold standard diagnostic tool. It confirms the clinical diagnosis of alcoholic hepatitis in about 85% of all patients and in up to 95% when significant hyperbilirubinemia is present.²⁰

However, whether a particular patient needs a biopsy is not always clear. The American Association for the Study of Liver Diseases (AASLD) recommends biopsy in patients who have a clinical diagnosis of severe alcoholic hepatitis for whom medical treatment is being considered and in those with an uncertain underlying diagnosis.

Findings on liver biopsy in alcoholic hepatitis include steatosis, hepatocyte ballooning, neutrophilic infiltration, Mallory bodies (which represent aggregated cytokeratin intermediate filaments and other proteins), and scarring with a typical perivenular distribution as opposed to the periportal fibrosis seen in chronic viral hepatitis. Some histologic findings, such as centrilobular necrosis, may overlap alcoholic hepatitis and nonalcoholic steatohepatitis.

In addition to confirming the diagnosis and staging the disease, liver biopsy has prognostic value. The severity of inflammation and cholestatic changes correlates with poor prognosis and may also predict response to corticosteroid treatment in severe cases of alcoholic hepatitis.²¹

However, the utility of liver biopsy in confirming the diagnosis and assessing the prognosis of alcoholic hepatitis is controversial for several reasons. Coagulopathy, thrombocytopenia, and ascites are all common in patients with alcoholic hepatitis, often making percutaneous liver biopsy contraindicated. Trans-
jugular liver biopsy is not universally available outside tertiary care centers.

The major enzymes involved in alcohol metabolism are CYP2E1 and ADH

Needed is a minimally invasive test for assessing this disease. Breath analysis might be such a test, offering a noninvasive means to study the composition of volatile organic compounds and elemental gases and an attractive method to evaluate health and disease in a patient-friendly manner. Our group devised a model based on breath levels of trimethylamine and pentane. When we tested it, we found that it distinguishes patients with alcoholic hepatitis from those with acute liver decompensation from causes other than alcohol and controls without liver disease with up to 90% sensitivity and 80% specificity.²²

ASSESSING THE SEVERITY OF ALCOHOLIC HEPATITIS

Several models have been developed to assess the severity of alcoholic hepatitis and guide treatment decisions (Table 2). 

The MDF (Maddrey Discriminant Function)⁶ system was the first scoring system developed and is still the most widely used. A score of 32 or higher indicates severe alcoholic hepatitis and has been used as the threshold for starting treatment with corticosteroids.⁶

The MDF has limitations. Patients with a score lower than 32 are considered not to have severe alcoholic hepatitis, but up to 17% of them still die. Also, since it uses the prothrombin time, its results can vary considerably among laboratories, depending on the sensitivity of the thromboplastin reagent used.

The MELD (Model for End-stage Liver Disease) score. Sheth et al²³ compared the MELD and the MDF scores in assessing the severity of alcoholic hepatitis. They found that the MELD performed as well as the MDF in predicting 30-day mortality. A MELD score of greater than 11 had a sensitivity in predicting 30-day mortality of 86% and a specificity of 81%, compared with 86% and 48%, respectively, for MDF scores greater than 32.

Another study found a MELD score of 21 to have the highest sensitivity and specificity in predicting mortality (an estimated 90-day death rate of 20%). Thus, a MELD score of 21 is an appropriate threshold for prompt consideration of specific therapies such as corticosteroids.²⁴

The MELD score has become increasingly important in patients with alcoholic hepatitis, as some of them may become candidates for liver transplantation (see below). Also, serial MELD scores in hospitalized patients have prognostic implications, since an increase of 2 or more points in the first week has been shown to predict in-hospital mortality.²⁵

The GAHS (Glasgow Alcoholic Hepatitis Score)²⁶ was shown to identify patients with alcoholic hepatitis who have an especially poor prognosis and need corticosteroid therapy. In those with a GAHS of 9 or higher, the 28-day survival rate was 78% with corticosteroid treatment and 52% without corticosteroid treatment; survival rates at 84 days were 59% and 38%, respectively.²⁶

The ABIC scoring system (Age, Serum Bilirubin, INR, and Serum Creatinine) stratifies patients by risk of death at 90 days²⁷:

• Score less than 6.71: low risk (100% survival)
• A score 6.71–8.99: intermediate risk (70% survival)
• A score 9.0 or higher: high risk (25% survival). 

Both the GAHS and ABIC score are limited by lack of external validation.

The Lille score.²⁸ While the above scores are used to identify patients at risk of death from alcoholic hepatitis and to decide on starting corticosteroids, the Lille score is designed to assess response to corticosteroids after 1 week of treatment. It is calculated based on five pretreatment variables and the change in serum bilirubin level at day 7 of corticosteroid therapy. Lille scores range from 0 to 1; a score higher than 0.45 is associated with a 75% mortality rate at 6 months and indicates a lack of response to corticosteroids and that these drugs should be discontinued.²⁸

MANAGEMENT

Supportive treatment

Abstinence from alcohol is the cornerstone of treatment of alcoholic hepatitis. Early management of alcohol abuse or dependence is, therefore, warranted in all patients with alcoholic hepatitis. Referral to addiction specialists, motivational therapies, and anticraving drugs such as baclofen can be utilized.

Treat alcohol withdrawal. Alcoholics who suddenly decrease or discontinue their alcohol use are at high risk of alcohol withdrawal syndrome. Within 24 hours after the last drink, patients can experience increases in their heart rate and blood pressure, along with irritability and hyperreflexia. Within the next few days, more dangerous complications including seizures and delirium tremens can arise.

Alcohol withdrawal symptoms should be treated with short-acting benzodiazepines or clomethiazole, keeping the risk of worsening encephalopathy in mind.²⁹ If present, complications of cirrhosis such as encephalopathy, ascites, and variceal bleeding should be managed.

Usual presentation: Rapid onset of jaundice in a person with a history of heavy alcohol use

Nutritional support is important. Protein-calorie malnutrition is common in alcoholics, as are deficiencies of vitamin A, vitamin D, thiamine, folate, pyridoxine, and zinc.³⁰ Although a randomized controlled trial comparing enteral nutrition (2,000 kcal/day) vs corticosteroids (prednisolone 40 mg/day) in patients with alcoholic hepatitis did not show any difference in the 28-day mortality rate, those who received nutritional support and survived the first month had a lower mortality rate than those treated with corticosteroids (8% vs 37%).³¹ A daily protein intake of 1.5 g per kilogram of body weight is therefore recommended, even in patients with hepatic encephalopathy.¹⁵

Combining enteral nutrition and corticosteroid treatment may have a synergistic effect but is yet to be investigated.

Screen for infection. Patients with alcoholic hepatitis should be screened for infection, as about 25% of those with severe alcoholic hepatitis have an infection at admission.³² Since many of these patients meet the criteria for systemic inflammatory response syndrome, infections can be particularly difficult to diagnose. Patients require close clinical monitoring as well as regular pancultures for early detection. Antibiotics are frequently started empirically even though we lack specific evidence-based guidelines on this practice.³³

Corticosteroids

Various studies have evaluated the role of corticosteroids in treating alcoholic hepatitis, differing considerably in sample populations, methods, and end points. Although the results of individual trials differ, meta-analyses indicate that corticosteroids have a moderate beneficial effect in patients with severe alcoholic hepatitis.

For example, Rambaldi et al³⁴ performed a meta-analysis that concluded the mortality rate was lower in alcoholic hepatitis patients with MDF scores of at least 32 or hepatic encephalopathy who were treated with corticosteroids than in controls (relative risk 0.37, 95% confidence interval 0.16–0.86).

Therefore, in the absence of contraindications, the AASLD recommends starting corticosteroids in patients with severe alcoholic hepatitis, defined as an MDF score of 32 or higher.²¹ The preferred agent is oral prednisolone 40 mg daily or parenteral methylprednisolone 32 mg daily for 4 weeks and then tapered over the next 2 to 4 weeks or abruptly discontinued. Because activation of prednisone is decreased in patients with liver disease, prednisolone (the active form) is preferred over prednisone (the inactive precursor).³⁵ In alcoholic hepatitis, the number needed to treat with corticosteroids to prevent one death has been calculated³⁶ at 5.

As mentioned, response to corticosteroids is commonly assessed at 1 week of treatment using the Lille score. A score higher than 0.45 predicts a poor response and should trigger discontinuation of corticosteroids, particularly in those classified as null responders (Lille score > 0.56).

Typical biochemical derangements include elevated AST and, to a lesser extent, ALT

Adverse effects of steroids include sepsis, gastrointestinal bleeding, and steroid psychosis. Of note, patients who have evidence of hepatorenal syndrome or gastrointestinal bleeding tend to have a less favorable response to corticosteroids. Also, while infections were once considered a contraindication to steroid therapy, recent evidence suggests that steroid use might not be precluded in infected patients after appropriate antibiotic therapy. Infections occur in about a quarter of all alcoholic hepatitis patients treated with steroids, more frequently in null responders (42.5%) than in responders (11.1%), which supports corticosteroid discontinuance at 1 week in null responders.³²

Pentoxifylline

An oral phosphodiesterase inhibitor, pentoxifylline, also inhibits production of several cytokines, including tumor necrosis factor alpha. At a dose of 400 mg orally three times daily for 4 weeks, pentoxifylline has been used in treating severe alcoholic hepatitis (MDF score ≥ 32) and is recommended especially if corticosteroids are contraindicated, as with sepsis.²¹

An early double-blind clinical trial randomized patients with severe alcoholic hepatitis to receive either pentoxifylline 400 mg orally three times daily or placebo. Of the patients who received pentoxifylline, 24.5% died during the index hospitalization, compared with 46.1% of patients who received placebo. This survival benefit was mainly related to a markedly lower incidence of hepatorenal syndrome as the cause of death in the pentoxifylline group than in the placebo group (50% vs 91.7% of deaths).³⁷

In a small clinical trial in patients with severe alcoholic hepatitis, pentoxifylline recipients had a higher 3-month survival rate than prednisolone recipients (35.29% vs 14.71%, P = .04).³⁸ However, a larger trial showed no improvement in 6-month survival with the combination of prednisolone and pentoxifylline compared with prednisolone alone (69.9% vs 69.2%, P = .91).³⁹ Also, a meta-analysis of five randomized clinical trials found no survival benefit with pentoxifylline therapy.⁴⁰

Of note, in the unfortunate subgroup of patients who have a poor response to corticosteroids, no alternative treatment, including pentoxifylline, has been shown to be effective.⁴¹

Prednisone or pentoxifylline? Very recently, results of the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial have been released.⁴² This is a large, multicenter, double-blinded clinical trial that aimed to provide a definitive answer to whether corticosteroids or pentoxifylline (or both) are beneficial in patients with alcoholic hepatitis. The study included 1,103 adult patients with severe alcoholic hepatitis (MDF score ≥ 32) who were randomized to monotherapy with prednisolone or pentoxifylline, combination therapy, or placebo. The primary end point was mortality at 28 days, and secondary end points included mortality at 90 days and at 1 year. Prednisolone reduced 28-day mortality by about 39%. In contrast, the 28-day mortality rate was similar in patients who received pentoxifylline and those who did not. Also, neither drug was significantly associated with a survival benefit beyond 28 days. The investigators concluded that pentoxifylline has no impact on disease progression and should not be used for the treatment of severe alcoholic hepatitis.⁴²

Other tumor necrosis factor alpha inhibitors not recommended

Two other tumor necrosis factor alpha inhibitors, infliximab and etanercept, have been tested in clinical trials in alcoholic hepatitis. Unfortunately, the results were not encouraging, with no major reduction in mortality.^43–45 In fact, these trials demonstrated a significantly increased risk of infections in the treatment groups. Therefore, these drugs are not recommended for treating alcoholic hepatitis.

A possible explanation is that tumor necrosis factor alpha plays an important role in liver regeneration, aiding in recovery from alcohol-induced liver injury, and inhibiting it can have deleterious consequences.

Other agents

A number of other agents have undergone clinical trials in alcoholic hepatitis.

N-acetylcysteine, an antioxidant that replenishes glutathione stores in hepatocytes, was evaluated in a randomized clinical trial in combination with prednisolone.⁴⁶ Although the 1-month mortality rate was significantly lower in the combination group than in the prednisolone-only group (8% vs 24%, P = .006), 3-month and 6-month mortality rates were not. Nonetheless, the rates of infection and hepatorenal syndrome were lower in the combination group. Therefore, corticosteroids and N-acetylcysteine may have synergistic effects, but the optimum duration of N-acetylcysteine therapy needs to be determined in further studies.

Vitamin E, silymarin, propylthiouracil, colchicine, and oxandrolone (an anabolic steroid) have also been studied, but with no convincing benefit.²¹

Role of liver transplantation

Liver transplantation for alcoholic liver disease has been a topic of great medical and social controversy. The view that alcoholic patients are responsible for their own illness led to caution when contemplating liver transplantation. Many countries require 6 months of abstinence from alcohol before placing a patient on the liver transplant list, posing a major obstacle to patients with alcoholic hepatitis, as almost all are active drinkers at the time of presentation and many will die within 6 months. Reasons for this 6-month rule include donor shortage and risk of recidivism.⁴⁷

Abstinence from alcohol is the cornerstone of treatment of alcoholic hepatitis

With regard to survival following alcoholic hepatitis, a study utilizing the United Network for Organ Sharing database matched patients with alcoholic hepatitis and alcoholic cirrhosis who underwent liver transplantation. Rates of 5-year graft survival were 75% in those with alcoholic hepatitis and 73% in those with alcoholic cirrhosis (P = .97), and rates of patient survival were 80% and 78% (P = .90), respectively. Proportional regression analysis adjusting for other variables showed no impact of the etiology of liver disease on graft or patient survival. The investigators concluded that liver transplantation could be considered in a select group of patients with alcoholic hepatitis who do not improve with medical therapy.⁴⁸

In a pivotal case-control prospective study,⁴⁹ 26 patients with Lille scores greater than 0.45 were listed for liver transplantation within a median of 13 days after nonresponse to medical therapy. The cumulative 6-month survival rate was higher in patients who received a liver transplant early than in those who did not (77% vs 23%, P < .001). This benefit was maintained through 2 years of follow-up (hazard ratio 6.08, P = .004). Of note, all these patients had supportive family members, no severe coexisting conditions, and a commitment to alcohol abstinence (although 3 patients resumed drinking after liver transplantation).⁴⁹

Although these studies support early liver transplantation in carefully selected patients with severe alcoholic hepatitis, the criteria for transplantation in this group need to be refined. Views on alcoholism also need to be reconciled, as strong evidence is emerging that implicates genetic and environmental influences on alcohol dependence.

Management algorithm

Adapted from the guidelines of the AASLD and European Association for the Study of the Liver.

Figure 2 shows a suggested management algorithm for alcoholic hepatitis, adapted from the guidelines of the AASLD and European Association for the Study of the Liver.

NEW THERAPIES NEEDED

Novel therapies for severe alcoholic hepatitis are urgently needed to help combat this devastating condition. Advances in understanding its pathophysiology have uncovered several new therapeutic targets, and new agents are already being evaluated in clinical trials.

IMM 124-E, a hyperimmune bovine colostrum enriched with immunoglobulin G anti-lipopolysaccharide, is going to be evaluated in combination with prednisolone in patients with severe alcoholic hepatitis.

Anakinra, an interleukin 1 receptor antagonist, has significant anti-inflammatory activity and is used to treat rheumatoid arthritis. A clinical trial to evaluate its role in alcoholic hepatitis has been designed in which patients with severe alcoholic hepatitis (defined as a MELD score ≥ 21) will be randomized to receive either methylprednisolone or a combination of anakinra, pentoxifylline, and zinc (a mineral that improves gut integrity).

Emricasan, an orally active caspase protease inhibitor, is another agent currently being tested in a phase 2 clinical trial in patients with severe alcoholic hepatitis. Since caspases induce apoptosis, inhibiting them should theoretically dampen alcohol-induced hepatocyte injury.

Interleukin 22, a hepatoprotective cytokine, shows promise as a treatment and will soon be evaluated in alcoholic hepatitis.

Alcoholic hepatitis, a severe manifestation of alcoholic liver disease, is rising in incidence. Complete abstinence from alcohol remains the cornerstone of treatment, while other specific interventions aim to decrease short-term mortality rates.

Despite current treatments, about 25% of patients with severe alcoholic hepatitis eventually die of it. For those who survive hospitalization, measures need to be taken to prevent recidivism. Although liver transplantation seems to hold promise, early transplantation is still largely experimental in alcoholic hepatitis and will likely be available to only a small subset of patients, especially in view of ethical issues and the possible wider implications for transplant centers.

New treatments will largely depend on a better understanding of the disease’s pathophysiology, and future clinical trials should evaluate therapies that improve short-term as well as long-term outcomes.

ACUTE HEPATIC DECOMPENSATION IN A HEAVY DRINKER

Excessive alcohol consumption is very common worldwide, is a major risk factor for liver disease, and is a leading cause of preventable death. Alcoholic cirrhosis is the eighth most common cause of death in the United States and in 2010 was responsible for nearly half of cirrhosis-related deaths worldwide.¹

Alcoholic liver disease is a spectrum. Nearly all heavy drinkers (ie, those consuming 40 g or more of alcohol per day, Table 1) have fatty liver changes, 20% to 40% develop fibrosis, 10% to 20% progress to cirrhosis, and of those with cirrhosis, 1% to 2% are diagnosed with hepatocellular carcinoma every year.²

Within this spectrum, alcoholic hepatitis is a well-defined clinical syndrome characterized by acute hepatic decompensation that typically results from long-standing alcohol abuse. Binge drinkers may also be at risk for alcoholic hepatitis, but good data on the association between drinking patterns and the risk of alcoholic hepatitis are limited.

Alcoholic hepatitis varies in severity from mild to life-threatening.³ Although its exact incidence is unknown, its prevalence in alcoholics has been estimated at 20%.⁴ Nearly half of patients with alcoholic hepatitis have cirrhosis at the time of their acute presentation, and these patients generally have a poor prognosis, with a 28-day death rate as high as 50% in severe cases.^5,6 Moreover, although alcoholic hepatitis develops in only a subset of patients with alcoholic liver disease, hospitalizations for it are increasing in the United States.⁷

Women are at higher risk of developing alcoholic hepatitis, an observation attributed to the effect of estrogens on oxidative stress and inflammation, lower gastric alcohol dehydrogenase levels resulting in slower first-pass metabolism of alcohol, and higher body fat content causing a lower volume of distribution for alcohol than in men.⁸ The incidence of alcoholic hepatitis is also influenced by a number of demographic and genetic factors as well as nutritional status and coexistence of other liver diseases.⁹ Most patients diagnosed with alcoholic hepatitis are active drinkers, but it can develop even after significantly reducing or stopping alcohol consumption.

FATTY ACIDS, ENZYMES, CYTOKINES, INFLAMMATION

Alcohol consumption induces fatty acid synthesis and inhibits fatty acid oxidation, thereby promoting fat deposition in the liver.

The major enzymes involved in alcohol metabolism are cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase. CYP2E1 is inducible and is up-regulated when excess alcohol is ingested, while alcohol dehydrogen-
ase function is relatively stable. Oxidative degradation of alcohol by these enzymes generates reactive oxygen species and acetaldehyde, inducing liver injury.¹⁰ Interestingly, it has been proposed that variations in the genes for these enzymes influence alcohol consumption and dependency as well as alcohol-driven tissue damage.

In addition, alcohol disrupts the intestinal mucosal barrier, allowing lipopolysaccharides from gram-negative bacteria to travel to the liver via the portal vein. These lipopolysaccharides then bind to and activate sinusoidal Kupffer cells, leading to production of several cytokines such as tumor necrosis factor alpha, interleukin 1, and transforming growth factor beta. These cytokines promote hepatocyte inflammation, apoptosis, and necrosis (Figure 1).¹¹

Besides activating the innate immune system, the reactive oxygen species resulting from alcohol metabolism interact with cellular components, leading to production of protein adducts. These act as antigens that activate the adaptive immune response, followed by B- and T-lymphocyte infiltration, which in turn contribute to liver injury and inflammation.¹²

THE DIAGNOSIS IS MAINLY CLINICAL

The diagnosis of alcoholic hepatitis is mainly clinical. In its usual presentation, jaundice develops rapidly in a person with a known history of heavy alcohol use. Other symptoms and signs may include ascites, encephalopathy, and fever. On examination, the liver may be enlarged and tender, and a hepatic bruit has been reported.¹³

Other classic signs of liver disease such as parotid enlargement, Dupuytren contracture, dilated abdominal wall veins, and spider nevi can be present, but none is highly specific or sensitive for alcoholic hepatitis.

Elevated liver enzymes and other clues

Laboratory tests are important in evaluating potential alcoholic hepatitis, although no single laboratory marker can definitively establish alcohol as the cause of liver disease. To detect alcohol consumption, biochemical markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), mean corpuscular volume, carbohydrate-deficient transferrin, and, more commonly, gamma-glutamyl transpeptidase are used.

In the acute setting, typical biochemical derangements in alcoholic hepatitis include elevated AST (up to 2 to 6 times the upper limit of normal; usually less than 300 IU/L) and elevated ALT to a lesser extent,¹⁴ with an AST-to-ALT ratio greater than 2. Neutrophilia, anemia, hyperbilirubinemia, and coagulopathy with an elevated international normalized ratio are common.

Patients with alcoholic hepatitis are also prone to develop bacterial infections, and about 7% develop hepatorenal syndrome, itself an ominous sign.¹⁵

Imaging studies are valuable in excluding other causes of abnormal liver test results in patients who abuse alcohol, such as biliary obstruction, infiltrative liver diseases, and hepatocellular carcinoma.

Screen for alcohol intake

During the initial evaluation of suspected alcoholic hepatitis, one should screen for excessive drinking. In a US Centers for Disease Control and Prevention study, only one of six US adults, including binge drinkers, said they had ever discussed alcohol consumption with a health professional.¹⁶ Many patients with alcoholic liver disease in general and alcoholic hepatitis in particular deny alcohol abuse or underreport their intake.¹⁷

Screening tests such as the CAGE questionnaire and the Alcohol Use Disorders Identification Test can be used to assess alcohol dependence or abuse.^18,19 The CAGE questionnaire consists of four questions:

• Have you ever felt you should cut down on your drinking?
• Have people annoyed you by criticizing your drinking?
• Have you ever felt guilty about your drinking?
• Have you ever had a drink first thing in the morning (an eye-opener) to steady your nerves or to get rid of a hangover?

A yes answer to two or more questions is considered clinically significant.

Is liver biopsy always needed?

Although alcoholic hepatitis can be suspected on the basis of clinical and biochemical clues, liver biopsy remains the gold standard diagnostic tool. It confirms the clinical diagnosis of alcoholic hepatitis in about 85% of all patients and in up to 95% when significant hyperbilirubinemia is present.²⁰

However, whether a particular patient needs a biopsy is not always clear. The American Association for the Study of Liver Diseases (AASLD) recommends biopsy in patients who have a clinical diagnosis of severe alcoholic hepatitis for whom medical treatment is being considered and in those with an uncertain underlying diagnosis.

Findings on liver biopsy in alcoholic hepatitis include steatosis, hepatocyte ballooning, neutrophilic infiltration, Mallory bodies (which represent aggregated cytokeratin intermediate filaments and other proteins), and scarring with a typical perivenular distribution as opposed to the periportal fibrosis seen in chronic viral hepatitis. Some histologic findings, such as centrilobular necrosis, may overlap alcoholic hepatitis and nonalcoholic steatohepatitis.

In addition to confirming the diagnosis and staging the disease, liver biopsy has prognostic value. The severity of inflammation and cholestatic changes correlates with poor prognosis and may also predict response to corticosteroid treatment in severe cases of alcoholic hepatitis.²¹

However, the utility of liver biopsy in confirming the diagnosis and assessing the prognosis of alcoholic hepatitis is controversial for several reasons. Coagulopathy, thrombocytopenia, and ascites are all common in patients with alcoholic hepatitis, often making percutaneous liver biopsy contraindicated. Trans-
jugular liver biopsy is not universally available outside tertiary care centers.

The major enzymes involved in alcohol metabolism are CYP2E1 and ADH

Needed is a minimally invasive test for assessing this disease. Breath analysis might be such a test, offering a noninvasive means to study the composition of volatile organic compounds and elemental gases and an attractive method to evaluate health and disease in a patient-friendly manner. Our group devised a model based on breath levels of trimethylamine and pentane. When we tested it, we found that it distinguishes patients with alcoholic hepatitis from those with acute liver decompensation from causes other than alcohol and controls without liver disease with up to 90% sensitivity and 80% specificity.²²

ASSESSING THE SEVERITY OF ALCOHOLIC HEPATITIS

Several models have been developed to assess the severity of alcoholic hepatitis and guide treatment decisions (Table 2). 

The MDF (Maddrey Discriminant Function)⁶ system was the first scoring system developed and is still the most widely used. A score of 32 or higher indicates severe alcoholic hepatitis and has been used as the threshold for starting treatment with corticosteroids.⁶

The MDF has limitations. Patients with a score lower than 32 are considered not to have severe alcoholic hepatitis, but up to 17% of them still die. Also, since it uses the prothrombin time, its results can vary considerably among laboratories, depending on the sensitivity of the thromboplastin reagent used.

The MELD (Model for End-stage Liver Disease) score. Sheth et al²³ compared the MELD and the MDF scores in assessing the severity of alcoholic hepatitis. They found that the MELD performed as well as the MDF in predicting 30-day mortality. A MELD score of greater than 11 had a sensitivity in predicting 30-day mortality of 86% and a specificity of 81%, compared with 86% and 48%, respectively, for MDF scores greater than 32.

Another study found a MELD score of 21 to have the highest sensitivity and specificity in predicting mortality (an estimated 90-day death rate of 20%). Thus, a MELD score of 21 is an appropriate threshold for prompt consideration of specific therapies such as corticosteroids.²⁴

The MELD score has become increasingly important in patients with alcoholic hepatitis, as some of them may become candidates for liver transplantation (see below). Also, serial MELD scores in hospitalized patients have prognostic implications, since an increase of 2 or more points in the first week has been shown to predict in-hospital mortality.²⁵

The GAHS (Glasgow Alcoholic Hepatitis Score)²⁶ was shown to identify patients with alcoholic hepatitis who have an especially poor prognosis and need corticosteroid therapy. In those with a GAHS of 9 or higher, the 28-day survival rate was 78% with corticosteroid treatment and 52% without corticosteroid treatment; survival rates at 84 days were 59% and 38%, respectively.²⁶

The ABIC scoring system (Age, Serum Bilirubin, INR, and Serum Creatinine) stratifies patients by risk of death at 90 days²⁷:

• Score less than 6.71: low risk (100% survival)
• A score 6.71–8.99: intermediate risk (70% survival)
• A score 9.0 or higher: high risk (25% survival). 

Both the GAHS and ABIC score are limited by lack of external validation.

The Lille score.²⁸ While the above scores are used to identify patients at risk of death from alcoholic hepatitis and to decide on starting corticosteroids, the Lille score is designed to assess response to corticosteroids after 1 week of treatment. It is calculated based on five pretreatment variables and the change in serum bilirubin level at day 7 of corticosteroid therapy. Lille scores range from 0 to 1; a score higher than 0.45 is associated with a 75% mortality rate at 6 months and indicates a lack of response to corticosteroids and that these drugs should be discontinued.²⁸

MANAGEMENT

Supportive treatment

Abstinence from alcohol is the cornerstone of treatment of alcoholic hepatitis. Early management of alcohol abuse or dependence is, therefore, warranted in all patients with alcoholic hepatitis. Referral to addiction specialists, motivational therapies, and anticraving drugs such as baclofen can be utilized.

Treat alcohol withdrawal. Alcoholics who suddenly decrease or discontinue their alcohol use are at high risk of alcohol withdrawal syndrome. Within 24 hours after the last drink, patients can experience increases in their heart rate and blood pressure, along with irritability and hyperreflexia. Within the next few days, more dangerous complications including seizures and delirium tremens can arise.

Alcohol withdrawal symptoms should be treated with short-acting benzodiazepines or clomethiazole, keeping the risk of worsening encephalopathy in mind.²⁹ If present, complications of cirrhosis such as encephalopathy, ascites, and variceal bleeding should be managed.

Usual presentation: Rapid onset of jaundice in a person with a history of heavy alcohol use

Nutritional support is important. Protein-calorie malnutrition is common in alcoholics, as are deficiencies of vitamin A, vitamin D, thiamine, folate, pyridoxine, and zinc.³⁰ Although a randomized controlled trial comparing enteral nutrition (2,000 kcal/day) vs corticosteroids (prednisolone 40 mg/day) in patients with alcoholic hepatitis did not show any difference in the 28-day mortality rate, those who received nutritional support and survived the first month had a lower mortality rate than those treated with corticosteroids (8% vs 37%).³¹ A daily protein intake of 1.5 g per kilogram of body weight is therefore recommended, even in patients with hepatic encephalopathy.¹⁵

Combining enteral nutrition and corticosteroid treatment may have a synergistic effect but is yet to be investigated.

Screen for infection. Patients with alcoholic hepatitis should be screened for infection, as about 25% of those with severe alcoholic hepatitis have an infection at admission.³² Since many of these patients meet the criteria for systemic inflammatory response syndrome, infections can be particularly difficult to diagnose. Patients require close clinical monitoring as well as regular pancultures for early detection. Antibiotics are frequently started empirically even though we lack specific evidence-based guidelines on this practice.³³

Corticosteroids

Various studies have evaluated the role of corticosteroids in treating alcoholic hepatitis, differing considerably in sample populations, methods, and end points. Although the results of individual trials differ, meta-analyses indicate that corticosteroids have a moderate beneficial effect in patients with severe alcoholic hepatitis.

For example, Rambaldi et al³⁴ performed a meta-analysis that concluded the mortality rate was lower in alcoholic hepatitis patients with MDF scores of at least 32 or hepatic encephalopathy who were treated with corticosteroids than in controls (relative risk 0.37, 95% confidence interval 0.16–0.86).

Therefore, in the absence of contraindications, the AASLD recommends starting corticosteroids in patients with severe alcoholic hepatitis, defined as an MDF score of 32 or higher.²¹ The preferred agent is oral prednisolone 40 mg daily or parenteral methylprednisolone 32 mg daily for 4 weeks and then tapered over the next 2 to 4 weeks or abruptly discontinued. Because activation of prednisone is decreased in patients with liver disease, prednisolone (the active form) is preferred over prednisone (the inactive precursor).³⁵ In alcoholic hepatitis, the number needed to treat with corticosteroids to prevent one death has been calculated³⁶ at 5.

As mentioned, response to corticosteroids is commonly assessed at 1 week of treatment using the Lille score. A score higher than 0.45 predicts a poor response and should trigger discontinuation of corticosteroids, particularly in those classified as null responders (Lille score > 0.56).

Typical biochemical derangements include elevated AST and, to a lesser extent, ALT

Adverse effects of steroids include sepsis, gastrointestinal bleeding, and steroid psychosis. Of note, patients who have evidence of hepatorenal syndrome or gastrointestinal bleeding tend to have a less favorable response to corticosteroids. Also, while infections were once considered a contraindication to steroid therapy, recent evidence suggests that steroid use might not be precluded in infected patients after appropriate antibiotic therapy. Infections occur in about a quarter of all alcoholic hepatitis patients treated with steroids, more frequently in null responders (42.5%) than in responders (11.1%), which supports corticosteroid discontinuance at 1 week in null responders.³²

Pentoxifylline

An oral phosphodiesterase inhibitor, pentoxifylline, also inhibits production of several cytokines, including tumor necrosis factor alpha. At a dose of 400 mg orally three times daily for 4 weeks, pentoxifylline has been used in treating severe alcoholic hepatitis (MDF score ≥ 32) and is recommended especially if corticosteroids are contraindicated, as with sepsis.²¹

An early double-blind clinical trial randomized patients with severe alcoholic hepatitis to receive either pentoxifylline 400 mg orally three times daily or placebo. Of the patients who received pentoxifylline, 24.5% died during the index hospitalization, compared with 46.1% of patients who received placebo. This survival benefit was mainly related to a markedly lower incidence of hepatorenal syndrome as the cause of death in the pentoxifylline group than in the placebo group (50% vs 91.7% of deaths).³⁷

In a small clinical trial in patients with severe alcoholic hepatitis, pentoxifylline recipients had a higher 3-month survival rate than prednisolone recipients (35.29% vs 14.71%, P = .04).³⁸ However, a larger trial showed no improvement in 6-month survival with the combination of prednisolone and pentoxifylline compared with prednisolone alone (69.9% vs 69.2%, P = .91).³⁹ Also, a meta-analysis of five randomized clinical trials found no survival benefit with pentoxifylline therapy.⁴⁰

Of note, in the unfortunate subgroup of patients who have a poor response to corticosteroids, no alternative treatment, including pentoxifylline, has been shown to be effective.⁴¹

Prednisone or pentoxifylline? Very recently, results of the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial have been released.⁴² This is a large, multicenter, double-blinded clinical trial that aimed to provide a definitive answer to whether corticosteroids or pentoxifylline (or both) are beneficial in patients with alcoholic hepatitis. The study included 1,103 adult patients with severe alcoholic hepatitis (MDF score ≥ 32) who were randomized to monotherapy with prednisolone or pentoxifylline, combination therapy, or placebo. The primary end point was mortality at 28 days, and secondary end points included mortality at 90 days and at 1 year. Prednisolone reduced 28-day mortality by about 39%. In contrast, the 28-day mortality rate was similar in patients who received pentoxifylline and those who did not. Also, neither drug was significantly associated with a survival benefit beyond 28 days. The investigators concluded that pentoxifylline has no impact on disease progression and should not be used for the treatment of severe alcoholic hepatitis.⁴²

Other tumor necrosis factor alpha inhibitors not recommended

Two other tumor necrosis factor alpha inhibitors, infliximab and etanercept, have been tested in clinical trials in alcoholic hepatitis. Unfortunately, the results were not encouraging, with no major reduction in mortality.^43–45 In fact, these trials demonstrated a significantly increased risk of infections in the treatment groups. Therefore, these drugs are not recommended for treating alcoholic hepatitis.

A possible explanation is that tumor necrosis factor alpha plays an important role in liver regeneration, aiding in recovery from alcohol-induced liver injury, and inhibiting it can have deleterious consequences.

Other agents

A number of other agents have undergone clinical trials in alcoholic hepatitis.

N-acetylcysteine, an antioxidant that replenishes glutathione stores in hepatocytes, was evaluated in a randomized clinical trial in combination with prednisolone.⁴⁶ Although the 1-month mortality rate was significantly lower in the combination group than in the prednisolone-only group (8% vs 24%, P = .006), 3-month and 6-month mortality rates were not. Nonetheless, the rates of infection and hepatorenal syndrome were lower in the combination group. Therefore, corticosteroids and N-acetylcysteine may have synergistic effects, but the optimum duration of N-acetylcysteine therapy needs to be determined in further studies.

Vitamin E, silymarin, propylthiouracil, colchicine, and oxandrolone (an anabolic steroid) have also been studied, but with no convincing benefit.²¹

Role of liver transplantation

Liver transplantation for alcoholic liver disease has been a topic of great medical and social controversy. The view that alcoholic patients are responsible for their own illness led to caution when contemplating liver transplantation. Many countries require 6 months of abstinence from alcohol before placing a patient on the liver transplant list, posing a major obstacle to patients with alcoholic hepatitis, as almost all are active drinkers at the time of presentation and many will die within 6 months. Reasons for this 6-month rule include donor shortage and risk of recidivism.⁴⁷

Abstinence from alcohol is the cornerstone of treatment of alcoholic hepatitis

With regard to survival following alcoholic hepatitis, a study utilizing the United Network for Organ Sharing database matched patients with alcoholic hepatitis and alcoholic cirrhosis who underwent liver transplantation. Rates of 5-year graft survival were 75% in those with alcoholic hepatitis and 73% in those with alcoholic cirrhosis (P = .97), and rates of patient survival were 80% and 78% (P = .90), respectively. Proportional regression analysis adjusting for other variables showed no impact of the etiology of liver disease on graft or patient survival. The investigators concluded that liver transplantation could be considered in a select group of patients with alcoholic hepatitis who do not improve with medical therapy.⁴⁸

In a pivotal case-control prospective study,⁴⁹ 26 patients with Lille scores greater than 0.45 were listed for liver transplantation within a median of 13 days after nonresponse to medical therapy. The cumulative 6-month survival rate was higher in patients who received a liver transplant early than in those who did not (77% vs 23%, P < .001). This benefit was maintained through 2 years of follow-up (hazard ratio 6.08, P = .004). Of note, all these patients had supportive family members, no severe coexisting conditions, and a commitment to alcohol abstinence (although 3 patients resumed drinking after liver transplantation).⁴⁹

Although these studies support early liver transplantation in carefully selected patients with severe alcoholic hepatitis, the criteria for transplantation in this group need to be refined. Views on alcoholism also need to be reconciled, as strong evidence is emerging that implicates genetic and environmental influences on alcohol dependence.

Management algorithm

Adapted from the guidelines of the AASLD and European Association for the Study of the Liver.

Figure 2 shows a suggested management algorithm for alcoholic hepatitis, adapted from the guidelines of the AASLD and European Association for the Study of the Liver.

NEW THERAPIES NEEDED

Novel therapies for severe alcoholic hepatitis are urgently needed to help combat this devastating condition. Advances in understanding its pathophysiology have uncovered several new therapeutic targets, and new agents are already being evaluated in clinical trials.

IMM 124-E, a hyperimmune bovine colostrum enriched with immunoglobulin G anti-lipopolysaccharide, is going to be evaluated in combination with prednisolone in patients with severe alcoholic hepatitis.

Anakinra, an interleukin 1 receptor antagonist, has significant anti-inflammatory activity and is used to treat rheumatoid arthritis. A clinical trial to evaluate its role in alcoholic hepatitis has been designed in which patients with severe alcoholic hepatitis (defined as a MELD score ≥ 21) will be randomized to receive either methylprednisolone or a combination of anakinra, pentoxifylline, and zinc (a mineral that improves gut integrity).

Emricasan, an orally active caspase protease inhibitor, is another agent currently being tested in a phase 2 clinical trial in patients with severe alcoholic hepatitis. Since caspases induce apoptosis, inhibiting them should theoretically dampen alcohol-induced hepatocyte injury.

Interleukin 22, a hepatoprotective cytokine, shows promise as a treatment and will soon be evaluated in alcoholic hepatitis.

Alcoholic hepatitis, a severe manifestation of alcoholic liver disease, is rising in incidence. Complete abstinence from alcohol remains the cornerstone of treatment, while other specific interventions aim to decrease short-term mortality rates.

Despite current treatments, about 25% of patients with severe alcoholic hepatitis eventually die of it. For those who survive hospitalization, measures need to be taken to prevent recidivism. Although liver transplantation seems to hold promise, early transplantation is still largely experimental in alcoholic hepatitis and will likely be available to only a small subset of patients, especially in view of ethical issues and the possible wider implications for transplant centers.

New treatments will largely depend on a better understanding of the disease’s pathophysiology, and future clinical trials should evaluate therapies that improve short-term as well as long-term outcomes.

ACUTE HEPATIC DECOMPENSATION IN A HEAVY DRINKER

Excessive alcohol consumption is very common worldwide, is a major risk factor for liver disease, and is a leading cause of preventable death. Alcoholic cirrhosis is the eighth most common cause of death in the United States and in 2010 was responsible for nearly half of cirrhosis-related deaths worldwide.¹

Alcoholic liver disease is a spectrum. Nearly all heavy drinkers (ie, those consuming 40 g or more of alcohol per day, Table 1) have fatty liver changes, 20% to 40% develop fibrosis, 10% to 20% progress to cirrhosis, and of those with cirrhosis, 1% to 2% are diagnosed with hepatocellular carcinoma every year.²

Within this spectrum, alcoholic hepatitis is a well-defined clinical syndrome characterized by acute hepatic decompensation that typically results from long-standing alcohol abuse. Binge drinkers may also be at risk for alcoholic hepatitis, but good data on the association between drinking patterns and the risk of alcoholic hepatitis are limited.

Alcoholic hepatitis varies in severity from mild to life-threatening.³ Although its exact incidence is unknown, its prevalence in alcoholics has been estimated at 20%.⁴ Nearly half of patients with alcoholic hepatitis have cirrhosis at the time of their acute presentation, and these patients generally have a poor prognosis, with a 28-day death rate as high as 50% in severe cases.^5,6 Moreover, although alcoholic hepatitis develops in only a subset of patients with alcoholic liver disease, hospitalizations for it are increasing in the United States.⁷

Women are at higher risk of developing alcoholic hepatitis, an observation attributed to the effect of estrogens on oxidative stress and inflammation, lower gastric alcohol dehydrogenase levels resulting in slower first-pass metabolism of alcohol, and higher body fat content causing a lower volume of distribution for alcohol than in men.⁸ The incidence of alcoholic hepatitis is also influenced by a number of demographic and genetic factors as well as nutritional status and coexistence of other liver diseases.⁹ Most patients diagnosed with alcoholic hepatitis are active drinkers, but it can develop even after significantly reducing or stopping alcohol consumption.

FATTY ACIDS, ENZYMES, CYTOKINES, INFLAMMATION

Alcohol consumption induces fatty acid synthesis and inhibits fatty acid oxidation, thereby promoting fat deposition in the liver.

The major enzymes involved in alcohol metabolism are cytochrome P450 2E1 (CYP2E1) and alcohol dehydrogenase. CYP2E1 is inducible and is up-regulated when excess alcohol is ingested, while alcohol dehydrogen-
ase function is relatively stable. Oxidative degradation of alcohol by these enzymes generates reactive oxygen species and acetaldehyde, inducing liver injury.¹⁰ Interestingly, it has been proposed that variations in the genes for these enzymes influence alcohol consumption and dependency as well as alcohol-driven tissue damage.

In addition, alcohol disrupts the intestinal mucosal barrier, allowing lipopolysaccharides from gram-negative bacteria to travel to the liver via the portal vein. These lipopolysaccharides then bind to and activate sinusoidal Kupffer cells, leading to production of several cytokines such as tumor necrosis factor alpha, interleukin 1, and transforming growth factor beta. These cytokines promote hepatocyte inflammation, apoptosis, and necrosis (Figure 1).¹¹

Besides activating the innate immune system, the reactive oxygen species resulting from alcohol metabolism interact with cellular components, leading to production of protein adducts. These act as antigens that activate the adaptive immune response, followed by B- and T-lymphocyte infiltration, which in turn contribute to liver injury and inflammation.¹²

THE DIAGNOSIS IS MAINLY CLINICAL

The diagnosis of alcoholic hepatitis is mainly clinical. In its usual presentation, jaundice develops rapidly in a person with a known history of heavy alcohol use. Other symptoms and signs may include ascites, encephalopathy, and fever. On examination, the liver may be enlarged and tender, and a hepatic bruit has been reported.¹³

Other classic signs of liver disease such as parotid enlargement, Dupuytren contracture, dilated abdominal wall veins, and spider nevi can be present, but none is highly specific or sensitive for alcoholic hepatitis.

Elevated liver enzymes and other clues

Laboratory tests are important in evaluating potential alcoholic hepatitis, although no single laboratory marker can definitively establish alcohol as the cause of liver disease. To detect alcohol consumption, biochemical markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), mean corpuscular volume, carbohydrate-deficient transferrin, and, more commonly, gamma-glutamyl transpeptidase are used.

In the acute setting, typical biochemical derangements in alcoholic hepatitis include elevated AST (up to 2 to 6 times the upper limit of normal; usually less than 300 IU/L) and elevated ALT to a lesser extent,¹⁴ with an AST-to-ALT ratio greater than 2. Neutrophilia, anemia, hyperbilirubinemia, and coagulopathy with an elevated international normalized ratio are common.

Patients with alcoholic hepatitis are also prone to develop bacterial infections, and about 7% develop hepatorenal syndrome, itself an ominous sign.¹⁵

Imaging studies are valuable in excluding other causes of abnormal liver test results in patients who abuse alcohol, such as biliary obstruction, infiltrative liver diseases, and hepatocellular carcinoma.

Screen for alcohol intake

During the initial evaluation of suspected alcoholic hepatitis, one should screen for excessive drinking. In a US Centers for Disease Control and Prevention study, only one of six US adults, including binge drinkers, said they had ever discussed alcohol consumption with a health professional.¹⁶ Many patients with alcoholic liver disease in general and alcoholic hepatitis in particular deny alcohol abuse or underreport their intake.¹⁷

Screening tests such as the CAGE questionnaire and the Alcohol Use Disorders Identification Test can be used to assess alcohol dependence or abuse.^18,19 The CAGE questionnaire consists of four questions:

• Have you ever felt you should cut down on your drinking?
• Have people annoyed you by criticizing your drinking?
• Have you ever felt guilty about your drinking?
• Have you ever had a drink first thing in the morning (an eye-opener) to steady your nerves or to get rid of a hangover?

A yes answer to two or more questions is considered clinically significant.

Is liver biopsy always needed?

Although alcoholic hepatitis can be suspected on the basis of clinical and biochemical clues, liver biopsy remains the gold standard diagnostic tool. It confirms the clinical diagnosis of alcoholic hepatitis in about 85% of all patients and in up to 95% when significant hyperbilirubinemia is present.²⁰

However, whether a particular patient needs a biopsy is not always clear. The American Association for the Study of Liver Diseases (AASLD) recommends biopsy in patients who have a clinical diagnosis of severe alcoholic hepatitis for whom medical treatment is being considered and in those with an uncertain underlying diagnosis.

Findings on liver biopsy in alcoholic hepatitis include steatosis, hepatocyte ballooning, neutrophilic infiltration, Mallory bodies (which represent aggregated cytokeratin intermediate filaments and other proteins), and scarring with a typical perivenular distribution as opposed to the periportal fibrosis seen in chronic viral hepatitis. Some histologic findings, such as centrilobular necrosis, may overlap alcoholic hepatitis and nonalcoholic steatohepatitis.

In addition to confirming the diagnosis and staging the disease, liver biopsy has prognostic value. The severity of inflammation and cholestatic changes correlates with poor prognosis and may also predict response to corticosteroid treatment in severe cases of alcoholic hepatitis.²¹

However, the utility of liver biopsy in confirming the diagnosis and assessing the prognosis of alcoholic hepatitis is controversial for several reasons. Coagulopathy, thrombocytopenia, and ascites are all common in patients with alcoholic hepatitis, often making percutaneous liver biopsy contraindicated. Trans-
jugular liver biopsy is not universally available outside tertiary care centers.

The major enzymes involved in alcohol metabolism are CYP2E1 and ADH

Needed is a minimally invasive test for assessing this disease. Breath analysis might be such a test, offering a noninvasive means to study the composition of volatile organic compounds and elemental gases and an attractive method to evaluate health and disease in a patient-friendly manner. Our group devised a model based on breath levels of trimethylamine and pentane. When we tested it, we found that it distinguishes patients with alcoholic hepatitis from those with acute liver decompensation from causes other than alcohol and controls without liver disease with up to 90% sensitivity and 80% specificity.²²

ASSESSING THE SEVERITY OF ALCOHOLIC HEPATITIS

Several models have been developed to assess the severity of alcoholic hepatitis and guide treatment decisions (Table 2). 

The MDF (Maddrey Discriminant Function)⁶ system was the first scoring system developed and is still the most widely used. A score of 32 or higher indicates severe alcoholic hepatitis and has been used as the threshold for starting treatment with corticosteroids.⁶

The MDF has limitations. Patients with a score lower than 32 are considered not to have severe alcoholic hepatitis, but up to 17% of them still die. Also, since it uses the prothrombin time, its results can vary considerably among laboratories, depending on the sensitivity of the thromboplastin reagent used.

The MELD (Model for End-stage Liver Disease) score. Sheth et al²³ compared the MELD and the MDF scores in assessing the severity of alcoholic hepatitis. They found that the MELD performed as well as the MDF in predicting 30-day mortality. A MELD score of greater than 11 had a sensitivity in predicting 30-day mortality of 86% and a specificity of 81%, compared with 86% and 48%, respectively, for MDF scores greater than 32.

Another study found a MELD score of 21 to have the highest sensitivity and specificity in predicting mortality (an estimated 90-day death rate of 20%). Thus, a MELD score of 21 is an appropriate threshold for prompt consideration of specific therapies such as corticosteroids.²⁴

The MELD score has become increasingly important in patients with alcoholic hepatitis, as some of them may become candidates for liver transplantation (see below). Also, serial MELD scores in hospitalized patients have prognostic implications, since an increase of 2 or more points in the first week has been shown to predict in-hospital mortality.²⁵

The GAHS (Glasgow Alcoholic Hepatitis Score)²⁶ was shown to identify patients with alcoholic hepatitis who have an especially poor prognosis and need corticosteroid therapy. In those with a GAHS of 9 or higher, the 28-day survival rate was 78% with corticosteroid treatment and 52% without corticosteroid treatment; survival rates at 84 days were 59% and 38%, respectively.²⁶

The ABIC scoring system (Age, Serum Bilirubin, INR, and Serum Creatinine) stratifies patients by risk of death at 90 days²⁷:

• Score less than 6.71: low risk (100% survival)
• A score 6.71–8.99: intermediate risk (70% survival)
• A score 9.0 or higher: high risk (25% survival). 

Both the GAHS and ABIC score are limited by lack of external validation.

The Lille score.²⁸ While the above scores are used to identify patients at risk of death from alcoholic hepatitis and to decide on starting corticosteroids, the Lille score is designed to assess response to corticosteroids after 1 week of treatment. It is calculated based on five pretreatment variables and the change in serum bilirubin level at day 7 of corticosteroid therapy. Lille scores range from 0 to 1; a score higher than 0.45 is associated with a 75% mortality rate at 6 months and indicates a lack of response to corticosteroids and that these drugs should be discontinued.²⁸

MANAGEMENT

Supportive treatment

Abstinence from alcohol is the cornerstone of treatment of alcoholic hepatitis. Early management of alcohol abuse or dependence is, therefore, warranted in all patients with alcoholic hepatitis. Referral to addiction specialists, motivational therapies, and anticraving drugs such as baclofen can be utilized.

Treat alcohol withdrawal. Alcoholics who suddenly decrease or discontinue their alcohol use are at high risk of alcohol withdrawal syndrome. Within 24 hours after the last drink, patients can experience increases in their heart rate and blood pressure, along with irritability and hyperreflexia. Within the next few days, more dangerous complications including seizures and delirium tremens can arise.

Alcohol withdrawal symptoms should be treated with short-acting benzodiazepines or clomethiazole, keeping the risk of worsening encephalopathy in mind.²⁹ If present, complications of cirrhosis such as encephalopathy, ascites, and variceal bleeding should be managed.

Usual presentation: Rapid onset of jaundice in a person with a history of heavy alcohol use

Nutritional support is important. Protein-calorie malnutrition is common in alcoholics, as are deficiencies of vitamin A, vitamin D, thiamine, folate, pyridoxine, and zinc.³⁰ Although a randomized controlled trial comparing enteral nutrition (2,000 kcal/day) vs corticosteroids (prednisolone 40 mg/day) in patients with alcoholic hepatitis did not show any difference in the 28-day mortality rate, those who received nutritional support and survived the first month had a lower mortality rate than those treated with corticosteroids (8% vs 37%).³¹ A daily protein intake of 1.5 g per kilogram of body weight is therefore recommended, even in patients with hepatic encephalopathy.¹⁵

Combining enteral nutrition and corticosteroid treatment may have a synergistic effect but is yet to be investigated.

Screen for infection. Patients with alcoholic hepatitis should be screened for infection, as about 25% of those with severe alcoholic hepatitis have an infection at admission.³² Since many of these patients meet the criteria for systemic inflammatory response syndrome, infections can be particularly difficult to diagnose. Patients require close clinical monitoring as well as regular pancultures for early detection. Antibiotics are frequently started empirically even though we lack specific evidence-based guidelines on this practice.³³

Corticosteroids

Various studies have evaluated the role of corticosteroids in treating alcoholic hepatitis, differing considerably in sample populations, methods, and end points. Although the results of individual trials differ, meta-analyses indicate that corticosteroids have a moderate beneficial effect in patients with severe alcoholic hepatitis.

For example, Rambaldi et al³⁴ performed a meta-analysis that concluded the mortality rate was lower in alcoholic hepatitis patients with MDF scores of at least 32 or hepatic encephalopathy who were treated with corticosteroids than in controls (relative risk 0.37, 95% confidence interval 0.16–0.86).

Therefore, in the absence of contraindications, the AASLD recommends starting corticosteroids in patients with severe alcoholic hepatitis, defined as an MDF score of 32 or higher.²¹ The preferred agent is oral prednisolone 40 mg daily or parenteral methylprednisolone 32 mg daily for 4 weeks and then tapered over the next 2 to 4 weeks or abruptly discontinued. Because activation of prednisone is decreased in patients with liver disease, prednisolone (the active form) is preferred over prednisone (the inactive precursor).³⁵ In alcoholic hepatitis, the number needed to treat with corticosteroids to prevent one death has been calculated³⁶ at 5.

As mentioned, response to corticosteroids is commonly assessed at 1 week of treatment using the Lille score. A score higher than 0.45 predicts a poor response and should trigger discontinuation of corticosteroids, particularly in those classified as null responders (Lille score > 0.56).

Typical biochemical derangements include elevated AST and, to a lesser extent, ALT

Adverse effects of steroids include sepsis, gastrointestinal bleeding, and steroid psychosis. Of note, patients who have evidence of hepatorenal syndrome or gastrointestinal bleeding tend to have a less favorable response to corticosteroids. Also, while infections were once considered a contraindication to steroid therapy, recent evidence suggests that steroid use might not be precluded in infected patients after appropriate antibiotic therapy. Infections occur in about a quarter of all alcoholic hepatitis patients treated with steroids, more frequently in null responders (42.5%) than in responders (11.1%), which supports corticosteroid discontinuance at 1 week in null responders.³²

Pentoxifylline

An oral phosphodiesterase inhibitor, pentoxifylline, also inhibits production of several cytokines, including tumor necrosis factor alpha. At a dose of 400 mg orally three times daily for 4 weeks, pentoxifylline has been used in treating severe alcoholic hepatitis (MDF score ≥ 32) and is recommended especially if corticosteroids are contraindicated, as with sepsis.²¹

An early double-blind clinical trial randomized patients with severe alcoholic hepatitis to receive either pentoxifylline 400 mg orally three times daily or placebo. Of the patients who received pentoxifylline, 24.5% died during the index hospitalization, compared with 46.1% of patients who received placebo. This survival benefit was mainly related to a markedly lower incidence of hepatorenal syndrome as the cause of death in the pentoxifylline group than in the placebo group (50% vs 91.7% of deaths).³⁷

In a small clinical trial in patients with severe alcoholic hepatitis, pentoxifylline recipients had a higher 3-month survival rate than prednisolone recipients (35.29% vs 14.71%, P = .04).³⁸ However, a larger trial showed no improvement in 6-month survival with the combination of prednisolone and pentoxifylline compared with prednisolone alone (69.9% vs 69.2%, P = .91).³⁹ Also, a meta-analysis of five randomized clinical trials found no survival benefit with pentoxifylline therapy.⁴⁰

Of note, in the unfortunate subgroup of patients who have a poor response to corticosteroids, no alternative treatment, including pentoxifylline, has been shown to be effective.⁴¹

Prednisone or pentoxifylline? Very recently, results of the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial have been released.⁴² This is a large, multicenter, double-blinded clinical trial that aimed to provide a definitive answer to whether corticosteroids or pentoxifylline (or both) are beneficial in patients with alcoholic hepatitis. The study included 1,103 adult patients with severe alcoholic hepatitis (MDF score ≥ 32) who were randomized to monotherapy with prednisolone or pentoxifylline, combination therapy, or placebo. The primary end point was mortality at 28 days, and secondary end points included mortality at 90 days and at 1 year. Prednisolone reduced 28-day mortality by about 39%. In contrast, the 28-day mortality rate was similar in patients who received pentoxifylline and those who did not. Also, neither drug was significantly associated with a survival benefit beyond 28 days. The investigators concluded that pentoxifylline has no impact on disease progression and should not be used for the treatment of severe alcoholic hepatitis.⁴²

Other tumor necrosis factor alpha inhibitors not recommended

Two other tumor necrosis factor alpha inhibitors, infliximab and etanercept, have been tested in clinical trials in alcoholic hepatitis. Unfortunately, the results were not encouraging, with no major reduction in mortality.^43–45 In fact, these trials demonstrated a significantly increased risk of infections in the treatment groups. Therefore, these drugs are not recommended for treating alcoholic hepatitis.

A possible explanation is that tumor necrosis factor alpha plays an important role in liver regeneration, aiding in recovery from alcohol-induced liver injury, and inhibiting it can have deleterious consequences.

Other agents

A number of other agents have undergone clinical trials in alcoholic hepatitis.

N-acetylcysteine, an antioxidant that replenishes glutathione stores in hepatocytes, was evaluated in a randomized clinical trial in combination with prednisolone.⁴⁶ Although the 1-month mortality rate was significantly lower in the combination group than in the prednisolone-only group (8% vs 24%, P = .006), 3-month and 6-month mortality rates were not. Nonetheless, the rates of infection and hepatorenal syndrome were lower in the combination group. Therefore, corticosteroids and N-acetylcysteine may have synergistic effects, but the optimum duration of N-acetylcysteine therapy needs to be determined in further studies.

Vitamin E, silymarin, propylthiouracil, colchicine, and oxandrolone (an anabolic steroid) have also been studied, but with no convincing benefit.²¹

Role of liver transplantation

Liver transplantation for alcoholic liver disease has been a topic of great medical and social controversy. The view that alcoholic patients are responsible for their own illness led to caution when contemplating liver transplantation. Many countries require 6 months of abstinence from alcohol before placing a patient on the liver transplant list, posing a major obstacle to patients with alcoholic hepatitis, as almost all are active drinkers at the time of presentation and many will die within 6 months. Reasons for this 6-month rule include donor shortage and risk of recidivism.⁴⁷

Abstinence from alcohol is the cornerstone of treatment of alcoholic hepatitis

With regard to survival following alcoholic hepatitis, a study utilizing the United Network for Organ Sharing database matched patients with alcoholic hepatitis and alcoholic cirrhosis who underwent liver transplantation. Rates of 5-year graft survival were 75% in those with alcoholic hepatitis and 73% in those with alcoholic cirrhosis (P = .97), and rates of patient survival were 80% and 78% (P = .90), respectively. Proportional regression analysis adjusting for other variables showed no impact of the etiology of liver disease on graft or patient survival. The investigators concluded that liver transplantation could be considered in a select group of patients with alcoholic hepatitis who do not improve with medical therapy.⁴⁸

In a pivotal case-control prospective study,⁴⁹ 26 patients with Lille scores greater than 0.45 were listed for liver transplantation within a median of 13 days after nonresponse to medical therapy. The cumulative 6-month survival rate was higher in patients who received a liver transplant early than in those who did not (77% vs 23%, P < .001). This benefit was maintained through 2 years of follow-up (hazard ratio 6.08, P = .004). Of note, all these patients had supportive family members, no severe coexisting conditions, and a commitment to alcohol abstinence (although 3 patients resumed drinking after liver transplantation).⁴⁹

Although these studies support early liver transplantation in carefully selected patients with severe alcoholic hepatitis, the criteria for transplantation in this group need to be refined. Views on alcoholism also need to be reconciled, as strong evidence is emerging that implicates genetic and environmental influences on alcohol dependence.

Management algorithm

Adapted from the guidelines of the AASLD and European Association for the Study of the Liver.

Figure 2 shows a suggested management algorithm for alcoholic hepatitis, adapted from the guidelines of the AASLD and European Association for the Study of the Liver.

NEW THERAPIES NEEDED

Novel therapies for severe alcoholic hepatitis are urgently needed to help combat this devastating condition. Advances in understanding its pathophysiology have uncovered several new therapeutic targets, and new agents are already being evaluated in clinical trials.

IMM 124-E, a hyperimmune bovine colostrum enriched with immunoglobulin G anti-lipopolysaccharide, is going to be evaluated in combination with prednisolone in patients with severe alcoholic hepatitis.

Anakinra, an interleukin 1 receptor antagonist, has significant anti-inflammatory activity and is used to treat rheumatoid arthritis. A clinical trial to evaluate its role in alcoholic hepatitis has been designed in which patients with severe alcoholic hepatitis (defined as a MELD score ≥ 21) will be randomized to receive either methylprednisolone or a combination of anakinra, pentoxifylline, and zinc (a mineral that improves gut integrity).

Emricasan, an orally active caspase protease inhibitor, is another agent currently being tested in a phase 2 clinical trial in patients with severe alcoholic hepatitis. Since caspases induce apoptosis, inhibiting them should theoretically dampen alcohol-induced hepatocyte injury.

Interleukin 22, a hepatoprotective cytokine, shows promise as a treatment and will soon be evaluated in alcoholic hepatitis.

A 22-year-old woman with a 1-year history of mild systemic lupus erythematosus presented with disproportionately severe constitutional symptoms of fatigue and malaise. Physical examination showed multiple follicular-based hyperkeratotic papules with coiled “corkscrew” hairs on the outer surface of the arms and on the front of the legs (Figure 1).  The patient reported a diet consisting mainly of white meat and processed foods. Although levels of serum folate, ferritin, zinc, and vitamins A, B₁, B₂, B₆, B₁₂, D, and E were within normal limits, the serum ascorbic acid level was low at 0.2 mg/dL (reference range 0.6–2.0 mg/dL). Ascorbic acid supplementation and dietary modification were recommended.

Ascorbic acid deficiency, or scurvy, is often considered a disease primarily of historical significance, with occurrences today limited to malnutrition or poverty.¹ However, 18% of adults in the United States consume less than the recommend daily allowance of ascorbic acid.² Ascorbic acid is minimally stored in the body,³ and scurvy can develop after 60 to 90 days of a diet free of ascorbic acid.⁴

Initial symptoms of fatigue, mood changes, and other constitutional symptoms are nonspecific, leading to a delay in diagnosis. Cutaneous manifestations include follicular hyperkeratosis associated with coiled or “corkscrew” hairs. Fragility of cutaneous blood vessels leads to perifollicular hemorrhages, petechiae, purpura, and ecchymoses. Extracutaneous manifestations are diverse and include oral involvement and intramuscular or intra-articular hemorrhage.¹ Clinicians should have a high index of suspicion in socially isolated adults, elderly patients, those with alcoholism, mental illness, or chronic illness, and those with restrictive dietary preferences, particularly with predominant intake of processed foods.⁵

A 22-year-old woman with a 1-year history of mild systemic lupus erythematosus presented with disproportionately severe constitutional symptoms of fatigue and malaise. Physical examination showed multiple follicular-based hyperkeratotic papules with coiled “corkscrew” hairs on the outer surface of the arms and on the front of the legs (Figure 1).  The patient reported a diet consisting mainly of white meat and processed foods. Although levels of serum folate, ferritin, zinc, and vitamins A, B₁, B₂, B₆, B₁₂, D, and E were within normal limits, the serum ascorbic acid level was low at 0.2 mg/dL (reference range 0.6–2.0 mg/dL). Ascorbic acid supplementation and dietary modification were recommended.

Ascorbic acid deficiency, or scurvy, is often considered a disease primarily of historical significance, with occurrences today limited to malnutrition or poverty.¹ However, 18% of adults in the United States consume less than the recommend daily allowance of ascorbic acid.² Ascorbic acid is minimally stored in the body,³ and scurvy can develop after 60 to 90 days of a diet free of ascorbic acid.⁴

Initial symptoms of fatigue, mood changes, and other constitutional symptoms are nonspecific, leading to a delay in diagnosis. Cutaneous manifestations include follicular hyperkeratosis associated with coiled or “corkscrew” hairs. Fragility of cutaneous blood vessels leads to perifollicular hemorrhages, petechiae, purpura, and ecchymoses. Extracutaneous manifestations are diverse and include oral involvement and intramuscular or intra-articular hemorrhage.¹ Clinicians should have a high index of suspicion in socially isolated adults, elderly patients, those with alcoholism, mental illness, or chronic illness, and those with restrictive dietary preferences, particularly with predominant intake of processed foods.⁵

A 22-year-old woman with a 1-year history of mild systemic lupus erythematosus presented with disproportionately severe constitutional symptoms of fatigue and malaise. Physical examination showed multiple follicular-based hyperkeratotic papules with coiled “corkscrew” hairs on the outer surface of the arms and on the front of the legs (Figure 1).  The patient reported a diet consisting mainly of white meat and processed foods. Although levels of serum folate, ferritin, zinc, and vitamins A, B₁, B₂, B₆, B₁₂, D, and E were within normal limits, the serum ascorbic acid level was low at 0.2 mg/dL (reference range 0.6–2.0 mg/dL). Ascorbic acid supplementation and dietary modification were recommended.

Ascorbic acid deficiency, or scurvy, is often considered a disease primarily of historical significance, with occurrences today limited to malnutrition or poverty.¹ However, 18% of adults in the United States consume less than the recommend daily allowance of ascorbic acid.² Ascorbic acid is minimally stored in the body,³ and scurvy can develop after 60 to 90 days of a diet free of ascorbic acid.⁴

Initial symptoms of fatigue, mood changes, and other constitutional symptoms are nonspecific, leading to a delay in diagnosis. Cutaneous manifestations include follicular hyperkeratosis associated with coiled or “corkscrew” hairs. Fragility of cutaneous blood vessels leads to perifollicular hemorrhages, petechiae, purpura, and ecchymoses. Extracutaneous manifestations are diverse and include oral involvement and intramuscular or intra-articular hemorrhage.¹ Clinicians should have a high index of suspicion in socially isolated adults, elderly patients, those with alcoholism, mental illness, or chronic illness, and those with restrictive dietary preferences, particularly with predominant intake of processed foods.⁵

Yes. Growing evidence demonstrates that the human papillomavirus (HPV) DNA test is more sensitive than the Papanicolaou (Pap) test, with a better negative predictive value—ie, women who have negative test results can be more certain that they are truly free of cervical cancer.^1–3

On April 24, 2014, the US Food and Drug Administration (FDA) approved the Cobas HPV test developed by Roche for use as the first-line screening test for cervical cancer in women age 25 and older.⁴ The approval follows the unanimous recommendation from an independent panel of experts, the Microbiology Devices Panel of the FDA’s Medical Devices Advisory Committee, on March 12, 2014.

PAP-HPV COTESTING IS EFFECTIVE BUT NOT PERFECT

Based on conclusive evidence of a direct link between HPV infection (specifically, infection with certain high-risk HPV genotypes) and almost all cases of invasive cervical cancer,^5,6 the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), American Society for Clinical Pathology (ASCP), US Preventive Services Task Force (USPSTF), and American Congress of Obstetricians and Gynecologists (ACOG) issued a consensus recommendation for Pap-HPV cotesting as the preferred screening strategy starting at age 30 and continuing through age 65.^7–9

Compared with Pap testing alone, cotesting offers improved detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and the ability to safely extend the screening interval to every 5 years in women who have negative results on both tests. It is an effective screening strategy and remains the standard of care today.

However, this strategy is not perfect and presents several problems for clinicians. The results of the two tests often conflict—the results of the Pap test might be positive while those of the HPV test are negative, or vice versa. Integrating the results of cotesting into triaging can be confusing and complicated. In addition, performing two tests on all women increases the cost of care. And furthermore, the cotesting strategy increases the number of women who require immediate or short-term follow-up,^1,2,10–12 such as colposcopy, which is unnecessary for many.

THE HPV TEST DETECTS 14 HIGH-RISK GENOTYPES

The FDA-approved HPV test detects 14 high-risk genotypes. The results for 12 of these are pooled and reported collectively as either positive or negative, while the other two—HPV 16 and HPV 18—are reported separately. (HPV 16 and HPV 18 are the highest-risk genotypes, and together they account for more than two-thirds of cases of invasive cervical cancer.)

ADVANTAGES OF HPV-ONLY TESTING: FINDINGS FROM THE ATHENA TRIAL

The FDA’s decision to approve the Cobas HPV test for use by itself for screening was based on the landmark ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial.¹³ ATHENA, the largest prospective study of cervical cancer screening performed in the United States to date, enrolled 47,208 women at 61 sites in 23 states. The study revealed the following findings:

The FDA has approved the test for this indication, and guideline committees are reviewing the data

• The HPV DNA test had higher sensitivity for detecting CIN3+ (37% higher than the Pap test) and equivalent specificity.
• The HPV test’s positive predictive value was nearly twice as high (12.25% vs 6.47%), and it had a higher negative predictive value (99.58% vs 99.41%) in detecting CIN3+ than with the Pap test.
• HPV testing by itself performed better than Pap-HPV cotesting, with positive predictive values of 12.25% vs 11.04% and negative predictive values of 99.58% vs 99.52% (data presented to the FDA Medical Devices Advisory Committee, Microbiology Panel. March 12, 2014. FDA Executive Summary).

For women whose results were negative for HPV 16 and 18 but positive for the 12-genotype pooled panel, the sample was automatically submitted for cytologic (Pap) testing. Reserving Pap testing for samples in this category improved the specificity of the test and resulted in fewer colposcopy referrals. The ATHENA researchers found that 11.4% of the participants who tested positive for either HPV 16 or 18 had CIN2+.¹³ Other large cohort studies^14,15 also showed that the short-term risk of developing CIN3+ reached 10% over 1 to 5 years in women who tested positive for HPV 16 or 18.

The proposed algorithm for screening (Figure 1) takes advantage of the superior sensitivity of the HPV test, the built-in risk stratification of HPV 16 and 18 genotyping, and the excellent specificity of the Pap test in triaging women whose results are positive for high-risk HPV genotypes other than HPV 16 and 18. Thus, women who have a negative HPV test result can be assured of remaining disease-free for 3 years. The algorithm also identifies women who are at highest risk, ie, those who test positive for HPV 16 or 18. In contrast, the current cotesting approach uses the Qiagen Hybrid Capture HPV testing system, which is a panel of 13 high-risk genotypes, but, if the result is positive, it does not tell you which one the patient has. Furthermore, the new algorithm provides efficient triage, using the Pap test, for women who test positive for the 12 other high-risk HPV genotypes.

Data from large clinical trials other than ATHENA are limited.

FDA APPROVAL DOES NOT CHANGE THE GUIDELINES—YET

The cervical cancer screening guidelines are developed by several organizations other than the FDA. The current guidelines issued by the ACS, ASCCP, ASCP, USPSTF, and ACOG in 2012 call for Pap testing every 3 years in women younger than 30 and Pap-HPV cotesting every 5 years in women ages 30 to 65.^7–9 However, FDA approval of the new indication of the HPV DNA test as a stand-alone first-line screening test is an important milestone. It heralds the shifting of the practice paradigm from morphologically based Pap testing to molecular testing in cervical cancer screening.

The ACS and ASCCP have announced that they are reviewing the evidence and may issue updated guidelines for clinicians in the near future.^16,17 We anticipate that other organizations may take similar steps. As primary care physicians, we need to stay tuned and follow the most up-to-date evidence-based practice guidelines to provide the best care for our patients.

Yes. Growing evidence demonstrates that the human papillomavirus (HPV) DNA test is more sensitive than the Papanicolaou (Pap) test, with a better negative predictive value—ie, women who have negative test results can be more certain that they are truly free of cervical cancer.^1–3

On April 24, 2014, the US Food and Drug Administration (FDA) approved the Cobas HPV test developed by Roche for use as the first-line screening test for cervical cancer in women age 25 and older.⁴ The approval follows the unanimous recommendation from an independent panel of experts, the Microbiology Devices Panel of the FDA’s Medical Devices Advisory Committee, on March 12, 2014.

PAP-HPV COTESTING IS EFFECTIVE BUT NOT PERFECT

Based on conclusive evidence of a direct link between HPV infection (specifically, infection with certain high-risk HPV genotypes) and almost all cases of invasive cervical cancer,^5,6 the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), American Society for Clinical Pathology (ASCP), US Preventive Services Task Force (USPSTF), and American Congress of Obstetricians and Gynecologists (ACOG) issued a consensus recommendation for Pap-HPV cotesting as the preferred screening strategy starting at age 30 and continuing through age 65.^7–9

Compared with Pap testing alone, cotesting offers improved detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and the ability to safely extend the screening interval to every 5 years in women who have negative results on both tests. It is an effective screening strategy and remains the standard of care today.

However, this strategy is not perfect and presents several problems for clinicians. The results of the two tests often conflict—the results of the Pap test might be positive while those of the HPV test are negative, or vice versa. Integrating the results of cotesting into triaging can be confusing and complicated. In addition, performing two tests on all women increases the cost of care. And furthermore, the cotesting strategy increases the number of women who require immediate or short-term follow-up,^1,2,10–12 such as colposcopy, which is unnecessary for many.

THE HPV TEST DETECTS 14 HIGH-RISK GENOTYPES

The FDA-approved HPV test detects 14 high-risk genotypes. The results for 12 of these are pooled and reported collectively as either positive or negative, while the other two—HPV 16 and HPV 18—are reported separately. (HPV 16 and HPV 18 are the highest-risk genotypes, and together they account for more than two-thirds of cases of invasive cervical cancer.)

ADVANTAGES OF HPV-ONLY TESTING: FINDINGS FROM THE ATHENA TRIAL

The FDA’s decision to approve the Cobas HPV test for use by itself for screening was based on the landmark ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial.¹³ ATHENA, the largest prospective study of cervical cancer screening performed in the United States to date, enrolled 47,208 women at 61 sites in 23 states. The study revealed the following findings:

The FDA has approved the test for this indication, and guideline committees are reviewing the data

• The HPV DNA test had higher sensitivity for detecting CIN3+ (37% higher than the Pap test) and equivalent specificity.
• The HPV test’s positive predictive value was nearly twice as high (12.25% vs 6.47%), and it had a higher negative predictive value (99.58% vs 99.41%) in detecting CIN3+ than with the Pap test.
• HPV testing by itself performed better than Pap-HPV cotesting, with positive predictive values of 12.25% vs 11.04% and negative predictive values of 99.58% vs 99.52% (data presented to the FDA Medical Devices Advisory Committee, Microbiology Panel. March 12, 2014. FDA Executive Summary).

For women whose results were negative for HPV 16 and 18 but positive for the 12-genotype pooled panel, the sample was automatically submitted for cytologic (Pap) testing. Reserving Pap testing for samples in this category improved the specificity of the test and resulted in fewer colposcopy referrals. The ATHENA researchers found that 11.4% of the participants who tested positive for either HPV 16 or 18 had CIN2+.¹³ Other large cohort studies^14,15 also showed that the short-term risk of developing CIN3+ reached 10% over 1 to 5 years in women who tested positive for HPV 16 or 18.

The proposed algorithm for screening (Figure 1) takes advantage of the superior sensitivity of the HPV test, the built-in risk stratification of HPV 16 and 18 genotyping, and the excellent specificity of the Pap test in triaging women whose results are positive for high-risk HPV genotypes other than HPV 16 and 18. Thus, women who have a negative HPV test result can be assured of remaining disease-free for 3 years. The algorithm also identifies women who are at highest risk, ie, those who test positive for HPV 16 or 18. In contrast, the current cotesting approach uses the Qiagen Hybrid Capture HPV testing system, which is a panel of 13 high-risk genotypes, but, if the result is positive, it does not tell you which one the patient has. Furthermore, the new algorithm provides efficient triage, using the Pap test, for women who test positive for the 12 other high-risk HPV genotypes.

Data from large clinical trials other than ATHENA are limited.

FDA APPROVAL DOES NOT CHANGE THE GUIDELINES—YET

The cervical cancer screening guidelines are developed by several organizations other than the FDA. The current guidelines issued by the ACS, ASCCP, ASCP, USPSTF, and ACOG in 2012 call for Pap testing every 3 years in women younger than 30 and Pap-HPV cotesting every 5 years in women ages 30 to 65.^7–9 However, FDA approval of the new indication of the HPV DNA test as a stand-alone first-line screening test is an important milestone. It heralds the shifting of the practice paradigm from morphologically based Pap testing to molecular testing in cervical cancer screening.

The ACS and ASCCP have announced that they are reviewing the evidence and may issue updated guidelines for clinicians in the near future.^16,17 We anticipate that other organizations may take similar steps. As primary care physicians, we need to stay tuned and follow the most up-to-date evidence-based practice guidelines to provide the best care for our patients.

Yes. Growing evidence demonstrates that the human papillomavirus (HPV) DNA test is more sensitive than the Papanicolaou (Pap) test, with a better negative predictive value—ie, women who have negative test results can be more certain that they are truly free of cervical cancer.^1–3

On April 24, 2014, the US Food and Drug Administration (FDA) approved the Cobas HPV test developed by Roche for use as the first-line screening test for cervical cancer in women age 25 and older.⁴ The approval follows the unanimous recommendation from an independent panel of experts, the Microbiology Devices Panel of the FDA’s Medical Devices Advisory Committee, on March 12, 2014.

PAP-HPV COTESTING IS EFFECTIVE BUT NOT PERFECT

Based on conclusive evidence of a direct link between HPV infection (specifically, infection with certain high-risk HPV genotypes) and almost all cases of invasive cervical cancer,^5,6 the American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), American Society for Clinical Pathology (ASCP), US Preventive Services Task Force (USPSTF), and American Congress of Obstetricians and Gynecologists (ACOG) issued a consensus recommendation for Pap-HPV cotesting as the preferred screening strategy starting at age 30 and continuing through age 65.^7–9

Compared with Pap testing alone, cotesting offers improved detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and the ability to safely extend the screening interval to every 5 years in women who have negative results on both tests. It is an effective screening strategy and remains the standard of care today.

However, this strategy is not perfect and presents several problems for clinicians. The results of the two tests often conflict—the results of the Pap test might be positive while those of the HPV test are negative, or vice versa. Integrating the results of cotesting into triaging can be confusing and complicated. In addition, performing two tests on all women increases the cost of care. And furthermore, the cotesting strategy increases the number of women who require immediate or short-term follow-up,^1,2,10–12 such as colposcopy, which is unnecessary for many.

THE HPV TEST DETECTS 14 HIGH-RISK GENOTYPES

The FDA-approved HPV test detects 14 high-risk genotypes. The results for 12 of these are pooled and reported collectively as either positive or negative, while the other two—HPV 16 and HPV 18—are reported separately. (HPV 16 and HPV 18 are the highest-risk genotypes, and together they account for more than two-thirds of cases of invasive cervical cancer.)

ADVANTAGES OF HPV-ONLY TESTING: FINDINGS FROM THE ATHENA TRIAL

The FDA’s decision to approve the Cobas HPV test for use by itself for screening was based on the landmark ATHENA (Addressing the Need for Advanced HPV Diagnostics) trial.¹³ ATHENA, the largest prospective study of cervical cancer screening performed in the United States to date, enrolled 47,208 women at 61 sites in 23 states. The study revealed the following findings:

The FDA has approved the test for this indication, and guideline committees are reviewing the data

• The HPV DNA test had higher sensitivity for detecting CIN3+ (37% higher than the Pap test) and equivalent specificity.
• The HPV test’s positive predictive value was nearly twice as high (12.25% vs 6.47%), and it had a higher negative predictive value (99.58% vs 99.41%) in detecting CIN3+ than with the Pap test.
• HPV testing by itself performed better than Pap-HPV cotesting, with positive predictive values of 12.25% vs 11.04% and negative predictive values of 99.58% vs 99.52% (data presented to the FDA Medical Devices Advisory Committee, Microbiology Panel. March 12, 2014. FDA Executive Summary).

For women whose results were negative for HPV 16 and 18 but positive for the 12-genotype pooled panel, the sample was automatically submitted for cytologic (Pap) testing. Reserving Pap testing for samples in this category improved the specificity of the test and resulted in fewer colposcopy referrals. The ATHENA researchers found that 11.4% of the participants who tested positive for either HPV 16 or 18 had CIN2+.¹³ Other large cohort studies^14,15 also showed that the short-term risk of developing CIN3+ reached 10% over 1 to 5 years in women who tested positive for HPV 16 or 18.

The proposed algorithm for screening (Figure 1) takes advantage of the superior sensitivity of the HPV test, the built-in risk stratification of HPV 16 and 18 genotyping, and the excellent specificity of the Pap test in triaging women whose results are positive for high-risk HPV genotypes other than HPV 16 and 18. Thus, women who have a negative HPV test result can be assured of remaining disease-free for 3 years. The algorithm also identifies women who are at highest risk, ie, those who test positive for HPV 16 or 18. In contrast, the current cotesting approach uses the Qiagen Hybrid Capture HPV testing system, which is a panel of 13 high-risk genotypes, but, if the result is positive, it does not tell you which one the patient has. Furthermore, the new algorithm provides efficient triage, using the Pap test, for women who test positive for the 12 other high-risk HPV genotypes.

Data from large clinical trials other than ATHENA are limited.

FDA APPROVAL DOES NOT CHANGE THE GUIDELINES—YET

The cervical cancer screening guidelines are developed by several organizations other than the FDA. The current guidelines issued by the ACS, ASCCP, ASCP, USPSTF, and ACOG in 2012 call for Pap testing every 3 years in women younger than 30 and Pap-HPV cotesting every 5 years in women ages 30 to 65.^7–9 However, FDA approval of the new indication of the HPV DNA test as a stand-alone first-line screening test is an important milestone. It heralds the shifting of the practice paradigm from morphologically based Pap testing to molecular testing in cervical cancer screening.

The ACS and ASCCP have announced that they are reviewing the evidence and may issue updated guidelines for clinicians in the near future.^16,17 We anticipate that other organizations may take similar steps. As primary care physicians, we need to stay tuned and follow the most up-to-date evidence-based practice guidelines to provide the best care for our patients.

A 44-year-old man presented with a 3-week history of a painless, nonhealing ulcer affecting the mucosa in the right angle of the mouth. He reported no fever, weight loss, or systemic symptoms of chronic disease. His medical history included chronic hepatitis C infection and human immunodeficiency virus (HIV) infection; his antiretroviral regimen for HIV was abacavir, lamivudine, and darunavir. His CD4+ T-cell count was 153 cells/mm³, and his viral load was 154.88 copies/mL. He formerly used injected drugs, and he currently smoked 20 cigarettes a day. He had no history of periodontal disease.

Oral examination showed poor oral hygiene and a solitary ulcerated lesion with an infiltrated base and indurated borders in the right oral commissure (Figure 1). There was also soft-tissue induration in the ipsilateral cheek. He had no other oral lesions or signs of neck lymphadenopathy.

Based on the clinical examination, a provisional diagnosis of malignancy was suspected, and an incisional biopsy of the ulcer was done. The findings on histopathologic study of the biopsy specimen (below; Figure 2) led to additional evaluation with chest radiography and thoracic computed tomography (Figure 3).

FURTHER WORKUP

Histologic study of the biopsy specimen showed ulcerated mucosa with extensive granulomatous inflammation and with caseation necrosis. Ziehl-Neelsen staining demonstrated a few acid-fast bacilli. The patient was then evaluated for pulmonary tuberculosis.

Chest radiography showed pulmonary infiltrates in both bases and the upper right lobe and cavitation in the upper left lobe. Thoracic computed tomography confirmed the presence of multiple cavitated lesions in both left and right lung fields. Sputum cultures were positive for Mycobacterium tuberculosis, an organism sensitive to several agents. Laboratory investigations that included blood cell counts, biochemical tests, and liver and kidney function tests were normal, with the exception of a low lymphocyte count.

ORAL TUBERCULOSIS SECONDARY TO ACTIVE PULMONARY TUBERCULOSIS

Even though the incidence of extrapulmonary tuberculosis has been increasing worldwide in recent years, cutaneous manifestations are uncommon (2% to 10%) and are seen mainly in immunosuppressed patients with coexisting tuberculosis infection of internal organs.¹ Oral manifestations of tuberculosis are extremely rare, accounting for 2% of cases of cutaneous manifestations.^1,2 For this reason and because of its clinical heterogeneity, oral tuberculosis is often not considered in the differential diagnosis of oral lesions.

The differential diagnosis of oral ulcers in patients with HIV includes adverse drug reactions (eg, nevirapine-induced Stevens-Johnson syndrome); oral ulcers and necrotizing gingivitis related to HIV-associated neutropenia; aphthous ulcers; oral ulcers in reactive arthritis; malignancies such as lymphoma, Kaposi sarcoma, and squamous cell carcinoma; and infections such as candidiasis, herpes simplex virus, cytomegalovirus, primary syphilis, mucosal leishmaniasis, histoplasmosis, and periorificial tuberculosis. Periorificial tuberculosis is more commonly seen in HIV patients, in whom extrapulmonary forms of tuberculosis are frequent.³

Oral tuberculosis is often mistaken for a malignancy such as squamous cell carcinoma; in fact, carcinoma coexists with tubercular ulcer in up to 3% of patients.² The typical clinical presentation of oral tuberculosis is one or more painful or painless ulcers with irregular borders, usually localized on the tongue (nearly half of cases⁴), and less frequently affecting the lip, buccal mucosa, gingiva, soft palate, and extraction sockets. It can also present as a nodule, fissure, vesicle, tuberculoma, tubercular papilloma, or periapical granuloma.^2,5

Oral tuberculosis may be primary but is more commonly secondary to internal-organ tuberculosis. Secondary disease is seen in patients with pulmonary forms (affecting 0.05% to 1.5% of patients with pulmonary tuberculosis^1,2) because of autoinoculation by infected sputum or hematogenous spread.^1,4,5

Clinicians should consider oral tuberculosis in the differential diagnosis of a nonhealing ulcer of the mouth, particularly in an immunosuppressed patient such as ours. It is also important to highlight the necessity of searching for a primary site of infection, more frequently in the lungs.

A 44-year-old man presented with a 3-week history of a painless, nonhealing ulcer affecting the mucosa in the right angle of the mouth. He reported no fever, weight loss, or systemic symptoms of chronic disease. His medical history included chronic hepatitis C infection and human immunodeficiency virus (HIV) infection; his antiretroviral regimen for HIV was abacavir, lamivudine, and darunavir. His CD4+ T-cell count was 153 cells/mm³, and his viral load was 154.88 copies/mL. He formerly used injected drugs, and he currently smoked 20 cigarettes a day. He had no history of periodontal disease.

Oral examination showed poor oral hygiene and a solitary ulcerated lesion with an infiltrated base and indurated borders in the right oral commissure (Figure 1). There was also soft-tissue induration in the ipsilateral cheek. He had no other oral lesions or signs of neck lymphadenopathy.

Based on the clinical examination, a provisional diagnosis of malignancy was suspected, and an incisional biopsy of the ulcer was done. The findings on histopathologic study of the biopsy specimen (below; Figure 2) led to additional evaluation with chest radiography and thoracic computed tomography (Figure 3).

FURTHER WORKUP

Histologic study of the biopsy specimen showed ulcerated mucosa with extensive granulomatous inflammation and with caseation necrosis. Ziehl-Neelsen staining demonstrated a few acid-fast bacilli. The patient was then evaluated for pulmonary tuberculosis.

Chest radiography showed pulmonary infiltrates in both bases and the upper right lobe and cavitation in the upper left lobe. Thoracic computed tomography confirmed the presence of multiple cavitated lesions in both left and right lung fields. Sputum cultures were positive for Mycobacterium tuberculosis, an organism sensitive to several agents. Laboratory investigations that included blood cell counts, biochemical tests, and liver and kidney function tests were normal, with the exception of a low lymphocyte count.

ORAL TUBERCULOSIS SECONDARY TO ACTIVE PULMONARY TUBERCULOSIS

Even though the incidence of extrapulmonary tuberculosis has been increasing worldwide in recent years, cutaneous manifestations are uncommon (2% to 10%) and are seen mainly in immunosuppressed patients with coexisting tuberculosis infection of internal organs.¹ Oral manifestations of tuberculosis are extremely rare, accounting for 2% of cases of cutaneous manifestations.^1,2 For this reason and because of its clinical heterogeneity, oral tuberculosis is often not considered in the differential diagnosis of oral lesions.

The differential diagnosis of oral ulcers in patients with HIV includes adverse drug reactions (eg, nevirapine-induced Stevens-Johnson syndrome); oral ulcers and necrotizing gingivitis related to HIV-associated neutropenia; aphthous ulcers; oral ulcers in reactive arthritis; malignancies such as lymphoma, Kaposi sarcoma, and squamous cell carcinoma; and infections such as candidiasis, herpes simplex virus, cytomegalovirus, primary syphilis, mucosal leishmaniasis, histoplasmosis, and periorificial tuberculosis. Periorificial tuberculosis is more commonly seen in HIV patients, in whom extrapulmonary forms of tuberculosis are frequent.³

Oral tuberculosis is often mistaken for a malignancy such as squamous cell carcinoma; in fact, carcinoma coexists with tubercular ulcer in up to 3% of patients.² The typical clinical presentation of oral tuberculosis is one or more painful or painless ulcers with irregular borders, usually localized on the tongue (nearly half of cases⁴), and less frequently affecting the lip, buccal mucosa, gingiva, soft palate, and extraction sockets. It can also present as a nodule, fissure, vesicle, tuberculoma, tubercular papilloma, or periapical granuloma.^2,5

Oral tuberculosis may be primary but is more commonly secondary to internal-organ tuberculosis. Secondary disease is seen in patients with pulmonary forms (affecting 0.05% to 1.5% of patients with pulmonary tuberculosis^1,2) because of autoinoculation by infected sputum or hematogenous spread.^1,4,5

Clinicians should consider oral tuberculosis in the differential diagnosis of a nonhealing ulcer of the mouth, particularly in an immunosuppressed patient such as ours. It is also important to highlight the necessity of searching for a primary site of infection, more frequently in the lungs.

A 44-year-old man presented with a 3-week history of a painless, nonhealing ulcer affecting the mucosa in the right angle of the mouth. He reported no fever, weight loss, or systemic symptoms of chronic disease. His medical history included chronic hepatitis C infection and human immunodeficiency virus (HIV) infection; his antiretroviral regimen for HIV was abacavir, lamivudine, and darunavir. His CD4+ T-cell count was 153 cells/mm³, and his viral load was 154.88 copies/mL. He formerly used injected drugs, and he currently smoked 20 cigarettes a day. He had no history of periodontal disease.

Oral examination showed poor oral hygiene and a solitary ulcerated lesion with an infiltrated base and indurated borders in the right oral commissure (Figure 1). There was also soft-tissue induration in the ipsilateral cheek. He had no other oral lesions or signs of neck lymphadenopathy.

Based on the clinical examination, a provisional diagnosis of malignancy was suspected, and an incisional biopsy of the ulcer was done. The findings on histopathologic study of the biopsy specimen (below; Figure 2) led to additional evaluation with chest radiography and thoracic computed tomography (Figure 3).

FURTHER WORKUP

Histologic study of the biopsy specimen showed ulcerated mucosa with extensive granulomatous inflammation and with caseation necrosis. Ziehl-Neelsen staining demonstrated a few acid-fast bacilli. The patient was then evaluated for pulmonary tuberculosis.

Chest radiography showed pulmonary infiltrates in both bases and the upper right lobe and cavitation in the upper left lobe. Thoracic computed tomography confirmed the presence of multiple cavitated lesions in both left and right lung fields. Sputum cultures were positive for Mycobacterium tuberculosis, an organism sensitive to several agents. Laboratory investigations that included blood cell counts, biochemical tests, and liver and kidney function tests were normal, with the exception of a low lymphocyte count.

ORAL TUBERCULOSIS SECONDARY TO ACTIVE PULMONARY TUBERCULOSIS

Even though the incidence of extrapulmonary tuberculosis has been increasing worldwide in recent years, cutaneous manifestations are uncommon (2% to 10%) and are seen mainly in immunosuppressed patients with coexisting tuberculosis infection of internal organs.¹ Oral manifestations of tuberculosis are extremely rare, accounting for 2% of cases of cutaneous manifestations.^1,2 For this reason and because of its clinical heterogeneity, oral tuberculosis is often not considered in the differential diagnosis of oral lesions.

The differential diagnosis of oral ulcers in patients with HIV includes adverse drug reactions (eg, nevirapine-induced Stevens-Johnson syndrome); oral ulcers and necrotizing gingivitis related to HIV-associated neutropenia; aphthous ulcers; oral ulcers in reactive arthritis; malignancies such as lymphoma, Kaposi sarcoma, and squamous cell carcinoma; and infections such as candidiasis, herpes simplex virus, cytomegalovirus, primary syphilis, mucosal leishmaniasis, histoplasmosis, and periorificial tuberculosis. Periorificial tuberculosis is more commonly seen in HIV patients, in whom extrapulmonary forms of tuberculosis are frequent.³

Oral tuberculosis is often mistaken for a malignancy such as squamous cell carcinoma; in fact, carcinoma coexists with tubercular ulcer in up to 3% of patients.² The typical clinical presentation of oral tuberculosis is one or more painful or painless ulcers with irregular borders, usually localized on the tongue (nearly half of cases⁴), and less frequently affecting the lip, buccal mucosa, gingiva, soft palate, and extraction sockets. It can also present as a nodule, fissure, vesicle, tuberculoma, tubercular papilloma, or periapical granuloma.^2,5

Oral tuberculosis may be primary but is more commonly secondary to internal-organ tuberculosis. Secondary disease is seen in patients with pulmonary forms (affecting 0.05% to 1.5% of patients with pulmonary tuberculosis^1,2) because of autoinoculation by infected sputum or hematogenous spread.^1,4,5

Clinicians should consider oral tuberculosis in the differential diagnosis of a nonhealing ulcer of the mouth, particularly in an immunosuppressed patient such as ours. It is also important to highlight the necessity of searching for a primary site of infection, more frequently in the lungs.

An obese 50-year-old man with hypertension, hyperlipidemia, recently diagnosed diabetes, and a history of grand mal seizures presented to the emergency room complaining of skin rash for 1 week. He denied having fever, chills, myalgia, abdominal pain, visual changes, recent changes in medications, or contact with anyone with similar symptoms.

He was a smoker, with a history of 20 pack-years; he denied abusing alcohol and taking illicit drugs.

He had no family history of diabetes, peripheral vascular disease, or coronary artery disease. His medications included lisinopril, simvastatin, niacin, metformin, and phenytoin.

On physical examination, the lesions were small, reddish-yellow, nonpruritic tender papules covering the extensor surfaces of the knees, the forearms, the abdomen, and the back (Figure 1). Laboratory test results:

• Total cholesterol 1,045 mg/dL (reference range 100–199)
• Triglycerides 7,855 mg/dL (30–149)
• Thyroid-stimulating hormone 0.52 mIU/L (0.4–5.5)
• Fasting blood glucose 441 mg/dL (65–100)
• Hemoglobin A_1c 12.6% (4.0–6.0)
• Total protein 7.2 g/dL (6.0–8.4)
• Albumin 4 g/dL (3.5–5.0)
• Creatinine 1 mg/dL (0.70–1.40)
• Glomerular filtration rate 79 mL/min/1.73 m² (> 60)
• Urinalysis showed no proteinuria.

Histologic analysis of a lesion-biopsy specimen showed dermal foamy macrophages and loose lipids, which confirmed the suspicion of eruptive xanthoma.

The patient was started on strict glycemic and lipid control. Metformin and statin doses were increased and insulin was added. Three months later, laboratory results showed total cholesterol 128 mg/dL, triglycerides 164 mg/dL, fasting blood glucose 88 mg/dL, and hemoglobin A_1c 5.5%. This was accompanied by  marked improvement of the skin lesions (Figure  2).

CAUSES AND DIFFERENTIAL DIAGNOSIS

Eruptive xanthoma is a cutaneous disease most commonly arising over the extensor surfaces of the extremities and on the buttocks and shoulders, and it can be caused by high levels of serum triglycerides and uncontrolled diabetes mellitus.¹ Hypothyroidism, end-stage renal disease, and nephrotic syndrome can cause secondary hypertriglyceridemia,² which can cause eruptive xanthoma in severe cases. Patients with eruptive xanthoma may also have ophthalmologic and gastrointestinal involvement, such as lipemia retinalis (salmon-colored retina with creamy-white retinal vessels), abdominal pain, and hepatosplenomegaly.³

Other types of xanthoma associated with dyslipidemia include tuberous, tendinous, and plane xanthoma. Tuberous xanthoma is a firm, painless, deeper, red-yellow, larger nodular lesion, and the size may vary.⁴ Tendinous xanthoma is a slowly enlarging subcutaneous nodule typically located near tendons or ligaments in the hands, feet, and the Achilles tendon. Plane xanthoma is a flat papule or patch that can occur anywhere on the body.

Eruptive xanthoma most commonly arises over extensor surfaces of the extremities, and on the buttocks and shoulders

The differential diagnosis includes disseminated granuloma annulare, non-Langerhans cell histiocytosis (xanthoma disseminatum, micronodular form of juvenile xanthogranuloma), and generalized eruptive histiocytoma. Eruptive xanthoma is differentiated from disseminated granuloma annulare by the abundance of perivascular histiocytes and xanthomized histiocytes, the presence of lipid deposits, and the deposition of hyaluronic acid on the edges.⁵ Xanthoma disseminatum consists of numerous, small, red-brown papules that are evenly spread on the face, skin-folds, trunk, and proximal extremities.⁶ Juvenile xanthogranuloma occurs mostly in children and is characterized by discrete orange-yellow nodules, which commonly appear on the scalp, face, and upper trunk. It is in most cases a solitary lesion, but multiple lesions may occur.⁷ Lesions of generalized eruptive histiocytoma are firm, erythematous or brownish papules that appear in successive crops over the face, trunk, and proximal surfaces of the limbs.

TREATMENT

Treatment of eruptive xanthoma involves dietary restriction, exercise, and drug therapy to control the hyperlipidemia and the diabetes.² Early recognition and proper control of hypertriglyceridemia can prevent sequelae such as acute pancreatitis.³

An obese 50-year-old man with hypertension, hyperlipidemia, recently diagnosed diabetes, and a history of grand mal seizures presented to the emergency room complaining of skin rash for 1 week. He denied having fever, chills, myalgia, abdominal pain, visual changes, recent changes in medications, or contact with anyone with similar symptoms.

He was a smoker, with a history of 20 pack-years; he denied abusing alcohol and taking illicit drugs.

He had no family history of diabetes, peripheral vascular disease, or coronary artery disease. His medications included lisinopril, simvastatin, niacin, metformin, and phenytoin.

On physical examination, the lesions were small, reddish-yellow, nonpruritic tender papules covering the extensor surfaces of the knees, the forearms, the abdomen, and the back (Figure 1). Laboratory test results:

• Total cholesterol 1,045 mg/dL (reference range 100–199)
• Triglycerides 7,855 mg/dL (30–149)
• Thyroid-stimulating hormone 0.52 mIU/L (0.4–5.5)
• Fasting blood glucose 441 mg/dL (65–100)
• Hemoglobin A_1c 12.6% (4.0–6.0)
• Total protein 7.2 g/dL (6.0–8.4)
• Albumin 4 g/dL (3.5–5.0)
• Creatinine 1 mg/dL (0.70–1.40)
• Glomerular filtration rate 79 mL/min/1.73 m² (> 60)
• Urinalysis showed no proteinuria.

Histologic analysis of a lesion-biopsy specimen showed dermal foamy macrophages and loose lipids, which confirmed the suspicion of eruptive xanthoma.

The patient was started on strict glycemic and lipid control. Metformin and statin doses were increased and insulin was added. Three months later, laboratory results showed total cholesterol 128 mg/dL, triglycerides 164 mg/dL, fasting blood glucose 88 mg/dL, and hemoglobin A_1c 5.5%. This was accompanied by  marked improvement of the skin lesions (Figure  2).

CAUSES AND DIFFERENTIAL DIAGNOSIS

Eruptive xanthoma is a cutaneous disease most commonly arising over the extensor surfaces of the extremities and on the buttocks and shoulders, and it can be caused by high levels of serum triglycerides and uncontrolled diabetes mellitus.¹ Hypothyroidism, end-stage renal disease, and nephrotic syndrome can cause secondary hypertriglyceridemia,² which can cause eruptive xanthoma in severe cases. Patients with eruptive xanthoma may also have ophthalmologic and gastrointestinal involvement, such as lipemia retinalis (salmon-colored retina with creamy-white retinal vessels), abdominal pain, and hepatosplenomegaly.³

Other types of xanthoma associated with dyslipidemia include tuberous, tendinous, and plane xanthoma. Tuberous xanthoma is a firm, painless, deeper, red-yellow, larger nodular lesion, and the size may vary.⁴ Tendinous xanthoma is a slowly enlarging subcutaneous nodule typically located near tendons or ligaments in the hands, feet, and the Achilles tendon. Plane xanthoma is a flat papule or patch that can occur anywhere on the body.

Eruptive xanthoma most commonly arises over extensor surfaces of the extremities, and on the buttocks and shoulders

The differential diagnosis includes disseminated granuloma annulare, non-Langerhans cell histiocytosis (xanthoma disseminatum, micronodular form of juvenile xanthogranuloma), and generalized eruptive histiocytoma. Eruptive xanthoma is differentiated from disseminated granuloma annulare by the abundance of perivascular histiocytes and xanthomized histiocytes, the presence of lipid deposits, and the deposition of hyaluronic acid on the edges.⁵ Xanthoma disseminatum consists of numerous, small, red-brown papules that are evenly spread on the face, skin-folds, trunk, and proximal extremities.⁶ Juvenile xanthogranuloma occurs mostly in children and is characterized by discrete orange-yellow nodules, which commonly appear on the scalp, face, and upper trunk. It is in most cases a solitary lesion, but multiple lesions may occur.⁷ Lesions of generalized eruptive histiocytoma are firm, erythematous or brownish papules that appear in successive crops over the face, trunk, and proximal surfaces of the limbs.

TREATMENT

Treatment of eruptive xanthoma involves dietary restriction, exercise, and drug therapy to control the hyperlipidemia and the diabetes.² Early recognition and proper control of hypertriglyceridemia can prevent sequelae such as acute pancreatitis.³

An obese 50-year-old man with hypertension, hyperlipidemia, recently diagnosed diabetes, and a history of grand mal seizures presented to the emergency room complaining of skin rash for 1 week. He denied having fever, chills, myalgia, abdominal pain, visual changes, recent changes in medications, or contact with anyone with similar symptoms.

He was a smoker, with a history of 20 pack-years; he denied abusing alcohol and taking illicit drugs.

He had no family history of diabetes, peripheral vascular disease, or coronary artery disease. His medications included lisinopril, simvastatin, niacin, metformin, and phenytoin.

On physical examination, the lesions were small, reddish-yellow, nonpruritic tender papules covering the extensor surfaces of the knees, the forearms, the abdomen, and the back (Figure 1). Laboratory test results:

• Total cholesterol 1,045 mg/dL (reference range 100–199)
• Triglycerides 7,855 mg/dL (30–149)
• Thyroid-stimulating hormone 0.52 mIU/L (0.4–5.5)
• Fasting blood glucose 441 mg/dL (65–100)
• Hemoglobin A_1c 12.6% (4.0–6.0)
• Total protein 7.2 g/dL (6.0–8.4)
• Albumin 4 g/dL (3.5–5.0)
• Creatinine 1 mg/dL (0.70–1.40)
• Glomerular filtration rate 79 mL/min/1.73 m² (> 60)
• Urinalysis showed no proteinuria.

Histologic analysis of a lesion-biopsy specimen showed dermal foamy macrophages and loose lipids, which confirmed the suspicion of eruptive xanthoma.

The patient was started on strict glycemic and lipid control. Metformin and statin doses were increased and insulin was added. Three months later, laboratory results showed total cholesterol 128 mg/dL, triglycerides 164 mg/dL, fasting blood glucose 88 mg/dL, and hemoglobin A_1c 5.5%. This was accompanied by  marked improvement of the skin lesions (Figure  2).

CAUSES AND DIFFERENTIAL DIAGNOSIS

Eruptive xanthoma is a cutaneous disease most commonly arising over the extensor surfaces of the extremities and on the buttocks and shoulders, and it can be caused by high levels of serum triglycerides and uncontrolled diabetes mellitus.¹ Hypothyroidism, end-stage renal disease, and nephrotic syndrome can cause secondary hypertriglyceridemia,² which can cause eruptive xanthoma in severe cases. Patients with eruptive xanthoma may also have ophthalmologic and gastrointestinal involvement, such as lipemia retinalis (salmon-colored retina with creamy-white retinal vessels), abdominal pain, and hepatosplenomegaly.³

Other types of xanthoma associated with dyslipidemia include tuberous, tendinous, and plane xanthoma. Tuberous xanthoma is a firm, painless, deeper, red-yellow, larger nodular lesion, and the size may vary.⁴ Tendinous xanthoma is a slowly enlarging subcutaneous nodule typically located near tendons or ligaments in the hands, feet, and the Achilles tendon. Plane xanthoma is a flat papule or patch that can occur anywhere on the body.

Eruptive xanthoma most commonly arises over extensor surfaces of the extremities, and on the buttocks and shoulders

The differential diagnosis includes disseminated granuloma annulare, non-Langerhans cell histiocytosis (xanthoma disseminatum, micronodular form of juvenile xanthogranuloma), and generalized eruptive histiocytoma. Eruptive xanthoma is differentiated from disseminated granuloma annulare by the abundance of perivascular histiocytes and xanthomized histiocytes, the presence of lipid deposits, and the deposition of hyaluronic acid on the edges.⁵ Xanthoma disseminatum consists of numerous, small, red-brown papules that are evenly spread on the face, skin-folds, trunk, and proximal extremities.⁶ Juvenile xanthogranuloma occurs mostly in children and is characterized by discrete orange-yellow nodules, which commonly appear on the scalp, face, and upper trunk. It is in most cases a solitary lesion, but multiple lesions may occur.⁷ Lesions of generalized eruptive histiocytoma are firm, erythematous or brownish papules that appear in successive crops over the face, trunk, and proximal surfaces of the limbs.

TREATMENT

Treatment of eruptive xanthoma involves dietary restriction, exercise, and drug therapy to control the hyperlipidemia and the diabetes.² Early recognition and proper control of hypertriglyceridemia can prevent sequelae such as acute pancreatitis.³

A 76-year-old man presented to the emergency department with right-sided exertional chest pain radiating to the right shoulder and arm associated with shortness of breath. His vital signs were normal.  On clinical examination, the cardiac apex was palpated on the right side, 9 cm from the midsternal line in the fifth intercostal space.

A standard left-sided 12-lead electrocardiogram (ECG) showed right-axis deviation and inverted P, QRS, and T waves in leads I and aVL (Figure 1). Although these changes are also seen when the right and left arm electrode wires are transposed, the precordial lead morphology in such a situation would usually be normal. In our patient, the precordial leads showed the absence or even slight reversal of R-wave progression, a feature indicative of dextrocardia.^1,2

In patients with dextrocardia, right-sided hookup of the electrodes is usually necessary for proper interpretation of the ECG. When this was done in our patient, the ECG showed a normal cardiac axis, a negative QRS complex in lead aVR, a positive P wave and other complexes in lead I, and normal R-wave progression in the precordial leads—findings suggestive of dextrocardia (Figure 2).

Chest radiography showed a right-sided cardiac silhouette (Figure 3), and computed tomography of the abdomen (Figure 4) revealed the liver positioned on the left side and the spleen on the right, confirming the diagnosis of situs inversus totalis. The ECG showed dextrocardia, but no other abnormalities. The patient eventually underwent coronary angiography, which showed nonobstructive coronary artery disease.

DEXTROCARDIA, OTHER CONGENITAL CARDIOVASCULAR MALFORMATIONS

Dextrocardia was first described in early 17th century.¹ Situs solitus is the normal position of the heart and viscera, whereas situs inversus is a mirror-image anatomic arrangement of the organs. Situs inversus with dextrocardia, also called situs inversus totalis, is a rare condition (with a prevalence of 1 in 8,000) in which the heart and descending aorta are on the right and the thoracic and abdominal viscera are usually mirror images of the normal morphology.^1,3,4 A mirror-image sinus node lies at the junction of the left superior vena cava and the left-sided (morphologic right) atrium.¹ People with situs inversus with dextrocardia are usually asymptomatic and have a normal life expectancy.^1,2 Situs inversus with levocardia is a rare condition in which the heart is in the normal position but the viscera are in the dextro-position. This anomaly has a prevalence of 1 in 22,000.⁵

Atrial situs almost always corresponds to visceral situs. However, when the alignment of the atria and viscera is inconsistent and situs cannot be determined clearly because of the malpositioning of organs, the condition is called “situs ambiguous.” This is very rare, with a prevalence of 1 in 40,000.⁶

Risk factors

The cause of congenital cardiovascular malformations such as these is not known, but risk factors include positive family history, maternal diabetes, and cocaine use in the first trimester.⁷

Negative complexes in lead I, positive complexes in aVR, and slight reversal of R-wave progression indicate dextrocardia

The prevalence of congenital heart disease in patients with situs inversus with dextrocardia is low and ranges from 2% to 5%. This is in contrast to situs solitus with dextrocardia (isolated dextrocardia), which is almost always associated with cardiovascular anomalies.^2,4 Kartagener syndrome—the triad of situs inversus, sinusitis, and bronchiectasis—occurs in 25% of people with situs inversus with dextrocardia.⁴ Situs inversus with levocardia is also frequently associated with cardiac anomalies.⁵

The major features of dextrocardia on ECG are:

• Negative P wave, QRS complex, and T wave in lead I
• Positive QRS complex in aVR
• Right-axis deviation
• Reversal of R-wave progression in the precordial leads.

Ventricular activation and repolarization are reversed, resulting in a negative QRS complex and an inverted T wave in lead I. The absence of R-wave progression in the precordial leads helps differentiate mirror-image dextrocardia from erroneously reversed limb-electrode placement, which shows normal R-wave progression from V₁ to V₆ while showing similar features to those seen in dextrocardia in the limb leads.² In right-sided hookup, the limb electrodes are reversed, and the chest electrodes are recorded from the right precordium.

CORONARY INTERVENTIONS REQUIRE SPECIAL CONSIDERATION

In patients with dextrocardia, coronary interventions can be challenging because of the mirror-image position of the coronary ostia and the aortic arch.⁸ These patients also need careful imaging, consideration of other associated congenital cardiac abnormalities, and detailed planning before cardiac surgery, including coronary artery bypass grafting.⁹

Patients with dextrocardia may present with cardiac symptoms localized to the right side of the body and have confusing clinical and diagnostic findings. Keeping dextrocardia and other such anomalies in mind can prevent delay in appropriately directed interventions. In a patient such as ours, the heart on the right side of the chest may indeed be “right.” Still, diagnostic tests to look for disorders encountered with dextrocardia may be necessary.

A 76-year-old man presented to the emergency department with right-sided exertional chest pain radiating to the right shoulder and arm associated with shortness of breath. His vital signs were normal.  On clinical examination, the cardiac apex was palpated on the right side, 9 cm from the midsternal line in the fifth intercostal space.

A standard left-sided 12-lead electrocardiogram (ECG) showed right-axis deviation and inverted P, QRS, and T waves in leads I and aVL (Figure 1). Although these changes are also seen when the right and left arm electrode wires are transposed, the precordial lead morphology in such a situation would usually be normal. In our patient, the precordial leads showed the absence or even slight reversal of R-wave progression, a feature indicative of dextrocardia.^1,2

In patients with dextrocardia, right-sided hookup of the electrodes is usually necessary for proper interpretation of the ECG. When this was done in our patient, the ECG showed a normal cardiac axis, a negative QRS complex in lead aVR, a positive P wave and other complexes in lead I, and normal R-wave progression in the precordial leads—findings suggestive of dextrocardia (Figure 2).

Chest radiography showed a right-sided cardiac silhouette (Figure 3), and computed tomography of the abdomen (Figure 4) revealed the liver positioned on the left side and the spleen on the right, confirming the diagnosis of situs inversus totalis. The ECG showed dextrocardia, but no other abnormalities. The patient eventually underwent coronary angiography, which showed nonobstructive coronary artery disease.

DEXTROCARDIA, OTHER CONGENITAL CARDIOVASCULAR MALFORMATIONS

Dextrocardia was first described in early 17th century.¹ Situs solitus is the normal position of the heart and viscera, whereas situs inversus is a mirror-image anatomic arrangement of the organs. Situs inversus with dextrocardia, also called situs inversus totalis, is a rare condition (with a prevalence of 1 in 8,000) in which the heart and descending aorta are on the right and the thoracic and abdominal viscera are usually mirror images of the normal morphology.^1,3,4 A mirror-image sinus node lies at the junction of the left superior vena cava and the left-sided (morphologic right) atrium.¹ People with situs inversus with dextrocardia are usually asymptomatic and have a normal life expectancy.^1,2 Situs inversus with levocardia is a rare condition in which the heart is in the normal position but the viscera are in the dextro-position. This anomaly has a prevalence of 1 in 22,000.⁵

Atrial situs almost always corresponds to visceral situs. However, when the alignment of the atria and viscera is inconsistent and situs cannot be determined clearly because of the malpositioning of organs, the condition is called “situs ambiguous.” This is very rare, with a prevalence of 1 in 40,000.⁶

Risk factors

The cause of congenital cardiovascular malformations such as these is not known, but risk factors include positive family history, maternal diabetes, and cocaine use in the first trimester.⁷

Negative complexes in lead I, positive complexes in aVR, and slight reversal of R-wave progression indicate dextrocardia

The prevalence of congenital heart disease in patients with situs inversus with dextrocardia is low and ranges from 2% to 5%. This is in contrast to situs solitus with dextrocardia (isolated dextrocardia), which is almost always associated with cardiovascular anomalies.^2,4 Kartagener syndrome—the triad of situs inversus, sinusitis, and bronchiectasis—occurs in 25% of people with situs inversus with dextrocardia.⁴ Situs inversus with levocardia is also frequently associated with cardiac anomalies.⁵

The major features of dextrocardia on ECG are:

• Negative P wave, QRS complex, and T wave in lead I
• Positive QRS complex in aVR
• Right-axis deviation
• Reversal of R-wave progression in the precordial leads.

Ventricular activation and repolarization are reversed, resulting in a negative QRS complex and an inverted T wave in lead I. The absence of R-wave progression in the precordial leads helps differentiate mirror-image dextrocardia from erroneously reversed limb-electrode placement, which shows normal R-wave progression from V₁ to V₆ while showing similar features to those seen in dextrocardia in the limb leads.² In right-sided hookup, the limb electrodes are reversed, and the chest electrodes are recorded from the right precordium.

CORONARY INTERVENTIONS REQUIRE SPECIAL CONSIDERATION

In patients with dextrocardia, coronary interventions can be challenging because of the mirror-image position of the coronary ostia and the aortic arch.⁸ These patients also need careful imaging, consideration of other associated congenital cardiac abnormalities, and detailed planning before cardiac surgery, including coronary artery bypass grafting.⁹

Patients with dextrocardia may present with cardiac symptoms localized to the right side of the body and have confusing clinical and diagnostic findings. Keeping dextrocardia and other such anomalies in mind can prevent delay in appropriately directed interventions. In a patient such as ours, the heart on the right side of the chest may indeed be “right.” Still, diagnostic tests to look for disorders encountered with dextrocardia may be necessary.

A 76-year-old man presented to the emergency department with right-sided exertional chest pain radiating to the right shoulder and arm associated with shortness of breath. His vital signs were normal.  On clinical examination, the cardiac apex was palpated on the right side, 9 cm from the midsternal line in the fifth intercostal space.

A standard left-sided 12-lead electrocardiogram (ECG) showed right-axis deviation and inverted P, QRS, and T waves in leads I and aVL (Figure 1). Although these changes are also seen when the right and left arm electrode wires are transposed, the precordial lead morphology in such a situation would usually be normal. In our patient, the precordial leads showed the absence or even slight reversal of R-wave progression, a feature indicative of dextrocardia.^1,2

In patients with dextrocardia, right-sided hookup of the electrodes is usually necessary for proper interpretation of the ECG. When this was done in our patient, the ECG showed a normal cardiac axis, a negative QRS complex in lead aVR, a positive P wave and other complexes in lead I, and normal R-wave progression in the precordial leads—findings suggestive of dextrocardia (Figure 2).

Chest radiography showed a right-sided cardiac silhouette (Figure 3), and computed tomography of the abdomen (Figure 4) revealed the liver positioned on the left side and the spleen on the right, confirming the diagnosis of situs inversus totalis. The ECG showed dextrocardia, but no other abnormalities. The patient eventually underwent coronary angiography, which showed nonobstructive coronary artery disease.

DEXTROCARDIA, OTHER CONGENITAL CARDIOVASCULAR MALFORMATIONS

Dextrocardia was first described in early 17th century.¹ Situs solitus is the normal position of the heart and viscera, whereas situs inversus is a mirror-image anatomic arrangement of the organs. Situs inversus with dextrocardia, also called situs inversus totalis, is a rare condition (with a prevalence of 1 in 8,000) in which the heart and descending aorta are on the right and the thoracic and abdominal viscera are usually mirror images of the normal morphology.^1,3,4 A mirror-image sinus node lies at the junction of the left superior vena cava and the left-sided (morphologic right) atrium.¹ People with situs inversus with dextrocardia are usually asymptomatic and have a normal life expectancy.^1,2 Situs inversus with levocardia is a rare condition in which the heart is in the normal position but the viscera are in the dextro-position. This anomaly has a prevalence of 1 in 22,000.⁵

Atrial situs almost always corresponds to visceral situs. However, when the alignment of the atria and viscera is inconsistent and situs cannot be determined clearly because of the malpositioning of organs, the condition is called “situs ambiguous.” This is very rare, with a prevalence of 1 in 40,000.⁶

Risk factors

The cause of congenital cardiovascular malformations such as these is not known, but risk factors include positive family history, maternal diabetes, and cocaine use in the first trimester.⁷

Negative complexes in lead I, positive complexes in aVR, and slight reversal of R-wave progression indicate dextrocardia

The prevalence of congenital heart disease in patients with situs inversus with dextrocardia is low and ranges from 2% to 5%. This is in contrast to situs solitus with dextrocardia (isolated dextrocardia), which is almost always associated with cardiovascular anomalies.^2,4 Kartagener syndrome—the triad of situs inversus, sinusitis, and bronchiectasis—occurs in 25% of people with situs inversus with dextrocardia.⁴ Situs inversus with levocardia is also frequently associated with cardiac anomalies.⁵

The major features of dextrocardia on ECG are:

• Negative P wave, QRS complex, and T wave in lead I
• Positive QRS complex in aVR
• Right-axis deviation
• Reversal of R-wave progression in the precordial leads.

Ventricular activation and repolarization are reversed, resulting in a negative QRS complex and an inverted T wave in lead I. The absence of R-wave progression in the precordial leads helps differentiate mirror-image dextrocardia from erroneously reversed limb-electrode placement, which shows normal R-wave progression from V₁ to V₆ while showing similar features to those seen in dextrocardia in the limb leads.² In right-sided hookup, the limb electrodes are reversed, and the chest electrodes are recorded from the right precordium.

CORONARY INTERVENTIONS REQUIRE SPECIAL CONSIDERATION

In patients with dextrocardia, coronary interventions can be challenging because of the mirror-image position of the coronary ostia and the aortic arch.⁸ These patients also need careful imaging, consideration of other associated congenital cardiac abnormalities, and detailed planning before cardiac surgery, including coronary artery bypass grafting.⁹

Patients with dextrocardia may present with cardiac symptoms localized to the right side of the body and have confusing clinical and diagnostic findings. Keeping dextrocardia and other such anomalies in mind can prevent delay in appropriately directed interventions. In a patient such as ours, the heart on the right side of the chest may indeed be “right.” Still, diagnostic tests to look for disorders encountered with dextrocardia may be necessary.

The article by Dr. Alison Colantino et al in this issue on when to resume anticoagulation after a hemorrhagic event is relevant to the discussion of clinical decision-making that I started here last month. My thoughts then were prompted by a commentary by Dr. Vinay Prasad on incorporating appropriate study outcomes in clinical decision-making (Cleve Clin J Med 2015; 82:146–150).

In the clinic or hospital, we make many decisions without being able to cite specific applicable clinical studies. I base some decisions on my overall impression from the literature (including formal trials), some on general recall of a specific study (which I hopefully either find time to review afterwards, or ask one of our trainees to read and discuss with our team the next day), and others on my knowledge of clinical guidelines or clearly accepted practice. Most clinical decisions are made without any directly applicable data from available clinical studies. This is the “art” of medicine.

Should this art make its way into our clinical journals, and if so, how extensively, and how should it be framed? It is relatively easy when we are talking about the science of clinical practice. Journals receive the (hopefully complete) data, get peer reviews to improve the paper, and publish it with the authors’ opinions presented in the discussion section. Then, dialogue ensues in the published literature, in educational lectures, and in blogs posted on the Internet. But where does the art go? Does it belong in our traditionally conservative textbooks or newer go-to online resources, which emphasize the need for authors to provide updated specific references for their treatment recommendations? We believe that after our best efforts at peer review it is appropriate to publish it in the CCJM because hopefully it can provide additional perspective on how we deliver care to our patients.

In the arena of new therapies, regulatory approval requires hard data documenting efficacy and safety. And that often leaves me without approved or sometimes even “proven effective” therapies to use when treating patients with relatively uncommon conditions, such as refractory uveitis with threatened visual loss or idiopathic aortitis. Yet I still need to treat the patient.

Another aspect of the art of medicine relates to how best to use therapies that have been approved. We have had antibiotics for many decades, but data are still being generated on how long to treat specific infections, and relatively few scenarios have been studied. Huge media coverage and (mostly) appropriate hype were generated over the need to treat patients with postmenopausal osteoporosis as diagnosed by dual-energy x-ray absorptiometry. But even after evidence emerged regarding atypical femoral fractures in patients receiving long-term bisphosphonate therapy, the question of how long treatment should continue remains more art than science.

The field of anticoagulation has seen many recent advances. We have new heparins, new target-specific oral anticoagulants, and a lot of new science on the natural history of some thrombotic disorders and the efficacy and safety of these new agents. But how long to treat specific thrombotic conditions, which agent to use, how intense the anticoagulation needs to be, when to use bridging therapy, and, as discussed by Dr. Colantino et al, when to resume anticoagulation after a hemorrhagic event mostly remain part of the art of medicine.

I highlight the Colantino paper in the context of both clinical and editorial decision-making because it is an example of experienced clinical authors discussing their solutions to thorny clinical scenarios we often face with inadequate data. While some journals avoid this approach, we embrace the opportunity to provide thoughtful expert opinions to our readers. We push authors from the start of the editorial process and through aggressive peer review to provide evidence to support their practice recommendations when appropriate. But we also encourage them to make recommendations and describe their own decision-making process in situations that may not be fully described in the literature.

Most of our readers do not have ready access to consultants who have had years of experience within multidisciplinary teams at referral institutions regularly managing patients with permutations of these complex clinical problems. Though generic consultation advice must be evaluated within the context of the specific patient, we hope that by framing the clinical issues with relevant clinical science the opinions of experienced authors will be of use in guiding your (and my) approach to similar clinical scenarios.

If you think we are not striking the right balance between the science and the art of medical practice, please let me know.

The article by Dr. Alison Colantino et al in this issue on when to resume anticoagulation after a hemorrhagic event is relevant to the discussion of clinical decision-making that I started here last month. My thoughts then were prompted by a commentary by Dr. Vinay Prasad on incorporating appropriate study outcomes in clinical decision-making (Cleve Clin J Med 2015; 82:146–150).

In the clinic or hospital, we make many decisions without being able to cite specific applicable clinical studies. I base some decisions on my overall impression from the literature (including formal trials), some on general recall of a specific study (which I hopefully either find time to review afterwards, or ask one of our trainees to read and discuss with our team the next day), and others on my knowledge of clinical guidelines or clearly accepted practice. Most clinical decisions are made without any directly applicable data from available clinical studies. This is the “art” of medicine.

Should this art make its way into our clinical journals, and if so, how extensively, and how should it be framed? It is relatively easy when we are talking about the science of clinical practice. Journals receive the (hopefully complete) data, get peer reviews to improve the paper, and publish it with the authors’ opinions presented in the discussion section. Then, dialogue ensues in the published literature, in educational lectures, and in blogs posted on the Internet. But where does the art go? Does it belong in our traditionally conservative textbooks or newer go-to online resources, which emphasize the need for authors to provide updated specific references for their treatment recommendations? We believe that after our best efforts at peer review it is appropriate to publish it in the CCJM because hopefully it can provide additional perspective on how we deliver care to our patients.

In the arena of new therapies, regulatory approval requires hard data documenting efficacy and safety. And that often leaves me without approved or sometimes even “proven effective” therapies to use when treating patients with relatively uncommon conditions, such as refractory uveitis with threatened visual loss or idiopathic aortitis. Yet I still need to treat the patient.

Another aspect of the art of medicine relates to how best to use therapies that have been approved. We have had antibiotics for many decades, but data are still being generated on how long to treat specific infections, and relatively few scenarios have been studied. Huge media coverage and (mostly) appropriate hype were generated over the need to treat patients with postmenopausal osteoporosis as diagnosed by dual-energy x-ray absorptiometry. But even after evidence emerged regarding atypical femoral fractures in patients receiving long-term bisphosphonate therapy, the question of how long treatment should continue remains more art than science.

The field of anticoagulation has seen many recent advances. We have new heparins, new target-specific oral anticoagulants, and a lot of new science on the natural history of some thrombotic disorders and the efficacy and safety of these new agents. But how long to treat specific thrombotic conditions, which agent to use, how intense the anticoagulation needs to be, when to use bridging therapy, and, as discussed by Dr. Colantino et al, when to resume anticoagulation after a hemorrhagic event mostly remain part of the art of medicine.

I highlight the Colantino paper in the context of both clinical and editorial decision-making because it is an example of experienced clinical authors discussing their solutions to thorny clinical scenarios we often face with inadequate data. While some journals avoid this approach, we embrace the opportunity to provide thoughtful expert opinions to our readers. We push authors from the start of the editorial process and through aggressive peer review to provide evidence to support their practice recommendations when appropriate. But we also encourage them to make recommendations and describe their own decision-making process in situations that may not be fully described in the literature.

Most of our readers do not have ready access to consultants who have had years of experience within multidisciplinary teams at referral institutions regularly managing patients with permutations of these complex clinical problems. Though generic consultation advice must be evaluated within the context of the specific patient, we hope that by framing the clinical issues with relevant clinical science the opinions of experienced authors will be of use in guiding your (and my) approach to similar clinical scenarios.

If you think we are not striking the right balance between the science and the art of medical practice, please let me know.

The article by Dr. Alison Colantino et al in this issue on when to resume anticoagulation after a hemorrhagic event is relevant to the discussion of clinical decision-making that I started here last month. My thoughts then were prompted by a commentary by Dr. Vinay Prasad on incorporating appropriate study outcomes in clinical decision-making (Cleve Clin J Med 2015; 82:146–150).

In the clinic or hospital, we make many decisions without being able to cite specific applicable clinical studies. I base some decisions on my overall impression from the literature (including formal trials), some on general recall of a specific study (which I hopefully either find time to review afterwards, or ask one of our trainees to read and discuss with our team the next day), and others on my knowledge of clinical guidelines or clearly accepted practice. Most clinical decisions are made without any directly applicable data from available clinical studies. This is the “art” of medicine.

Should this art make its way into our clinical journals, and if so, how extensively, and how should it be framed? It is relatively easy when we are talking about the science of clinical practice. Journals receive the (hopefully complete) data, get peer reviews to improve the paper, and publish it with the authors’ opinions presented in the discussion section. Then, dialogue ensues in the published literature, in educational lectures, and in blogs posted on the Internet. But where does the art go? Does it belong in our traditionally conservative textbooks or newer go-to online resources, which emphasize the need for authors to provide updated specific references for their treatment recommendations? We believe that after our best efforts at peer review it is appropriate to publish it in the CCJM because hopefully it can provide additional perspective on how we deliver care to our patients.

In the arena of new therapies, regulatory approval requires hard data documenting efficacy and safety. And that often leaves me without approved or sometimes even “proven effective” therapies to use when treating patients with relatively uncommon conditions, such as refractory uveitis with threatened visual loss or idiopathic aortitis. Yet I still need to treat the patient.

Another aspect of the art of medicine relates to how best to use therapies that have been approved. We have had antibiotics for many decades, but data are still being generated on how long to treat specific infections, and relatively few scenarios have been studied. Huge media coverage and (mostly) appropriate hype were generated over the need to treat patients with postmenopausal osteoporosis as diagnosed by dual-energy x-ray absorptiometry. But even after evidence emerged regarding atypical femoral fractures in patients receiving long-term bisphosphonate therapy, the question of how long treatment should continue remains more art than science.

The field of anticoagulation has seen many recent advances. We have new heparins, new target-specific oral anticoagulants, and a lot of new science on the natural history of some thrombotic disorders and the efficacy and safety of these new agents. But how long to treat specific thrombotic conditions, which agent to use, how intense the anticoagulation needs to be, when to use bridging therapy, and, as discussed by Dr. Colantino et al, when to resume anticoagulation after a hemorrhagic event mostly remain part of the art of medicine.

I highlight the Colantino paper in the context of both clinical and editorial decision-making because it is an example of experienced clinical authors discussing their solutions to thorny clinical scenarios we often face with inadequate data. While some journals avoid this approach, we embrace the opportunity to provide thoughtful expert opinions to our readers. We push authors from the start of the editorial process and through aggressive peer review to provide evidence to support their practice recommendations when appropriate. But we also encourage them to make recommendations and describe their own decision-making process in situations that may not be fully described in the literature.

Most of our readers do not have ready access to consultants who have had years of experience within multidisciplinary teams at referral institutions regularly managing patients with permutations of these complex clinical problems. Though generic consultation advice must be evaluated within the context of the specific patient, we hope that by framing the clinical issues with relevant clinical science the opinions of experienced authors will be of use in guiding your (and my) approach to similar clinical scenarios.

If you think we are not striking the right balance between the science and the art of medical practice, please let me know.

If a patient receiving anticoagulant therapy suffers a bleeding event, the patient and physician must decide whether and how soon to restart the therapy, and with what agent.

Foremost on our minds tends to be the risk of another hemorrhage. Subtler to appreciate immediately after an event is the continued risk of thrombosis, often from the same medical condition that prompted anticoagulation therapy in the first place (Table 1).

Complicating the decision, there may be a rebound effect: some thrombotic events such as pulmonary embolism and atrial fibrillation-related stroke may be more likely to occur in the first weeks after stopping warfarin than during similar intervals in patients who have not been taking it.^1–3 The same thing may happen with the newer, target-specific oral anticoagulants.^4–6

Although we have evidence-based guidelines for initiating and managing anticoagulant therapy, ample data on adverse events, and protocols for reversing anticoagulation if bleeding occurs, we do not have clear guidelines on restarting anticoagulation after a hemorrhagic event.

In this article, we outline a practical framework for approaching this clinical dilemma. Used in conjunction with consideration of a patient’s values and preferences as well as input from experts, this framework can help clinicians guide their patients through this challenging clinical decision. It consists of five questions:

• Why is the patient on anticoagulation, and what is the risk of thromboembolism without it?
• What was the clinical impact of the hemorrhage, and what is the risk of rebleeding if anticoagulation is resumed?
• What additional patient factors should be taken into consideration?
• How long should we wait before restarting anticoagulation?
• Would a newer drug be a better choice?

BLEEDING OCCURS IN 2% TO 3% OF PATIENTS PER YEAR

Most of our information on anticoagulation is about vitamin K antagonists—principally warfarin, in use since the 1950s. Among patients taking warfarin outside of clinical trials, the risk of major bleeding is estimated at 2% to 3% per year.⁷

However, the target-specific oral anticoagulants rivaroxaban (Xarelto), apixaban (Eliquis),  dabigatran (Pradaxa) and edoxaban (Savaysa) are being used more and more, and we include them in our discussion insofar as we have information on them. The rates of bleeding with these new drugs in clinical trials have been comparable to or lower than those with warfarin.⁸ Postmarketing surveillance is under way.

WHY IS THE PATIENT ON ANTICOAGULATION? WHAT IS THE RISK WITHOUT IT?

Common, evidence-based indications for anticoagulation are to prevent complications in patients with venous thromboembolism and to prevent stroke in patients with atrial fibrillation or a mechanical heart valve. Other uses, such as in heart failure and its sequelae, pulmonary hypertension, and splanchnic or hepatic vein thrombosis, have less robust evidence to support them.

When anticoagulation-related bleeding occurs, it is essential to review why the patient is taking the drug and the risk of thromboembolism without it. Some indications pose a higher risk of thromboembolism than others and so argue more strongly for continuing the treatment.

Douketis et al⁹ developed a risk-stratification scheme for perioperative thromboembolism. We have modified it by adding the CHA₂DS₂-VASc score (Table 2),^9–11 and believe it can be used more widely.

High-risk indications

Conditions that pose a high risk of thrombosis almost always require restarting anticoagulation. Here, the most appropriate question nearly always is not if anticoagulation should be restarted, but when. Examples:

• A mechanical mitral valve
• Antiphospholipid antibody syndrome with recurrent thromboembolic events.

Lower-risk indications

Lower-risk indications allow more leeway in determining if anticoagulation should be resumed. The most straightforward cases fall well within established guidelines. Examples:

• Atrial fibrillation and a CHA₂DS₂-VASc score of 1. The 2014 guidelines from the American College of Cardiology, American Heart Association, and Heart Rhythm Society¹⁰ suggest that patients with nonvalvular atrial fibrillation and a CHA₂DS₂-VASc score of 1 have three options: an oral anticoagulant, aspirin, and no antithrombotic therapy. If such a patient on anticoagulant therapy subsequently experiences a major gastrointestinal hemorrhage requiring transfusion and intensive care and no definitively treatable source of bleeding is found on endoscopy, one can argue that the risks of continued anticoagulation (recurrent bleeding) now exceed the benefits and that the patient would be better served by aspirin or even no antithrombotic therapy.

• After 6 months of anticoagulation for unprovoked deep vein thrombosis. Several studies showed that aspirin reduced the risk of recurrent venous thromboembolism in patients who completed an initial 6-month course of anticoagulation.^12–15 Though these studies did not specifically compare aspirin with warfarin or target-specific oral anticoagulants in preventing recurrent venous thromboembolism after a hemorrhage, it is reasonable to extrapolate their results to this situation.

If the risk of recurrent hemorrhage on anticoagulation is considered to be too great, then aspirin is an alternative to no anticoagulation, as it reduces the risk of recurrent venous thromboembolism.¹⁶ However, we advise caution if the bleeding lesion may be specifically exacerbated by aspirin, particularly upper gastrointestinal ulcers.

Moderate-risk indications

• After a partial course of anticoagulation for provoked venous thromboembolism. Suppose a patient in the 10th week of a planned 12-week course of anticoagulation for a surgically provoked, first deep vein thrombosis presents with abdominal pain and is found to have a retroperitoneal hematoma. In light of the risk of recurrent bleeding vs the benefit of resuming anticoagulation for the limited remaining period, her 12-week treatment course can reasonably be shortened to 10 weeks.

The risk of recurrent venous thromboembolism when a patient is off anticoagulation decreases with time from the initial event. The highest risk, estimated at 0.3% to 1.3% per day, is in the first 4 weeks, falling to 0.03% to 0.2% per day in weeks 5 through 12, and 0.05% per day thereafter.^17–20

The risk of recurrent venous thromboembolism is greatest immediately after the event and decreases over time

Additionally, a pooled analysis of seven randomized trials suggests that patients with isolated, distal deep vein thrombosis provoked by a temporary risk factor did not have a high risk of recurrence after being treated for 4 to 6 weeks.²¹ These analyses are based on vitamin K antagonists, though it seems reasonable to extrapolate this information to the target-specific oral anticoagulants.

More challenging are situations in which the evidence supporting the initial or continued need for anticoagulation is less robust, such as in heart failure, pulmonary hypertension, or splanchnic and hepatic vein thrombosis. In these cases, the lack of strong evidence supporting the use of anticoagulation should make us hesitate to resume it after bleeding.

WHAT WAS THE CLINICAL IMPACT? WHAT IS THE RISK OF REBLEEDING?

Different groups have defined major and minor bleeding in different ways.^22,23 Several have proposed criteria to standardize how bleeding events (on warfarin and otherwise) are classified,^23–25 but the definitions differ.

Specifically, all agree that a “major” bleeding event is one that is fatal, involves bleeding into a major organ, or leads to a substantial decline in hemoglobin level. However, the Thrombolysis in Myocardial Infarction trials use a decline of more than 5 g/dL in their definition,^23,25 while the International Society on Thrombosis and Haemostasis uses 2 g/dL.²⁴

Here, we review the clinical impact of the most common sources of anticoagulation-related hemorrhage—gastrointestinal, soft tissue, and urinary tract²⁶—as well as intracerebral hemorrhage, a less common but more uniformly devastating event.²⁷

Clinical impact of gastrointestinal hemorrhage

Each year, about 4.5% of patients taking warfarin have a gastrointestinal hemorrhage, though not all of these events are major.²⁸ Evolving data suggest that the newer agents (particularly dabigatran, rivaroxaban, and edoxaban) pose a higher risk of gastrointestinal bleeding than warfarin.²⁹ Patients may need plasma and blood transfusions and intravenous phytonadione, all of which carry risks, albeit small.

Frequently, endoscopy is needed to find the source of bleeding and to control it. If this does not work, angiographic intervention to infuse vasoconstrictors or embolic coils into the culprit artery may be required, and some patients need surgery. Each intervention carries its own risk.

Clinical impact of soft-tissue hemorrhage

Soft-tissue hemorrhage accounts for more than 20% of warfarin-related bleeding events²⁶; as yet, we know of no data on the rate with the new drugs. Soft-tissue hemorrhage is often localized to the large muscles of the retroperitoneum and legs. Though retroperitoneal hemorrhage accounts for a relatively small portion of soft-tissue hemorrhages, it is associated with high rates of morbidity and death and will therefore be our focus.²⁶

Some indications for anticoagulation pose a higher risk of thromboembolism than others

Much of the clinical impact of retroperitoneal hemorrhage is from a mass effect that causes abdominal compartment syndrome, hydroureter, ileus, abscess formation, and acute and chronic pain. At least 20% of cases are associated with femoral neuropathy. It can also lead to deep vein thrombosis from venous compression, coupled with hypercoagulability in response to bleeding. Brisk bleeding can lead to shock and death, and the mortality rate in retroperitoneal hemorrhage is estimated at 20% or higher.³⁰

In many cases, the retroperitoneal hemorrhage will self-tamponade and the blood will be reabsorbed once the bleeding has stopped, but uncontrolled bleeding may require surgical or angiographic intervention.³⁰

Clinical impact of urinary tract hemorrhage

Gross or microscopic hematuria can be found in an estimated 2% to 24% of patients taking warfarin^31–33; data are lacking for the target-specific oral anticoagulants. Interventions required to manage urinary tract bleeding include bladder irrigation and, less often, transfusion.³¹ Since a significant number of cases of hematuria are due to neoplastic disease,³² a diagnostic workup with radiographic imaging of the upper tract and cystoscopy of the lower tract is usually required.³¹ While life-threatening hemorrhage is uncommon, complications such as transient urinary obstruction from clots may occur.

Clinical impact of intracranial hemorrhage

Intracranial hemorrhage is the most feared and deadly of the bleeding complications of anticoagulation. The incidence in patients on warfarin is estimated at 2% to 3% per year, which is markedly higher than the estimated incidence of 25 per 100,000 person-years in the general population.³⁴ Emerging data indicate that the newer drugs are also associated with a risk of intracranial hemorrhage, though the risk is about half that with vitamin K antagonists.³⁵ Intracranial hemorrhage leads to death or disability in 76% of cases, compared with 3% of cases of bleeding from the gastrointestinal or urinary tract.²⁷

Regardless of the source of bleeding, hospitalization is likely to be required and may be  prolonged, with attendant risks of nosocomial harms such as infection.

Risk of rebleeding

Given the scope and severity of anticoagulation-related bleeding, there is strong interest in predicting and preventing it. By some estimates, the incidence of recurrent bleeding after resuming vitamin K antagonists is 8% to 13%.²² Although there are several indices for predicting the risk of major bleeding when starting anticoagulation, there are currently no validated tools to estimate a patient’s risk of rebleeding.³⁶

The patient factor that most consistently predicts major bleeding is a history of bleeding, particularly from the gastrointestinal tract. Finding and controlling the source of bleeding is important.^26,37 For example, a patient with gross hematuria who is found on cystoscopy to have a urothelial papilloma is unlikely to have rebleeding if the tumor is successfully resected and serial follow-up shows no regrowth. In contrast, consider a patient with a major gastrointestinal hemorrhage, the source of which remains elusive after upper, lower, and capsule endoscopy or, alternatively, is suspected to be from one of multiple angiodysplastic lesions. Without definitive source management, this patient faces a high risk of rebleeding.

With or without anticoagulation, after a first intracranial hemorrhage the risk of another one is estimated at 2% to 4% per year.³⁴ An observational study found a recurrence rate of 7.5% when vitamin K antagonist therapy was started after an intracranial hemorrhage (though not all patients were on a vitamin K antagonist at the time of the first hemorrhage).³⁸

Evolving data suggest the newer oral agents pose a higher risk of GI bleeding

Patients with lobar hemorrhage and those with suspected cerebral amyloid angiopathy may be at particularly high risk if anticoagulation is resumed. Conversely, initial events attributed to uncontrolled hypertension that subsequently can be well controlled may portend a lower risk of rebleeding.³⁴ For other types of intracranial hemorrhage, recurrence rates can be even higher. Irrespective of anticoagulation, one prospective study estimated the crude annual rebleeding rate with untreated arteriovenous malformations to be 7%.³⁹ In chronic subdural hematoma, the recurrence rate after initial drainage has been estimated at 9.2% to 26.5%, with use of anticoagulants (in this case, vitamin K antagonists) being an independent predictor of recurrence.⁴⁰

WHAT OTHER PATIENT FACTORS NEED CONSIDERATION?

Target INR on warfarin

An important factor influencing the risk of bleeding with warfarin is the intensity of this therapy.³⁷ A meta-analysis⁴¹ found that the risks of major hemorrhage and thromboembolism are minimized if the goal international normalized ratio (INR) is 2.0 to 3.0. When considering resuming anticoagulation after bleeding, make sure the therapeutic target is appropriate.³⁷

Table 3 summarizes recommended therapeutic ranges for frequently encountered indications for warfarin.^36,42,43

INR at time of the event and challenges in controlling it

The decision to resume anticoagulation in patients who bled while using warfarin must take into account the actual INR at the time of the event.

For example, consider a patient whose INR values are consistently in the therapeutic range.  While on vacation, he receives ciprofloxacin for acute prostatitis from an urgent care team, and no adjustment to INR monitoring or warfarin dose is made. Several days later, he presents with lower gastrointestinal bleeding. His INR is 8, and colonoscopy reveals diverticulosis with a bleeding vessel, responsive to endoscopic therapy. After controlling the source of bleeding and reinforcing the need to always review new medications for potential interactions with anticoagulation, it is reasonable to expect that he once again will be able to keep his INR in the therapeutic range.

A patient on anticoagulation for the same indication but who has a history of repeated supratherapeutic levels, poor adherence, or poor access to INR monitoring poses very different concerns about resuming anticoagulation (as well as which agent to use, as we discuss below).

Of note, a high INR alone does not explain bleeding. It is estimated that a workup for gastrointestinal bleeding and gross hematuria uncovers previously undetected lesions in approximately one-third of cases involving warfarin.²⁶ A similar malignancy-unmasking effect is now recognized in patients using the target-specific oral agents who experience gastrointestinal bleeding.⁴⁴ Accordingly, we recommend a comprehensive source evaluation for any anticoagulation-related hemorrhage.

Comorbid conditions

Comorbid conditions associated with bleeding include cancer, end-stage renal disease, liver disease, arterial hypertension, prior stroke, and alcohol abuse.^37,45 Gait instability, regardless of cause, may also increase the risk of trauma-related hemorrhage, but some have estimated that a patient would need to fall multiple times per week to contraindicate anticoagulation on the basis of falls alone.⁴⁶

Concurrent medications

Concomitant therapies, including antiplatelet drugs and nonsteroidal anti-inflammatory drugs, increase bleeding risk.^47,48 Aspirin and the nonsteroidals, in addition to having antiplatelet effects, also can cause gastric erosion.³⁷ In evaluating whether and when to restart anticoagulation, it is advisable to review the role that concomitant therapies may have had in the index bleeding event and to evaluate the risks and benefits of these other agents.

The factor that most consistently predicts major bleeding is a history of bleeding, particularly gastrointestinal bleeding

Additionally, warfarin has many interactions. Although the newer drugs are lauded for having fewer interactions, they are not completely free of them, and the potential for interactions must always be reviewed.⁴⁹ Further, unlike warfarin therapy, therapy with the newer agents is not routinely monitored with laboratory tests, so toxicity (or underdosing) may not be recognized until an adverse clinical event occurs. Ultimately, it may be safer to resume anticoagulation after a contributing drug can be safely discontinued.

Advanced age

The influence that the patient’s age should have on the decision to restart anticoagulation is unclear. Although the risk of intracranial hemorrhage increases with age, particularly after age 80, limited data exist in this population, particularly with regard to rebleeding. Further, age is a major risk factor for most thrombotic events, including venous thromboembolism and stroke from atrial fibrillation, so although the risks of anticoagulation may be higher, the benefits may also be higher than in younger patients.^37,46 We discourage using age alone as a reason to withhold anticoagulation after a hemorrhage.

HOW LONG SHOULD WE WAIT TO RESTART ANTICOAGULATION?

We lack conclusive data on how long to wait to restart anticoagulation after an anticoagulation-associated hemorrhage.

The decision is complicated by evidence suggesting a rebound effect, with an increased risk of pulmonary embolism and atrial fibrillation-related stroke during the first 90 days of interruption of therapy with warfarin as well as with target-specific oral anticoagulants.^3–8 In anticoagulation-associated retroperitoneal bleeding, there is increased risk of deep vein thrombosis from compression, even if venous thromboembolism was not the initial indication for anticoagulation.³⁰

In patients with intracranial hemorrhage, evidence suggests that the intracranial hemorrhage itself increases the risk of arterial and venous thromboembolic events. Irrespective of whether a patient was previously on anticoagulation, the risk of arterial and venous thromboembolic events approaches 7% during the initial intracranial hemorrhage-related hospitalization and 9% during the first 90 days.^34,50,51

To date, the only information we have about when to resume anticoagulation comes from patients taking vitamin K antagonists.

Timing after gastrointestinal bleeding

Small case series suggest that in the first 2 months after warfarin-associated gastrointestinal bleeding, there is substantial risk of rebleeding when anticoagulation is resumed—and of thrombosis when it is not.^52,53 Two retrospective cohort studies may provide some guidance in this dilemma.^28,54

A workup for GI bleeding and gross hematuria uncovers previously undetected lesions in about one-third of cases involving warfarin

Witt et al²⁸ followed 442 patients who presented with gastrointestinal bleeding from any site during warfarin therapy for varied indications for up to 90 days after the index bleeding event. The risk of death was three times lower in patients who restarted warfarin than in those who did not, and their rate of thrombotic events was 10 times lower. The risk of recurrent gastrointestinal bleeding was statistically insignificant, and there were no fatal bleeding events. Anticoagulant therapy was generally resumed within 1 week of the bleeding event, at a median of 4 days.^28,55

Qureshi et al⁵⁴ performed a retrospective cohort study of 1,329 patients with  nonvalvular atrial fibrillation who had experienced a gastrointestinal hemorrhage while taking warfarin. They found that resuming warfarin after 7 days was not associated with a higher risk of recurrent gastrointestinal bleeding and that the rates of death and thromboembolism were lower than in patients who resumed warfarin after 30 days. On the other hand, the risk of recurrent gastrointestinal bleeding was significantly greater if therapy was resumed within the first week.

In view of these studies, we believe that most patients should resume anticoagulation after 4 to 7 days of interruption after gastrointestinal bleeding.⁵⁵

Timing after soft-tissue hemorrhage

The literature on resuming anticoagulation after soft-tissue hemorrhage is sparse. A retrospective study⁵² looked at this question in patients with spontaneous rectal sheath hematoma who had been receiving  antiplatelet drugs, intravenous heparin, vitamin K antagonists, or a combination of these, but not target-specific agents. More than half of the patients were on vitamin K antagonists at the time of hemorrhage. Analysis suggested that when benefits of resuming anticoagulation are believed to outweigh risks, it is reasonable to resume anticoagulation 4 days after the index event.⁵⁶

Timing after intracranial hemorrhage

Anticoagulation should not be considered within the first 24 hours after intracranial hemorrhage, as over 70% of patients develop some amount of hematoma expansion during this time.^34,57 The period thereafter poses a challenge, as the risk of hematoma expansion decreases while the risk of arterial and venous thromboembolism is ongoing and cumulative.⁵⁰

Perhaps surprisingly, national guidelines suggest starting prophylactic-dosed anticoagulation early in all intracranial hemorrhage patients, including those not previously on warfarin.^58,59 In a randomized trial, Boeer et al⁶⁰ concluded that starting low-dose subcutaneous heparin the day after an intracranial hemorrhage decreased the risk of thromboembolism without increasing the risk of rebleeding.⁶⁰ Dickmann et al⁶¹ similarly concluded that there was no increased risk of rebleeding with early prophylactic-dosed subcutaneous heparin.⁶¹ Optimal mechanical thromboprophylaxis, including graduated compression stockings and intermittent pneumatic compression stockings, is also encouraged.³⁴

We discourage using age alone as a reason to withhold anticoagulation after a hemorrhage

Expert opinion remains divided on when and if anticoagulants should be resumed.^34,62 The American Heart Association suggests that in nonvalvular atrial fibrillation, long-term anticoagulation should be avoided after spontaneous lobar hemorrhage; antiplatelet agents can be considered instead.⁵⁸ In nonlobar hemorrhage, the American Heart Association suggests that anticoagulation be considered, depending on strength of indication, 7 to 10 days after the onset.⁵⁸ The European Stroke Initiative suggests patients with strong indications for anticoagulation be restarted on warfarin 10 to 14 days after the event, depending on the risk of thromboembolism and recurrent intracranial hemorrhage.⁵⁹ Others suggest delaying resumption to 10 to 30 weeks after an index intracranial hemorrhage.⁶³

Overall, in the immediate acute period of intracranial hemorrhage, most patients will likely benefit from acute reversal of anticoagulation, followed by institution of prophylactic-dose anticoagulation after the first 24 hours. Going forward, patients who remain at higher risk of a recurrence of anticoagulant-related intracranial hemorrhage (such as those with lobar hemorrhage, suspected cerebral amyloid angiopathy, and other high-risk factors) than of thromboembolic events may be best managed without anticoagulants. Alternatively, patients with deep hemispheric intracranial hemorrhage, hypertension that can be well controlled, and a high risk of serious thromboembolism may experience net benefit from restarting anticoagulation.³⁴

We recommend considering restarting anticoagulation 7 days after the onset of intracranial hemorrhage in patients at high risk of thromboembolism and after at least 14 days for patients at lower risk (Table 2). Discussions with neurologic and neurosurgical consultants should also inform this timing decision.

WOULD A NEWER DRUG BE A BETTER CHOICE?

The emergence of target-specific oral anticoagulants, including factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban and the direct thrombin inhibitor dabigatran etexilate, presents further challenges in managing anticoagulation after hemorrhage. Table 4 summarizes the current FDA-approved indications.^64–67

These newer agents are attractive because, compared with warfarin, they have wider therapeutic windows, faster onset and offset of action, and fewer drug and food interactions.⁶⁸ A meta-analysis of data available to date suggests that the new drugs, compared with warfarin, show a favorable risk-benefit profile with reductions in stroke, intracranial hemorrhage, and mortality with similar overall major bleeding rates, except for a possible increase in gastrointestinal bleeding.⁶⁸

However, when managing anticoagulation after a bleeding event, the newer agents are challenging for two reasons: they may be associated with a higher incidence of gastrointestinal bleeding than warfarin, and they lack the typical reversal agents that can be used to manage an acute bleeding event.^68,69

In individual studies comparing warfarin with dabigatran,⁷⁰ rivaroxaban,⁷¹ apixaban,⁷² or edoxaban⁷³ for stroke prevention in patients with atrial fibrillation, there was no significant difference in the rate of major bleeding between dabigatran in its higher dose (150 mg twice a day) or rivaroxaban compared with warfarin.^70,71 The risk of major bleeding was actually lower with apixaban⁷² and edoxaban.⁷³

In regard to specific types of major bleeding, the rate of intracranial hemorrhage was significantly lower with dabigatran, rivaroxaban, apixaban, and edoxaban than with warfarin.^35,68–73 Some have proposed that since the brain is high in tissue factor, inhibition of tissue factor-factor VIIa complexes by vitamin K antagonists leaves the brain vulnerable to hemorrhage. Others suggest that the targeted mechanism of target-specific agents, as opposed to the multiple pathways in both the intrinsic and extrinsic coagulation cascade that vitamin K antagonists affect, may explain this difference.^35,74,75

However, some studies suggest that rivaroxaban and the higher doses of dabigatran and edoxaban are associated with higher rates of major gastrointestinal bleeding compared with warfarin.^69–71,76 But apixaban demonstrated no significant difference in gastrointestinal bleeding, and instead demonstrated rates of gastrointestinal bleeding comparable to that with aspirin for stroke prevention in atrial fibrillation.⁷²

The new oral anticoagulants lack antidotes or reversal agents such as phytonadione and fresh-frozen plasma that are available to manage warfarin-associated bleeding events. Other proposed reversal options for the new agents include activated charcoal (if the drugs were taken recently enough to remain in the gastrointestinal tract) and concentrated clotting factor product, though research is ongoing in regards to the most appropriate use in clinical practice.^37,69 Unlike rivaroxaban and apixaban, dabigatran has low plasma protein binding and is dialyzable, which provides another strategy in managing dabigatran-related bleeding.⁶⁹

We believe most patients should resume anticoagulation after 4 to 7 days of interruption after GI bleeding

Of note, the above bleeding risk calculations relate to the first anticoagulant-related bleeding event, though presumably the same risk comparison across agents may be applicable to rebleeding events. Given the data above, when anticoagulation is to be resumed after an intracranial hemorrhage, the risk of rebleeding, particularly in the form of recurrent intracranial hemorrhage, may be lower if a target-specific oral anticoagulant is used.⁷⁵ Similarly, when anticoagulation is to be resumed after a gastrointestinal bleeding event, reinitiation with warfarin or apixaban therapy may present the lowest risk of recurrent gastrointestinal rebleeding. In other sources of bleeding, such as retroperitoneal bleeding, we suggest consideration of transitioning to warfarin, given the availability of reversal agents in the event of recurrent bleeding.

Other important drug-specific factors that must be noted when selecting an agent with which to resume anticoagulation after a hemorrhage include the following:

• In patients with significant renal impairment, the choice of agent will be limited to a vitamin K antagonist.⁷⁷
• A meta-analysis of randomized clinical trials suggests that in the elderly (age 75 and older) target-specific oral anticoagulants did not cause excess bleeding and were associated with at least equal efficacy compared with vitamin K antagonists.⁷⁸
• Target-specific oral anticoagulants may be beneficial in patients who have challenges in achieving INR targets, as evidence suggests that switching to them is associated with a reduction in bleeding for patients who struggle to maintain an appropriately therapeutic INR.⁶⁸ On the other hand, if there is concern that a patient may occasionally miss doses of an anticoagulant, given the rapid onset and offset of action of target-specific agents compared with warfarin, a missed dose of a target-specific agent may result in faster dissolution of anticoagulant effect and increased risk of thrombotic events, and lapses in anticoagulation will not be identified by routine drug monitoring.^6–8,75 As such, it is vital to have a frank discussion with any patient who has difficulty maintaining therapeutic INRs on warfarin treatment to make sure that he or she is not missing doses.
• If there is no clear and compelling reason to select a particular agent, cost considerations should be taken into account. We have included estimated 30-day pricing for the various agents in Table 4. 

If a patient receiving anticoagulant therapy suffers a bleeding event, the patient and physician must decide whether and how soon to restart the therapy, and with what agent.

Foremost on our minds tends to be the risk of another hemorrhage. Subtler to appreciate immediately after an event is the continued risk of thrombosis, often from the same medical condition that prompted anticoagulation therapy in the first place (Table 1).

Complicating the decision, there may be a rebound effect: some thrombotic events such as pulmonary embolism and atrial fibrillation-related stroke may be more likely to occur in the first weeks after stopping warfarin than during similar intervals in patients who have not been taking it.^1–3 The same thing may happen with the newer, target-specific oral anticoagulants.^4–6

Although we have evidence-based guidelines for initiating and managing anticoagulant therapy, ample data on adverse events, and protocols for reversing anticoagulation if bleeding occurs, we do not have clear guidelines on restarting anticoagulation after a hemorrhagic event.

In this article, we outline a practical framework for approaching this clinical dilemma. Used in conjunction with consideration of a patient’s values and preferences as well as input from experts, this framework can help clinicians guide their patients through this challenging clinical decision. It consists of five questions:

• Why is the patient on anticoagulation, and what is the risk of thromboembolism without it?
• What was the clinical impact of the hemorrhage, and what is the risk of rebleeding if anticoagulation is resumed?
• What additional patient factors should be taken into consideration?
• How long should we wait before restarting anticoagulation?
• Would a newer drug be a better choice?

BLEEDING OCCURS IN 2% TO 3% OF PATIENTS PER YEAR

Most of our information on anticoagulation is about vitamin K antagonists—principally warfarin, in use since the 1950s. Among patients taking warfarin outside of clinical trials, the risk of major bleeding is estimated at 2% to 3% per year.⁷

However, the target-specific oral anticoagulants rivaroxaban (Xarelto), apixaban (Eliquis),  dabigatran (Pradaxa) and edoxaban (Savaysa) are being used more and more, and we include them in our discussion insofar as we have information on them. The rates of bleeding with these new drugs in clinical trials have been comparable to or lower than those with warfarin.⁸ Postmarketing surveillance is under way.

WHY IS THE PATIENT ON ANTICOAGULATION? WHAT IS THE RISK WITHOUT IT?

Common, evidence-based indications for anticoagulation are to prevent complications in patients with venous thromboembolism and to prevent stroke in patients with atrial fibrillation or a mechanical heart valve. Other uses, such as in heart failure and its sequelae, pulmonary hypertension, and splanchnic or hepatic vein thrombosis, have less robust evidence to support them.

When anticoagulation-related bleeding occurs, it is essential to review why the patient is taking the drug and the risk of thromboembolism without it. Some indications pose a higher risk of thromboembolism than others and so argue more strongly for continuing the treatment.

Douketis et al⁹ developed a risk-stratification scheme for perioperative thromboembolism. We have modified it by adding the CHA₂DS₂-VASc score (Table 2),^9–11 and believe it can be used more widely.

High-risk indications

Conditions that pose a high risk of thrombosis almost always require restarting anticoagulation. Here, the most appropriate question nearly always is not if anticoagulation should be restarted, but when. Examples:

• A mechanical mitral valve
• Antiphospholipid antibody syndrome with recurrent thromboembolic events.

Lower-risk indications

Lower-risk indications allow more leeway in determining if anticoagulation should be resumed. The most straightforward cases fall well within established guidelines. Examples:

• Atrial fibrillation and a CHA₂DS₂-VASc score of 1. The 2014 guidelines from the American College of Cardiology, American Heart Association, and Heart Rhythm Society¹⁰ suggest that patients with nonvalvular atrial fibrillation and a CHA₂DS₂-VASc score of 1 have three options: an oral anticoagulant, aspirin, and no antithrombotic therapy. If such a patient on anticoagulant therapy subsequently experiences a major gastrointestinal hemorrhage requiring transfusion and intensive care and no definitively treatable source of bleeding is found on endoscopy, one can argue that the risks of continued anticoagulation (recurrent bleeding) now exceed the benefits and that the patient would be better served by aspirin or even no antithrombotic therapy.

• After 6 months of anticoagulation for unprovoked deep vein thrombosis. Several studies showed that aspirin reduced the risk of recurrent venous thromboembolism in patients who completed an initial 6-month course of anticoagulation.^12–15 Though these studies did not specifically compare aspirin with warfarin or target-specific oral anticoagulants in preventing recurrent venous thromboembolism after a hemorrhage, it is reasonable to extrapolate their results to this situation.

If the risk of recurrent hemorrhage on anticoagulation is considered to be too great, then aspirin is an alternative to no anticoagulation, as it reduces the risk of recurrent venous thromboembolism.¹⁶ However, we advise caution if the bleeding lesion may be specifically exacerbated by aspirin, particularly upper gastrointestinal ulcers.

Moderate-risk indications

• After a partial course of anticoagulation for provoked venous thromboembolism. Suppose a patient in the 10th week of a planned 12-week course of anticoagulation for a surgically provoked, first deep vein thrombosis presents with abdominal pain and is found to have a retroperitoneal hematoma. In light of the risk of recurrent bleeding vs the benefit of resuming anticoagulation for the limited remaining period, her 12-week treatment course can reasonably be shortened to 10 weeks.

The risk of recurrent venous thromboembolism when a patient is off anticoagulation decreases with time from the initial event. The highest risk, estimated at 0.3% to 1.3% per day, is in the first 4 weeks, falling to 0.03% to 0.2% per day in weeks 5 through 12, and 0.05% per day thereafter.^17–20

The risk of recurrent venous thromboembolism is greatest immediately after the event and decreases over time

Additionally, a pooled analysis of seven randomized trials suggests that patients with isolated, distal deep vein thrombosis provoked by a temporary risk factor did not have a high risk of recurrence after being treated for 4 to 6 weeks.²¹ These analyses are based on vitamin K antagonists, though it seems reasonable to extrapolate this information to the target-specific oral anticoagulants.

More challenging are situations in which the evidence supporting the initial or continued need for anticoagulation is less robust, such as in heart failure, pulmonary hypertension, or splanchnic and hepatic vein thrombosis. In these cases, the lack of strong evidence supporting the use of anticoagulation should make us hesitate to resume it after bleeding.

WHAT WAS THE CLINICAL IMPACT? WHAT IS THE RISK OF REBLEEDING?

Different groups have defined major and minor bleeding in different ways.^22,23 Several have proposed criteria to standardize how bleeding events (on warfarin and otherwise) are classified,^23–25 but the definitions differ.

Specifically, all agree that a “major” bleeding event is one that is fatal, involves bleeding into a major organ, or leads to a substantial decline in hemoglobin level. However, the Thrombolysis in Myocardial Infarction trials use a decline of more than 5 g/dL in their definition,^23,25 while the International Society on Thrombosis and Haemostasis uses 2 g/dL.²⁴

Here, we review the clinical impact of the most common sources of anticoagulation-related hemorrhage—gastrointestinal, soft tissue, and urinary tract²⁶—as well as intracerebral hemorrhage, a less common but more uniformly devastating event.²⁷

Clinical impact of gastrointestinal hemorrhage

Each year, about 4.5% of patients taking warfarin have a gastrointestinal hemorrhage, though not all of these events are major.²⁸ Evolving data suggest that the newer agents (particularly dabigatran, rivaroxaban, and edoxaban) pose a higher risk of gastrointestinal bleeding than warfarin.²⁹ Patients may need plasma and blood transfusions and intravenous phytonadione, all of which carry risks, albeit small.

Frequently, endoscopy is needed to find the source of bleeding and to control it. If this does not work, angiographic intervention to infuse vasoconstrictors or embolic coils into the culprit artery may be required, and some patients need surgery. Each intervention carries its own risk.

Clinical impact of soft-tissue hemorrhage

Soft-tissue hemorrhage accounts for more than 20% of warfarin-related bleeding events²⁶; as yet, we know of no data on the rate with the new drugs. Soft-tissue hemorrhage is often localized to the large muscles of the retroperitoneum and legs. Though retroperitoneal hemorrhage accounts for a relatively small portion of soft-tissue hemorrhages, it is associated with high rates of morbidity and death and will therefore be our focus.²⁶

Some indications for anticoagulation pose a higher risk of thromboembolism than others

Much of the clinical impact of retroperitoneal hemorrhage is from a mass effect that causes abdominal compartment syndrome, hydroureter, ileus, abscess formation, and acute and chronic pain. At least 20% of cases are associated with femoral neuropathy. It can also lead to deep vein thrombosis from venous compression, coupled with hypercoagulability in response to bleeding. Brisk bleeding can lead to shock and death, and the mortality rate in retroperitoneal hemorrhage is estimated at 20% or higher.³⁰

In many cases, the retroperitoneal hemorrhage will self-tamponade and the blood will be reabsorbed once the bleeding has stopped, but uncontrolled bleeding may require surgical or angiographic intervention.³⁰

Clinical impact of urinary tract hemorrhage

Gross or microscopic hematuria can be found in an estimated 2% to 24% of patients taking warfarin^31–33; data are lacking for the target-specific oral anticoagulants. Interventions required to manage urinary tract bleeding include bladder irrigation and, less often, transfusion.³¹ Since a significant number of cases of hematuria are due to neoplastic disease,³² a diagnostic workup with radiographic imaging of the upper tract and cystoscopy of the lower tract is usually required.³¹ While life-threatening hemorrhage is uncommon, complications such as transient urinary obstruction from clots may occur.

Clinical impact of intracranial hemorrhage

Intracranial hemorrhage is the most feared and deadly of the bleeding complications of anticoagulation. The incidence in patients on warfarin is estimated at 2% to 3% per year, which is markedly higher than the estimated incidence of 25 per 100,000 person-years in the general population.³⁴ Emerging data indicate that the newer drugs are also associated with a risk of intracranial hemorrhage, though the risk is about half that with vitamin K antagonists.³⁵ Intracranial hemorrhage leads to death or disability in 76% of cases, compared with 3% of cases of bleeding from the gastrointestinal or urinary tract.²⁷

Regardless of the source of bleeding, hospitalization is likely to be required and may be  prolonged, with attendant risks of nosocomial harms such as infection.

Risk of rebleeding

Given the scope and severity of anticoagulation-related bleeding, there is strong interest in predicting and preventing it. By some estimates, the incidence of recurrent bleeding after resuming vitamin K antagonists is 8% to 13%.²² Although there are several indices for predicting the risk of major bleeding when starting anticoagulation, there are currently no validated tools to estimate a patient’s risk of rebleeding.³⁶

The patient factor that most consistently predicts major bleeding is a history of bleeding, particularly from the gastrointestinal tract. Finding and controlling the source of bleeding is important.^26,37 For example, a patient with gross hematuria who is found on cystoscopy to have a urothelial papilloma is unlikely to have rebleeding if the tumor is successfully resected and serial follow-up shows no regrowth. In contrast, consider a patient with a major gastrointestinal hemorrhage, the source of which remains elusive after upper, lower, and capsule endoscopy or, alternatively, is suspected to be from one of multiple angiodysplastic lesions. Without definitive source management, this patient faces a high risk of rebleeding.

With or without anticoagulation, after a first intracranial hemorrhage the risk of another one is estimated at 2% to 4% per year.³⁴ An observational study found a recurrence rate of 7.5% when vitamin K antagonist therapy was started after an intracranial hemorrhage (though not all patients were on a vitamin K antagonist at the time of the first hemorrhage).³⁸

Evolving data suggest the newer oral agents pose a higher risk of GI bleeding

Patients with lobar hemorrhage and those with suspected cerebral amyloid angiopathy may be at particularly high risk if anticoagulation is resumed. Conversely, initial events attributed to uncontrolled hypertension that subsequently can be well controlled may portend a lower risk of rebleeding.³⁴ For other types of intracranial hemorrhage, recurrence rates can be even higher. Irrespective of anticoagulation, one prospective study estimated the crude annual rebleeding rate with untreated arteriovenous malformations to be 7%.³⁹ In chronic subdural hematoma, the recurrence rate after initial drainage has been estimated at 9.2% to 26.5%, with use of anticoagulants (in this case, vitamin K antagonists) being an independent predictor of recurrence.⁴⁰

WHAT OTHER PATIENT FACTORS NEED CONSIDERATION?

Target INR on warfarin

An important factor influencing the risk of bleeding with warfarin is the intensity of this therapy.³⁷ A meta-analysis⁴¹ found that the risks of major hemorrhage and thromboembolism are minimized if the goal international normalized ratio (INR) is 2.0 to 3.0. When considering resuming anticoagulation after bleeding, make sure the therapeutic target is appropriate.³⁷

Table 3 summarizes recommended therapeutic ranges for frequently encountered indications for warfarin.^36,42,43

INR at time of the event and challenges in controlling it

The decision to resume anticoagulation in patients who bled while using warfarin must take into account the actual INR at the time of the event.

For example, consider a patient whose INR values are consistently in the therapeutic range.  While on vacation, he receives ciprofloxacin for acute prostatitis from an urgent care team, and no adjustment to INR monitoring or warfarin dose is made. Several days later, he presents with lower gastrointestinal bleeding. His INR is 8, and colonoscopy reveals diverticulosis with a bleeding vessel, responsive to endoscopic therapy. After controlling the source of bleeding and reinforcing the need to always review new medications for potential interactions with anticoagulation, it is reasonable to expect that he once again will be able to keep his INR in the therapeutic range.

A patient on anticoagulation for the same indication but who has a history of repeated supratherapeutic levels, poor adherence, or poor access to INR monitoring poses very different concerns about resuming anticoagulation (as well as which agent to use, as we discuss below).

Of note, a high INR alone does not explain bleeding. It is estimated that a workup for gastrointestinal bleeding and gross hematuria uncovers previously undetected lesions in approximately one-third of cases involving warfarin.²⁶ A similar malignancy-unmasking effect is now recognized in patients using the target-specific oral agents who experience gastrointestinal bleeding.⁴⁴ Accordingly, we recommend a comprehensive source evaluation for any anticoagulation-related hemorrhage.

Comorbid conditions

Comorbid conditions associated with bleeding include cancer, end-stage renal disease, liver disease, arterial hypertension, prior stroke, and alcohol abuse.^37,45 Gait instability, regardless of cause, may also increase the risk of trauma-related hemorrhage, but some have estimated that a patient would need to fall multiple times per week to contraindicate anticoagulation on the basis of falls alone.⁴⁶

Concurrent medications

Concomitant therapies, including antiplatelet drugs and nonsteroidal anti-inflammatory drugs, increase bleeding risk.^47,48 Aspirin and the nonsteroidals, in addition to having antiplatelet effects, also can cause gastric erosion.³⁷ In evaluating whether and when to restart anticoagulation, it is advisable to review the role that concomitant therapies may have had in the index bleeding event and to evaluate the risks and benefits of these other agents.

The factor that most consistently predicts major bleeding is a history of bleeding, particularly gastrointestinal bleeding

Additionally, warfarin has many interactions. Although the newer drugs are lauded for having fewer interactions, they are not completely free of them, and the potential for interactions must always be reviewed.⁴⁹ Further, unlike warfarin therapy, therapy with the newer agents is not routinely monitored with laboratory tests, so toxicity (or underdosing) may not be recognized until an adverse clinical event occurs. Ultimately, it may be safer to resume anticoagulation after a contributing drug can be safely discontinued.

Advanced age

The influence that the patient’s age should have on the decision to restart anticoagulation is unclear. Although the risk of intracranial hemorrhage increases with age, particularly after age 80, limited data exist in this population, particularly with regard to rebleeding. Further, age is a major risk factor for most thrombotic events, including venous thromboembolism and stroke from atrial fibrillation, so although the risks of anticoagulation may be higher, the benefits may also be higher than in younger patients.^37,46 We discourage using age alone as a reason to withhold anticoagulation after a hemorrhage.

HOW LONG SHOULD WE WAIT TO RESTART ANTICOAGULATION?

We lack conclusive data on how long to wait to restart anticoagulation after an anticoagulation-associated hemorrhage.

The decision is complicated by evidence suggesting a rebound effect, with an increased risk of pulmonary embolism and atrial fibrillation-related stroke during the first 90 days of interruption of therapy with warfarin as well as with target-specific oral anticoagulants.^3–8 In anticoagulation-associated retroperitoneal bleeding, there is increased risk of deep vein thrombosis from compression, even if venous thromboembolism was not the initial indication for anticoagulation.³⁰

In patients with intracranial hemorrhage, evidence suggests that the intracranial hemorrhage itself increases the risk of arterial and venous thromboembolic events. Irrespective of whether a patient was previously on anticoagulation, the risk of arterial and venous thromboembolic events approaches 7% during the initial intracranial hemorrhage-related hospitalization and 9% during the first 90 days.^34,50,51

To date, the only information we have about when to resume anticoagulation comes from patients taking vitamin K antagonists.

Timing after gastrointestinal bleeding

Small case series suggest that in the first 2 months after warfarin-associated gastrointestinal bleeding, there is substantial risk of rebleeding when anticoagulation is resumed—and of thrombosis when it is not.^52,53 Two retrospective cohort studies may provide some guidance in this dilemma.^28,54

A workup for GI bleeding and gross hematuria uncovers previously undetected lesions in about one-third of cases involving warfarin

Witt et al²⁸ followed 442 patients who presented with gastrointestinal bleeding from any site during warfarin therapy for varied indications for up to 90 days after the index bleeding event. The risk of death was three times lower in patients who restarted warfarin than in those who did not, and their rate of thrombotic events was 10 times lower. The risk of recurrent gastrointestinal bleeding was statistically insignificant, and there were no fatal bleeding events. Anticoagulant therapy was generally resumed within 1 week of the bleeding event, at a median of 4 days.^28,55

Qureshi et al⁵⁴ performed a retrospective cohort study of 1,329 patients with  nonvalvular atrial fibrillation who had experienced a gastrointestinal hemorrhage while taking warfarin. They found that resuming warfarin after 7 days was not associated with a higher risk of recurrent gastrointestinal bleeding and that the rates of death and thromboembolism were lower than in patients who resumed warfarin after 30 days. On the other hand, the risk of recurrent gastrointestinal bleeding was significantly greater if therapy was resumed within the first week.

In view of these studies, we believe that most patients should resume anticoagulation after 4 to 7 days of interruption after gastrointestinal bleeding.⁵⁵

Timing after soft-tissue hemorrhage

The literature on resuming anticoagulation after soft-tissue hemorrhage is sparse. A retrospective study⁵² looked at this question in patients with spontaneous rectal sheath hematoma who had been receiving  antiplatelet drugs, intravenous heparin, vitamin K antagonists, or a combination of these, but not target-specific agents. More than half of the patients were on vitamin K antagonists at the time of hemorrhage. Analysis suggested that when benefits of resuming anticoagulation are believed to outweigh risks, it is reasonable to resume anticoagulation 4 days after the index event.⁵⁶

Timing after intracranial hemorrhage

Anticoagulation should not be considered within the first 24 hours after intracranial hemorrhage, as over 70% of patients develop some amount of hematoma expansion during this time.^34,57 The period thereafter poses a challenge, as the risk of hematoma expansion decreases while the risk of arterial and venous thromboembolism is ongoing and cumulative.⁵⁰

Perhaps surprisingly, national guidelines suggest starting prophylactic-dosed anticoagulation early in all intracranial hemorrhage patients, including those not previously on warfarin.^58,59 In a randomized trial, Boeer et al⁶⁰ concluded that starting low-dose subcutaneous heparin the day after an intracranial hemorrhage decreased the risk of thromboembolism without increasing the risk of rebleeding.⁶⁰ Dickmann et al⁶¹ similarly concluded that there was no increased risk of rebleeding with early prophylactic-dosed subcutaneous heparin.⁶¹ Optimal mechanical thromboprophylaxis, including graduated compression stockings and intermittent pneumatic compression stockings, is also encouraged.³⁴

We discourage using age alone as a reason to withhold anticoagulation after a hemorrhage

Expert opinion remains divided on when and if anticoagulants should be resumed.^34,62 The American Heart Association suggests that in nonvalvular atrial fibrillation, long-term anticoagulation should be avoided after spontaneous lobar hemorrhage; antiplatelet agents can be considered instead.⁵⁸ In nonlobar hemorrhage, the American Heart Association suggests that anticoagulation be considered, depending on strength of indication, 7 to 10 days after the onset.⁵⁸ The European Stroke Initiative suggests patients with strong indications for anticoagulation be restarted on warfarin 10 to 14 days after the event, depending on the risk of thromboembolism and recurrent intracranial hemorrhage.⁵⁹ Others suggest delaying resumption to 10 to 30 weeks after an index intracranial hemorrhage.⁶³

Overall, in the immediate acute period of intracranial hemorrhage, most patients will likely benefit from acute reversal of anticoagulation, followed by institution of prophylactic-dose anticoagulation after the first 24 hours. Going forward, patients who remain at higher risk of a recurrence of anticoagulant-related intracranial hemorrhage (such as those with lobar hemorrhage, suspected cerebral amyloid angiopathy, and other high-risk factors) than of thromboembolic events may be best managed without anticoagulants. Alternatively, patients with deep hemispheric intracranial hemorrhage, hypertension that can be well controlled, and a high risk of serious thromboembolism may experience net benefit from restarting anticoagulation.³⁴

We recommend considering restarting anticoagulation 7 days after the onset of intracranial hemorrhage in patients at high risk of thromboembolism and after at least 14 days for patients at lower risk (Table 2). Discussions with neurologic and neurosurgical consultants should also inform this timing decision.

WOULD A NEWER DRUG BE A BETTER CHOICE?

The emergence of target-specific oral anticoagulants, including factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban and the direct thrombin inhibitor dabigatran etexilate, presents further challenges in managing anticoagulation after hemorrhage. Table 4 summarizes the current FDA-approved indications.^64–67

These newer agents are attractive because, compared with warfarin, they have wider therapeutic windows, faster onset and offset of action, and fewer drug and food interactions.⁶⁸ A meta-analysis of data available to date suggests that the new drugs, compared with warfarin, show a favorable risk-benefit profile with reductions in stroke, intracranial hemorrhage, and mortality with similar overall major bleeding rates, except for a possible increase in gastrointestinal bleeding.⁶⁸

However, when managing anticoagulation after a bleeding event, the newer agents are challenging for two reasons: they may be associated with a higher incidence of gastrointestinal bleeding than warfarin, and they lack the typical reversal agents that can be used to manage an acute bleeding event.^68,69

In individual studies comparing warfarin with dabigatran,⁷⁰ rivaroxaban,⁷¹ apixaban,⁷² or edoxaban⁷³ for stroke prevention in patients with atrial fibrillation, there was no significant difference in the rate of major bleeding between dabigatran in its higher dose (150 mg twice a day) or rivaroxaban compared with warfarin.^70,71 The risk of major bleeding was actually lower with apixaban⁷² and edoxaban.⁷³

In regard to specific types of major bleeding, the rate of intracranial hemorrhage was significantly lower with dabigatran, rivaroxaban, apixaban, and edoxaban than with warfarin.^35,68–73 Some have proposed that since the brain is high in tissue factor, inhibition of tissue factor-factor VIIa complexes by vitamin K antagonists leaves the brain vulnerable to hemorrhage. Others suggest that the targeted mechanism of target-specific agents, as opposed to the multiple pathways in both the intrinsic and extrinsic coagulation cascade that vitamin K antagonists affect, may explain this difference.^35,74,75

However, some studies suggest that rivaroxaban and the higher doses of dabigatran and edoxaban are associated with higher rates of major gastrointestinal bleeding compared with warfarin.^69–71,76 But apixaban demonstrated no significant difference in gastrointestinal bleeding, and instead demonstrated rates of gastrointestinal bleeding comparable to that with aspirin for stroke prevention in atrial fibrillation.⁷²

The new oral anticoagulants lack antidotes or reversal agents such as phytonadione and fresh-frozen plasma that are available to manage warfarin-associated bleeding events. Other proposed reversal options for the new agents include activated charcoal (if the drugs were taken recently enough to remain in the gastrointestinal tract) and concentrated clotting factor product, though research is ongoing in regards to the most appropriate use in clinical practice.^37,69 Unlike rivaroxaban and apixaban, dabigatran has low plasma protein binding and is dialyzable, which provides another strategy in managing dabigatran-related bleeding.⁶⁹

We believe most patients should resume anticoagulation after 4 to 7 days of interruption after GI bleeding

Of note, the above bleeding risk calculations relate to the first anticoagulant-related bleeding event, though presumably the same risk comparison across agents may be applicable to rebleeding events. Given the data above, when anticoagulation is to be resumed after an intracranial hemorrhage, the risk of rebleeding, particularly in the form of recurrent intracranial hemorrhage, may be lower if a target-specific oral anticoagulant is used.⁷⁵ Similarly, when anticoagulation is to be resumed after a gastrointestinal bleeding event, reinitiation with warfarin or apixaban therapy may present the lowest risk of recurrent gastrointestinal rebleeding. In other sources of bleeding, such as retroperitoneal bleeding, we suggest consideration of transitioning to warfarin, given the availability of reversal agents in the event of recurrent bleeding.

Other important drug-specific factors that must be noted when selecting an agent with which to resume anticoagulation after a hemorrhage include the following:

• In patients with significant renal impairment, the choice of agent will be limited to a vitamin K antagonist.⁷⁷
• A meta-analysis of randomized clinical trials suggests that in the elderly (age 75 and older) target-specific oral anticoagulants did not cause excess bleeding and were associated with at least equal efficacy compared with vitamin K antagonists.⁷⁸
• Target-specific oral anticoagulants may be beneficial in patients who have challenges in achieving INR targets, as evidence suggests that switching to them is associated with a reduction in bleeding for patients who struggle to maintain an appropriately therapeutic INR.⁶⁸ On the other hand, if there is concern that a patient may occasionally miss doses of an anticoagulant, given the rapid onset and offset of action of target-specific agents compared with warfarin, a missed dose of a target-specific agent may result in faster dissolution of anticoagulant effect and increased risk of thrombotic events, and lapses in anticoagulation will not be identified by routine drug monitoring.^6–8,75 As such, it is vital to have a frank discussion with any patient who has difficulty maintaining therapeutic INRs on warfarin treatment to make sure that he or she is not missing doses.
• If there is no clear and compelling reason to select a particular agent, cost considerations should be taken into account. We have included estimated 30-day pricing for the various agents in Table 4. 

If a patient receiving anticoagulant therapy suffers a bleeding event, the patient and physician must decide whether and how soon to restart the therapy, and with what agent.

Foremost on our minds tends to be the risk of another hemorrhage. Subtler to appreciate immediately after an event is the continued risk of thrombosis, often from the same medical condition that prompted anticoagulation therapy in the first place (Table 1).

Complicating the decision, there may be a rebound effect: some thrombotic events such as pulmonary embolism and atrial fibrillation-related stroke may be more likely to occur in the first weeks after stopping warfarin than during similar intervals in patients who have not been taking it.^1–3 The same thing may happen with the newer, target-specific oral anticoagulants.^4–6

Although we have evidence-based guidelines for initiating and managing anticoagulant therapy, ample data on adverse events, and protocols for reversing anticoagulation if bleeding occurs, we do not have clear guidelines on restarting anticoagulation after a hemorrhagic event.

In this article, we outline a practical framework for approaching this clinical dilemma. Used in conjunction with consideration of a patient’s values and preferences as well as input from experts, this framework can help clinicians guide their patients through this challenging clinical decision. It consists of five questions:

• Why is the patient on anticoagulation, and what is the risk of thromboembolism without it?
• What was the clinical impact of the hemorrhage, and what is the risk of rebleeding if anticoagulation is resumed?
• What additional patient factors should be taken into consideration?
• How long should we wait before restarting anticoagulation?
• Would a newer drug be a better choice?

BLEEDING OCCURS IN 2% TO 3% OF PATIENTS PER YEAR

Most of our information on anticoagulation is about vitamin K antagonists—principally warfarin, in use since the 1950s. Among patients taking warfarin outside of clinical trials, the risk of major bleeding is estimated at 2% to 3% per year.⁷

However, the target-specific oral anticoagulants rivaroxaban (Xarelto), apixaban (Eliquis),  dabigatran (Pradaxa) and edoxaban (Savaysa) are being used more and more, and we include them in our discussion insofar as we have information on them. The rates of bleeding with these new drugs in clinical trials have been comparable to or lower than those with warfarin.⁸ Postmarketing surveillance is under way.

WHY IS THE PATIENT ON ANTICOAGULATION? WHAT IS THE RISK WITHOUT IT?

Common, evidence-based indications for anticoagulation are to prevent complications in patients with venous thromboembolism and to prevent stroke in patients with atrial fibrillation or a mechanical heart valve. Other uses, such as in heart failure and its sequelae, pulmonary hypertension, and splanchnic or hepatic vein thrombosis, have less robust evidence to support them.

When anticoagulation-related bleeding occurs, it is essential to review why the patient is taking the drug and the risk of thromboembolism without it. Some indications pose a higher risk of thromboembolism than others and so argue more strongly for continuing the treatment.

Douketis et al⁹ developed a risk-stratification scheme for perioperative thromboembolism. We have modified it by adding the CHA₂DS₂-VASc score (Table 2),^9–11 and believe it can be used more widely.

High-risk indications

Conditions that pose a high risk of thrombosis almost always require restarting anticoagulation. Here, the most appropriate question nearly always is not if anticoagulation should be restarted, but when. Examples:

• A mechanical mitral valve
• Antiphospholipid antibody syndrome with recurrent thromboembolic events.

Lower-risk indications

Lower-risk indications allow more leeway in determining if anticoagulation should be resumed. The most straightforward cases fall well within established guidelines. Examples:

• Atrial fibrillation and a CHA₂DS₂-VASc score of 1. The 2014 guidelines from the American College of Cardiology, American Heart Association, and Heart Rhythm Society¹⁰ suggest that patients with nonvalvular atrial fibrillation and a CHA₂DS₂-VASc score of 1 have three options: an oral anticoagulant, aspirin, and no antithrombotic therapy. If such a patient on anticoagulant therapy subsequently experiences a major gastrointestinal hemorrhage requiring transfusion and intensive care and no definitively treatable source of bleeding is found on endoscopy, one can argue that the risks of continued anticoagulation (recurrent bleeding) now exceed the benefits and that the patient would be better served by aspirin or even no antithrombotic therapy.

• After 6 months of anticoagulation for unprovoked deep vein thrombosis. Several studies showed that aspirin reduced the risk of recurrent venous thromboembolism in patients who completed an initial 6-month course of anticoagulation.^12–15 Though these studies did not specifically compare aspirin with warfarin or target-specific oral anticoagulants in preventing recurrent venous thromboembolism after a hemorrhage, it is reasonable to extrapolate their results to this situation.

If the risk of recurrent hemorrhage on anticoagulation is considered to be too great, then aspirin is an alternative to no anticoagulation, as it reduces the risk of recurrent venous thromboembolism.¹⁶ However, we advise caution if the bleeding lesion may be specifically exacerbated by aspirin, particularly upper gastrointestinal ulcers.

Moderate-risk indications

• After a partial course of anticoagulation for provoked venous thromboembolism. Suppose a patient in the 10th week of a planned 12-week course of anticoagulation for a surgically provoked, first deep vein thrombosis presents with abdominal pain and is found to have a retroperitoneal hematoma. In light of the risk of recurrent bleeding vs the benefit of resuming anticoagulation for the limited remaining period, her 12-week treatment course can reasonably be shortened to 10 weeks.

The risk of recurrent venous thromboembolism when a patient is off anticoagulation decreases with time from the initial event. The highest risk, estimated at 0.3% to 1.3% per day, is in the first 4 weeks, falling to 0.03% to 0.2% per day in weeks 5 through 12, and 0.05% per day thereafter.^17–20

The risk of recurrent venous thromboembolism is greatest immediately after the event and decreases over time

Additionally, a pooled analysis of seven randomized trials suggests that patients with isolated, distal deep vein thrombosis provoked by a temporary risk factor did not have a high risk of recurrence after being treated for 4 to 6 weeks.²¹ These analyses are based on vitamin K antagonists, though it seems reasonable to extrapolate this information to the target-specific oral anticoagulants.

More challenging are situations in which the evidence supporting the initial or continued need for anticoagulation is less robust, such as in heart failure, pulmonary hypertension, or splanchnic and hepatic vein thrombosis. In these cases, the lack of strong evidence supporting the use of anticoagulation should make us hesitate to resume it after bleeding.

WHAT WAS THE CLINICAL IMPACT? WHAT IS THE RISK OF REBLEEDING?

Different groups have defined major and minor bleeding in different ways.^22,23 Several have proposed criteria to standardize how bleeding events (on warfarin and otherwise) are classified,^23–25 but the definitions differ.

Specifically, all agree that a “major” bleeding event is one that is fatal, involves bleeding into a major organ, or leads to a substantial decline in hemoglobin level. However, the Thrombolysis in Myocardial Infarction trials use a decline of more than 5 g/dL in their definition,^23,25 while the International Society on Thrombosis and Haemostasis uses 2 g/dL.²⁴

Here, we review the clinical impact of the most common sources of anticoagulation-related hemorrhage—gastrointestinal, soft tissue, and urinary tract²⁶—as well as intracerebral hemorrhage, a less common but more uniformly devastating event.²⁷

Clinical impact of gastrointestinal hemorrhage

Each year, about 4.5% of patients taking warfarin have a gastrointestinal hemorrhage, though not all of these events are major.²⁸ Evolving data suggest that the newer agents (particularly dabigatran, rivaroxaban, and edoxaban) pose a higher risk of gastrointestinal bleeding than warfarin.²⁹ Patients may need plasma and blood transfusions and intravenous phytonadione, all of which carry risks, albeit small.

Frequently, endoscopy is needed to find the source of bleeding and to control it. If this does not work, angiographic intervention to infuse vasoconstrictors or embolic coils into the culprit artery may be required, and some patients need surgery. Each intervention carries its own risk.

Clinical impact of soft-tissue hemorrhage

Soft-tissue hemorrhage accounts for more than 20% of warfarin-related bleeding events²⁶; as yet, we know of no data on the rate with the new drugs. Soft-tissue hemorrhage is often localized to the large muscles of the retroperitoneum and legs. Though retroperitoneal hemorrhage accounts for a relatively small portion of soft-tissue hemorrhages, it is associated with high rates of morbidity and death and will therefore be our focus.²⁶

Some indications for anticoagulation pose a higher risk of thromboembolism than others

Much of the clinical impact of retroperitoneal hemorrhage is from a mass effect that causes abdominal compartment syndrome, hydroureter, ileus, abscess formation, and acute and chronic pain. At least 20% of cases are associated with femoral neuropathy. It can also lead to deep vein thrombosis from venous compression, coupled with hypercoagulability in response to bleeding. Brisk bleeding can lead to shock and death, and the mortality rate in retroperitoneal hemorrhage is estimated at 20% or higher.³⁰

In many cases, the retroperitoneal hemorrhage will self-tamponade and the blood will be reabsorbed once the bleeding has stopped, but uncontrolled bleeding may require surgical or angiographic intervention.³⁰

Clinical impact of urinary tract hemorrhage

Gross or microscopic hematuria can be found in an estimated 2% to 24% of patients taking warfarin^31–33; data are lacking for the target-specific oral anticoagulants. Interventions required to manage urinary tract bleeding include bladder irrigation and, less often, transfusion.³¹ Since a significant number of cases of hematuria are due to neoplastic disease,³² a diagnostic workup with radiographic imaging of the upper tract and cystoscopy of the lower tract is usually required.³¹ While life-threatening hemorrhage is uncommon, complications such as transient urinary obstruction from clots may occur.

Clinical impact of intracranial hemorrhage

Intracranial hemorrhage is the most feared and deadly of the bleeding complications of anticoagulation. The incidence in patients on warfarin is estimated at 2% to 3% per year, which is markedly higher than the estimated incidence of 25 per 100,000 person-years in the general population.³⁴ Emerging data indicate that the newer drugs are also associated with a risk of intracranial hemorrhage, though the risk is about half that with vitamin K antagonists.³⁵ Intracranial hemorrhage leads to death or disability in 76% of cases, compared with 3% of cases of bleeding from the gastrointestinal or urinary tract.²⁷

Regardless of the source of bleeding, hospitalization is likely to be required and may be  prolonged, with attendant risks of nosocomial harms such as infection.

Risk of rebleeding

Given the scope and severity of anticoagulation-related bleeding, there is strong interest in predicting and preventing it. By some estimates, the incidence of recurrent bleeding after resuming vitamin K antagonists is 8% to 13%.²² Although there are several indices for predicting the risk of major bleeding when starting anticoagulation, there are currently no validated tools to estimate a patient’s risk of rebleeding.³⁶

The patient factor that most consistently predicts major bleeding is a history of bleeding, particularly from the gastrointestinal tract. Finding and controlling the source of bleeding is important.^26,37 For example, a patient with gross hematuria who is found on cystoscopy to have a urothelial papilloma is unlikely to have rebleeding if the tumor is successfully resected and serial follow-up shows no regrowth. In contrast, consider a patient with a major gastrointestinal hemorrhage, the source of which remains elusive after upper, lower, and capsule endoscopy or, alternatively, is suspected to be from one of multiple angiodysplastic lesions. Without definitive source management, this patient faces a high risk of rebleeding.

With or without anticoagulation, after a first intracranial hemorrhage the risk of another one is estimated at 2% to 4% per year.³⁴ An observational study found a recurrence rate of 7.5% when vitamin K antagonist therapy was started after an intracranial hemorrhage (though not all patients were on a vitamin K antagonist at the time of the first hemorrhage).³⁸

Evolving data suggest the newer oral agents pose a higher risk of GI bleeding

Patients with lobar hemorrhage and those with suspected cerebral amyloid angiopathy may be at particularly high risk if anticoagulation is resumed. Conversely, initial events attributed to uncontrolled hypertension that subsequently can be well controlled may portend a lower risk of rebleeding.³⁴ For other types of intracranial hemorrhage, recurrence rates can be even higher. Irrespective of anticoagulation, one prospective study estimated the crude annual rebleeding rate with untreated arteriovenous malformations to be 7%.³⁹ In chronic subdural hematoma, the recurrence rate after initial drainage has been estimated at 9.2% to 26.5%, with use of anticoagulants (in this case, vitamin K antagonists) being an independent predictor of recurrence.⁴⁰

WHAT OTHER PATIENT FACTORS NEED CONSIDERATION?

Target INR on warfarin

An important factor influencing the risk of bleeding with warfarin is the intensity of this therapy.³⁷ A meta-analysis⁴¹ found that the risks of major hemorrhage and thromboembolism are minimized if the goal international normalized ratio (INR) is 2.0 to 3.0. When considering resuming anticoagulation after bleeding, make sure the therapeutic target is appropriate.³⁷

Table 3 summarizes recommended therapeutic ranges for frequently encountered indications for warfarin.^36,42,43

INR at time of the event and challenges in controlling it

The decision to resume anticoagulation in patients who bled while using warfarin must take into account the actual INR at the time of the event.

For example, consider a patient whose INR values are consistently in the therapeutic range.  While on vacation, he receives ciprofloxacin for acute prostatitis from an urgent care team, and no adjustment to INR monitoring or warfarin dose is made. Several days later, he presents with lower gastrointestinal bleeding. His INR is 8, and colonoscopy reveals diverticulosis with a bleeding vessel, responsive to endoscopic therapy. After controlling the source of bleeding and reinforcing the need to always review new medications for potential interactions with anticoagulation, it is reasonable to expect that he once again will be able to keep his INR in the therapeutic range.

A patient on anticoagulation for the same indication but who has a history of repeated supratherapeutic levels, poor adherence, or poor access to INR monitoring poses very different concerns about resuming anticoagulation (as well as which agent to use, as we discuss below).

Of note, a high INR alone does not explain bleeding. It is estimated that a workup for gastrointestinal bleeding and gross hematuria uncovers previously undetected lesions in approximately one-third of cases involving warfarin.²⁶ A similar malignancy-unmasking effect is now recognized in patients using the target-specific oral agents who experience gastrointestinal bleeding.⁴⁴ Accordingly, we recommend a comprehensive source evaluation for any anticoagulation-related hemorrhage.

Comorbid conditions

Comorbid conditions associated with bleeding include cancer, end-stage renal disease, liver disease, arterial hypertension, prior stroke, and alcohol abuse.^37,45 Gait instability, regardless of cause, may also increase the risk of trauma-related hemorrhage, but some have estimated that a patient would need to fall multiple times per week to contraindicate anticoagulation on the basis of falls alone.⁴⁶

Concurrent medications

Concomitant therapies, including antiplatelet drugs and nonsteroidal anti-inflammatory drugs, increase bleeding risk.^47,48 Aspirin and the nonsteroidals, in addition to having antiplatelet effects, also can cause gastric erosion.³⁷ In evaluating whether and when to restart anticoagulation, it is advisable to review the role that concomitant therapies may have had in the index bleeding event and to evaluate the risks and benefits of these other agents.

The factor that most consistently predicts major bleeding is a history of bleeding, particularly gastrointestinal bleeding

Additionally, warfarin has many interactions. Although the newer drugs are lauded for having fewer interactions, they are not completely free of them, and the potential for interactions must always be reviewed.⁴⁹ Further, unlike warfarin therapy, therapy with the newer agents is not routinely monitored with laboratory tests, so toxicity (or underdosing) may not be recognized until an adverse clinical event occurs. Ultimately, it may be safer to resume anticoagulation after a contributing drug can be safely discontinued.

Advanced age

The influence that the patient’s age should have on the decision to restart anticoagulation is unclear. Although the risk of intracranial hemorrhage increases with age, particularly after age 80, limited data exist in this population, particularly with regard to rebleeding. Further, age is a major risk factor for most thrombotic events, including venous thromboembolism and stroke from atrial fibrillation, so although the risks of anticoagulation may be higher, the benefits may also be higher than in younger patients.^37,46 We discourage using age alone as a reason to withhold anticoagulation after a hemorrhage.

HOW LONG SHOULD WE WAIT TO RESTART ANTICOAGULATION?

We lack conclusive data on how long to wait to restart anticoagulation after an anticoagulation-associated hemorrhage.

The decision is complicated by evidence suggesting a rebound effect, with an increased risk of pulmonary embolism and atrial fibrillation-related stroke during the first 90 days of interruption of therapy with warfarin as well as with target-specific oral anticoagulants.^3–8 In anticoagulation-associated retroperitoneal bleeding, there is increased risk of deep vein thrombosis from compression, even if venous thromboembolism was not the initial indication for anticoagulation.³⁰

In patients with intracranial hemorrhage, evidence suggests that the intracranial hemorrhage itself increases the risk of arterial and venous thromboembolic events. Irrespective of whether a patient was previously on anticoagulation, the risk of arterial and venous thromboembolic events approaches 7% during the initial intracranial hemorrhage-related hospitalization and 9% during the first 90 days.^34,50,51

To date, the only information we have about when to resume anticoagulation comes from patients taking vitamin K antagonists.

Timing after gastrointestinal bleeding

Small case series suggest that in the first 2 months after warfarin-associated gastrointestinal bleeding, there is substantial risk of rebleeding when anticoagulation is resumed—and of thrombosis when it is not.^52,53 Two retrospective cohort studies may provide some guidance in this dilemma.^28,54

A workup for GI bleeding and gross hematuria uncovers previously undetected lesions in about one-third of cases involving warfarin

Witt et al²⁸ followed 442 patients who presented with gastrointestinal bleeding from any site during warfarin therapy for varied indications for up to 90 days after the index bleeding event. The risk of death was three times lower in patients who restarted warfarin than in those who did not, and their rate of thrombotic events was 10 times lower. The risk of recurrent gastrointestinal bleeding was statistically insignificant, and there were no fatal bleeding events. Anticoagulant therapy was generally resumed within 1 week of the bleeding event, at a median of 4 days.^28,55

Qureshi et al⁵⁴ performed a retrospective cohort study of 1,329 patients with  nonvalvular atrial fibrillation who had experienced a gastrointestinal hemorrhage while taking warfarin. They found that resuming warfarin after 7 days was not associated with a higher risk of recurrent gastrointestinal bleeding and that the rates of death and thromboembolism were lower than in patients who resumed warfarin after 30 days. On the other hand, the risk of recurrent gastrointestinal bleeding was significantly greater if therapy was resumed within the first week.

In view of these studies, we believe that most patients should resume anticoagulation after 4 to 7 days of interruption after gastrointestinal bleeding.⁵⁵

Timing after soft-tissue hemorrhage

The literature on resuming anticoagulation after soft-tissue hemorrhage is sparse. A retrospective study⁵² looked at this question in patients with spontaneous rectal sheath hematoma who had been receiving  antiplatelet drugs, intravenous heparin, vitamin K antagonists, or a combination of these, but not target-specific agents. More than half of the patients were on vitamin K antagonists at the time of hemorrhage. Analysis suggested that when benefits of resuming anticoagulation are believed to outweigh risks, it is reasonable to resume anticoagulation 4 days after the index event.⁵⁶

Timing after intracranial hemorrhage

Anticoagulation should not be considered within the first 24 hours after intracranial hemorrhage, as over 70% of patients develop some amount of hematoma expansion during this time.^34,57 The period thereafter poses a challenge, as the risk of hematoma expansion decreases while the risk of arterial and venous thromboembolism is ongoing and cumulative.⁵⁰

Perhaps surprisingly, national guidelines suggest starting prophylactic-dosed anticoagulation early in all intracranial hemorrhage patients, including those not previously on warfarin.^58,59 In a randomized trial, Boeer et al⁶⁰ concluded that starting low-dose subcutaneous heparin the day after an intracranial hemorrhage decreased the risk of thromboembolism without increasing the risk of rebleeding.⁶⁰ Dickmann et al⁶¹ similarly concluded that there was no increased risk of rebleeding with early prophylactic-dosed subcutaneous heparin.⁶¹ Optimal mechanical thromboprophylaxis, including graduated compression stockings and intermittent pneumatic compression stockings, is also encouraged.³⁴

We discourage using age alone as a reason to withhold anticoagulation after a hemorrhage

Expert opinion remains divided on when and if anticoagulants should be resumed.^34,62 The American Heart Association suggests that in nonvalvular atrial fibrillation, long-term anticoagulation should be avoided after spontaneous lobar hemorrhage; antiplatelet agents can be considered instead.⁵⁸ In nonlobar hemorrhage, the American Heart Association suggests that anticoagulation be considered, depending on strength of indication, 7 to 10 days after the onset.⁵⁸ The European Stroke Initiative suggests patients with strong indications for anticoagulation be restarted on warfarin 10 to 14 days after the event, depending on the risk of thromboembolism and recurrent intracranial hemorrhage.⁵⁹ Others suggest delaying resumption to 10 to 30 weeks after an index intracranial hemorrhage.⁶³

Overall, in the immediate acute period of intracranial hemorrhage, most patients will likely benefit from acute reversal of anticoagulation, followed by institution of prophylactic-dose anticoagulation after the first 24 hours. Going forward, patients who remain at higher risk of a recurrence of anticoagulant-related intracranial hemorrhage (such as those with lobar hemorrhage, suspected cerebral amyloid angiopathy, and other high-risk factors) than of thromboembolic events may be best managed without anticoagulants. Alternatively, patients with deep hemispheric intracranial hemorrhage, hypertension that can be well controlled, and a high risk of serious thromboembolism may experience net benefit from restarting anticoagulation.³⁴

We recommend considering restarting anticoagulation 7 days after the onset of intracranial hemorrhage in patients at high risk of thromboembolism and after at least 14 days for patients at lower risk (Table 2). Discussions with neurologic and neurosurgical consultants should also inform this timing decision.

WOULD A NEWER DRUG BE A BETTER CHOICE?

The emergence of target-specific oral anticoagulants, including factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban and the direct thrombin inhibitor dabigatran etexilate, presents further challenges in managing anticoagulation after hemorrhage. Table 4 summarizes the current FDA-approved indications.^64–67

These newer agents are attractive because, compared with warfarin, they have wider therapeutic windows, faster onset and offset of action, and fewer drug and food interactions.⁶⁸ A meta-analysis of data available to date suggests that the new drugs, compared with warfarin, show a favorable risk-benefit profile with reductions in stroke, intracranial hemorrhage, and mortality with similar overall major bleeding rates, except for a possible increase in gastrointestinal bleeding.⁶⁸

However, when managing anticoagulation after a bleeding event, the newer agents are challenging for two reasons: they may be associated with a higher incidence of gastrointestinal bleeding than warfarin, and they lack the typical reversal agents that can be used to manage an acute bleeding event.^68,69

In individual studies comparing warfarin with dabigatran,⁷⁰ rivaroxaban,⁷¹ apixaban,⁷² or edoxaban⁷³ for stroke prevention in patients with atrial fibrillation, there was no significant difference in the rate of major bleeding between dabigatran in its higher dose (150 mg twice a day) or rivaroxaban compared with warfarin.^70,71 The risk of major bleeding was actually lower with apixaban⁷² and edoxaban.⁷³

In regard to specific types of major bleeding, the rate of intracranial hemorrhage was significantly lower with dabigatran, rivaroxaban, apixaban, and edoxaban than with warfarin.^35,68–73 Some have proposed that since the brain is high in tissue factor, inhibition of tissue factor-factor VIIa complexes by vitamin K antagonists leaves the brain vulnerable to hemorrhage. Others suggest that the targeted mechanism of target-specific agents, as opposed to the multiple pathways in both the intrinsic and extrinsic coagulation cascade that vitamin K antagonists affect, may explain this difference.^35,74,75

However, some studies suggest that rivaroxaban and the higher doses of dabigatran and edoxaban are associated with higher rates of major gastrointestinal bleeding compared with warfarin.^69–71,76 But apixaban demonstrated no significant difference in gastrointestinal bleeding, and instead demonstrated rates of gastrointestinal bleeding comparable to that with aspirin for stroke prevention in atrial fibrillation.⁷²

The new oral anticoagulants lack antidotes or reversal agents such as phytonadione and fresh-frozen plasma that are available to manage warfarin-associated bleeding events. Other proposed reversal options for the new agents include activated charcoal (if the drugs were taken recently enough to remain in the gastrointestinal tract) and concentrated clotting factor product, though research is ongoing in regards to the most appropriate use in clinical practice.^37,69 Unlike rivaroxaban and apixaban, dabigatran has low plasma protein binding and is dialyzable, which provides another strategy in managing dabigatran-related bleeding.⁶⁹

We believe most patients should resume anticoagulation after 4 to 7 days of interruption after GI bleeding

Of note, the above bleeding risk calculations relate to the first anticoagulant-related bleeding event, though presumably the same risk comparison across agents may be applicable to rebleeding events. Given the data above, when anticoagulation is to be resumed after an intracranial hemorrhage, the risk of rebleeding, particularly in the form of recurrent intracranial hemorrhage, may be lower if a target-specific oral anticoagulant is used.⁷⁵ Similarly, when anticoagulation is to be resumed after a gastrointestinal bleeding event, reinitiation with warfarin or apixaban therapy may present the lowest risk of recurrent gastrointestinal rebleeding. In other sources of bleeding, such as retroperitoneal bleeding, we suggest consideration of transitioning to warfarin, given the availability of reversal agents in the event of recurrent bleeding.

Other important drug-specific factors that must be noted when selecting an agent with which to resume anticoagulation after a hemorrhage include the following:

• In patients with significant renal impairment, the choice of agent will be limited to a vitamin K antagonist.⁷⁷
• A meta-analysis of randomized clinical trials suggests that in the elderly (age 75 and older) target-specific oral anticoagulants did not cause excess bleeding and were associated with at least equal efficacy compared with vitamin K antagonists.⁷⁸
• Target-specific oral anticoagulants may be beneficial in patients who have challenges in achieving INR targets, as evidence suggests that switching to them is associated with a reduction in bleeding for patients who struggle to maintain an appropriately therapeutic INR.⁶⁸ On the other hand, if there is concern that a patient may occasionally miss doses of an anticoagulant, given the rapid onset and offset of action of target-specific agents compared with warfarin, a missed dose of a target-specific agent may result in faster dissolution of anticoagulant effect and increased risk of thrombotic events, and lapses in anticoagulation will not be identified by routine drug monitoring.^6–8,75 As such, it is vital to have a frank discussion with any patient who has difficulty maintaining therapeutic INRs on warfarin treatment to make sure that he or she is not missing doses.
• If there is no clear and compelling reason to select a particular agent, cost considerations should be taken into account. We have included estimated 30-day pricing for the various agents in Table 4. 

Intraneural ganglion cysts of peripheral nerves occurring within the epineural sheath are rare.^1-7 Case reports exist primarily within the neurosurgical literature, but very little in the orthopedic literature describes this condition. The peripheral nerve most commonly affected by an intraneural ganglion is the common peroneal nerve (CPN).^2,8,9 Such ganglia most often afflict middle-aged men with a history of micro- or macro-trauma and present with typical clinical manifestations of calf pain and progressive symptoms of ipsilateral foot drop and lower leg paresthesia.^2-5,10-12 The mechanism by which these ganglia form is not well understood and, as a result, treatment options are debated.⁶ Recent development of a “unified articular theory,” suggests that such intraneural ganglia of the CPN are fed by a small, recurrent articular branch of the CPN.^6,12,13 Cadaveric studies indicate that this branch originates from the deep peroneal nerve, just millimeters distal to the bifurcation of the CPN, and extends to the superior tibiofibular joint, providing direct access for cyst fluid to enter the CPN following the path of least resistance.^7,8,12,14 Therefore, according to the unified articular theory, the recommended treatment involves division of the articular branch, allowing the ganglion to be decompressed.⁶

We present a case of a 41-year-old man with an intraneural ganglion cyst of the CPN who was successfully treated, according to the recommendations of the unified articular theory. It is important for orthopedic surgeons to read about and recognize this condition, because knowledge of the operative technique outlined in our report allows it to be treated quite effectively. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 41-year-old man presented with a 2-month history of traumatic left lateral knee pain with numbness and weakness to the left foot and ankle. Initial examination showed a mild restriction of lumbosacral range of motion, with no complaints of lower back pain. Sciatic root stretch signs were negative. Strength testing of the lower extremities revealed 3+/5 strength of ankle dorsiflexion and great toe extension on the left side. There was a mild alteration in sensation to light touch on the lateral side of the left foot. Tenderness, without swelling, was present around the left fibular head. There was a positive Tinel sign over the peroneal nerve at the level of the fibular neck.

The patient was initially treated with anti-inflammatories and activity modification. An electromyogram (EMG)/nerve conduction study of the lower extremity showed a left peroneal nerve neurapraxia at the level of the fibular head. Noncontrast magnetic resonance imaging (MRI) of the left knee showed a “slightly prominent vein coursing posterior to the fibular head near the expected location of the common peroneal nerve,” according to the radiologist’s notes (Figure 1). The patient exhibited improvement with use of anti-inflammatories over several months. There was an increase in his ankle dorsiflexion strength to 4/5 and improvement in his pain and numbness.

Approximately 7 months after his initial presentation, the patient developed a marked worsening—increased numbness and weakness to ankle dorsiflexion—of his original symptoms. A repeat EMG/nerve conduction study of the lower extremity showed a persistent peroneal nerve neuropathy with a persistent denervation of the extensor hallucis longus, tibialis anterior, and extensor digitorum brevis muscles.

Because of continuing symptoms and increasing pain, the patient had surgery 8 months after his initial presentation. At that time, a markedly thickened peroneal nerve was identified. An incision in the epineural sheath released a clear gelatinous fluid consistent with a ganglion cyst. Through the epineural incision, the nerve was decompressed by manually “milking” the fluid from within the sheath. Approximately  30 mL of mucinous fluid was obtained and sent to pathology. No cells were identified.

Postoperatively, the patient noted a marked improvement in his pain. By 2 weeks postoperatively, the numbness in his foot had resolved. At 6 weeks after surgery, the strength of his tibialis anterior and extensor hallucis longus muscles had improved from 3+ to 4-, and he was free of pain.

At 2 months postoperatively, the patient redeveloped pain and numbness, and noted progressive weakness of his left foot and ankle. A repeat MRI of the left knee showed a dilated tubular structure corresponding to the course of the CPN. Comparison of this MRI with the initial MRI showed that the “prominent vein” was actually the dilated CPN.

He was taken to the operating room again 5 months after his first operation. At this time, the CPN was again noted to be markedly dilated (Figure 2). The nerve was explored and a recurrent branch to the proximal tibiofibular joint was identified and divided (Figures 3, 4). Through the divided branch, the CPN could be decompressed by manually “milking” the nerve in a proximal-to-distal direction, expressing clear gelatinous fluid consistent with a ganglion cyst (Figure 5). Pathology of the excised portion of the recurrent nerve was consistent with an intraneural ganglion cyst.

By 2 weeks postoperatively, the numbness of the patient’s left foot had completely resolved, as did his pain. By 3 months after surgery, his extensor hallucis longus strength was 5/5, and ankle dorsiflexion was 4-/5. At 6 months, his ankle dorsiflexion strength was 5/5, and he was completely asymptomatic. At 2 years postoperatively, he remained completely asymptomatic. A follow-up MRI of the left knee showed a ganglion cyst present at the proximal tibiofibular joint with resolution of the intraneural ganglion cyst within the CPN (Figure 6).

Discussion

Intraneural ganglia of peripheral nerves are relatively rare, most commonly occurring in the CPN.^6,8,9 A literature search reveals that this condition is only sparsely reported in orthopedic journals. This report, therefore, describes this rare, yet curable, condition. As noted, without appropriate intervention, the condition has a high likelihood of recurrence with only a brief interruption of symptoms.^6,8,9,12

The operative technique delineated in this report relies heavily on research demonstrating that peroneal intraneural ganglia develop from the superior tibiofibular joint and gain access to the CPN via the recurrent articular branch.^8,13 Research indicates that such ganglia preferentially proceed proximally along the deep portion of the CPN, within the epineurium.⁶ This hypothesis was corroborated in our case by the swollen appearance of the CPN proximal to its bifurcation.

Currently, there is no consensus on treatment of intraneural ganglion cysts of the CPN. However, evidence suggests that disconnection of the recurrent branch of the CPN may be important in successfully treating the condition.^6,9,14 This unified articular theory was initially proposed by Spinner and colleagues¹² in 2003 and recommends that surgical treatment focus on the articular branch as the source of cyst fluid.^6,9,12,14 This theory by Spinner and coauthors^12,14 was substantiated in our case: Once the articular branch was disconnected, cyst fluid was easily expressed via antegrade massage through the disconnected end. Pathologic analysis of a portion of the detached articular branch is also recommended to rule out other cystic lesions, such as cystic shwannomas.¹⁴

The history of the unified articular theory began in the mid-1990s, when Dr. Robert Spinner, board certified in both orthopedic and neurologic surgery, began researching causes of intraneural ganglion cysts. At the time, such ganglia were often treated by radical resection of the nerve and the cyst. Based on his review of literature, and his own cases, Spinner¹⁵ developed the theory that, just as with extraneural ganglia, these cysts are fed by fluid from the joint. According to Spinner,⁹ the sources of such connections were very small articular nerve branches that connect the nerve to the joint. His research led him to the original citation of such an intraneural ganglion of the ulnar nerve, first described by Dr. M. Beauchene, a French physician, in 1810.¹⁶ Spinner also discovered that Beauchene’s original dissection specimen had been preserved and was displayed in a medical museum in Paris. When Spinner went to France to view the specimen, he indeed found an intraneural ganglion of the ulnar nerve. On closer inspection, Spinner also discovered a small articular nerve branch containing a “hollow lumen” that would have been capable of allowing the passage of fluid into the nerve and leading to the development of a cyst.¹⁶

In our case, in the first operation, a simple incisional decompression of the CPN was performed. Unfortunately, the ganglion cyst quickly recurred, as did the patient’s symptoms. In the second surgical procedure, the articular branch connecting the peroneal nerve to the proximal tibiofibular joint was incised and disconnected from the nerve. This allowed the nerve to be decompressed and prevented a recurrence of the ganglion cyst within the nerve with complete resolution of the patient’s symptoms. This difference alone most likely accounts for the rapid recurrence of symptoms after the initial operation, since the fluid was simply drained, but the source was not detached, allowing the ganglion to recur.^6,12,14 This is similar in theory to excising the attachment of a ganglion cyst at the wrist from the underlying joint capsule rather than performing a needle aspiration or puncturing of the cyst.¹²

Regarding the imaging techniques used to identify intraneural ganglia, it is essential that the surgeon be aware of the unified articular theory and the likely presence of an articular branch. Such branches are extremely small and may be easily missed on imaging and intraoperatively.^17,18 MRI is the best method to image these cysts because of its superior ability to visualize soft-tissue lesions.^18,19 Intraneural ganglion cysts typically appear as homogenous, lobulated, well-circumscribed masses that are hyperintense on T2-weighted MRI.^3,19 Gadolinium may also offer diagnostic utility, because these masses do not enhance with its use on T1-weighted MRI.^3,17,19 By employing these techniques, one may easily view most of the ganglion cyst. To image the small articular branch, Spinner and colleagues¹⁷ recommend thin-section images with high–spatial resolution T2-imaging. They also advocate obtaining multiple image views and planes to increase the likelihood of successful imaging.¹⁷ 

The applications of the unified articular theory also extend beyond intraneural ganglia of the CPN. While the CPN is the most common location for intraneural ganglion occurrence,^6,17,20 cases have also been described of intraneural ganglion cysts of the tibial nerve at the proximal tibiofibular joint, as well as via the posterior tibial and medial plantar nerves at the subtalar joint within the tarsal tunnel.^11,18-23 Most cases involving the posterior tibial and medial plantar nerves were found in patients presenting with signs of tarsal tunnel syndrome.^22,23 Intraneural ganglia have also been found within the superficial peroneal nerve arising from the inferior tibiofibular joint.²⁰ In certain cases, these ganglia have also been noted to connect to the joint via a small articular branch.^19,22 In 1 case of an intraneural ganglion of the tibial nerve at the superior tibiofibular joint, initial conservative surgery led to early recurrence of symptoms.¹⁹ Just as in our case, the patient returned to the operating room and, after isolation and ligation of an articular branch, the patient experienced long-term resolution of both the symptoms and the cyst.¹⁹

Given the overwhelming evidence in support of the unified articular theory, we agree with the recommendation by Spinner and colleagues¹⁹ to search for an articular branch both via preoperative imaging and during the operation itself in all cases of intraneural ganglia. Assuming the mechanism of cyst formation is the same in most cases of intraneural ganglia, one could reasonably apply the same surgical techniques used in our case to the management of all intraneural ganglia, drastically reducing recurrence rates.

Conclusion

Based on research and corroborated by this case, the key to successful operative treatment of a common peroneal intraneural ganglion is division of the recurrent articular branch, which connects the proximal tibiofibular joint to the CPN.^6,9,11,12,14 Evidence has shown that disconnecting the articular branch and disrupting the source of the intraneural ganglion can resolve the condition and dramatically diminish the chance of recurrence.^6,8,12,14 This has become known as the unified articular theory.^6,12,14 Reports also suggest that, without disconnecting this articular branch, intraneural ganglion recurrence rates may be higher than 30%.^6,12,14,19 This case, therefore, supports the findings of previous authors^9-11,14 and provides an example of successful utilization of the treatment protocol delineated by Spinner and colleagues.^10,11

Intraneural ganglion cysts of peripheral nerves occurring within the epineural sheath are rare.^1-7 Case reports exist primarily within the neurosurgical literature, but very little in the orthopedic literature describes this condition. The peripheral nerve most commonly affected by an intraneural ganglion is the common peroneal nerve (CPN).^2,8,9 Such ganglia most often afflict middle-aged men with a history of micro- or macro-trauma and present with typical clinical manifestations of calf pain and progressive symptoms of ipsilateral foot drop and lower leg paresthesia.^2-5,10-12 The mechanism by which these ganglia form is not well understood and, as a result, treatment options are debated.⁶ Recent development of a “unified articular theory,” suggests that such intraneural ganglia of the CPN are fed by a small, recurrent articular branch of the CPN.^6,12,13 Cadaveric studies indicate that this branch originates from the deep peroneal nerve, just millimeters distal to the bifurcation of the CPN, and extends to the superior tibiofibular joint, providing direct access for cyst fluid to enter the CPN following the path of least resistance.^7,8,12,14 Therefore, according to the unified articular theory, the recommended treatment involves division of the articular branch, allowing the ganglion to be decompressed.⁶

We present a case of a 41-year-old man with an intraneural ganglion cyst of the CPN who was successfully treated, according to the recommendations of the unified articular theory. It is important for orthopedic surgeons to read about and recognize this condition, because knowledge of the operative technique outlined in our report allows it to be treated quite effectively. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 41-year-old man presented with a 2-month history of traumatic left lateral knee pain with numbness and weakness to the left foot and ankle. Initial examination showed a mild restriction of lumbosacral range of motion, with no complaints of lower back pain. Sciatic root stretch signs were negative. Strength testing of the lower extremities revealed 3+/5 strength of ankle dorsiflexion and great toe extension on the left side. There was a mild alteration in sensation to light touch on the lateral side of the left foot. Tenderness, without swelling, was present around the left fibular head. There was a positive Tinel sign over the peroneal nerve at the level of the fibular neck.

The patient was initially treated with anti-inflammatories and activity modification. An electromyogram (EMG)/nerve conduction study of the lower extremity showed a left peroneal nerve neurapraxia at the level of the fibular head. Noncontrast magnetic resonance imaging (MRI) of the left knee showed a “slightly prominent vein coursing posterior to the fibular head near the expected location of the common peroneal nerve,” according to the radiologist’s notes (Figure 1). The patient exhibited improvement with use of anti-inflammatories over several months. There was an increase in his ankle dorsiflexion strength to 4/5 and improvement in his pain and numbness.

Approximately 7 months after his initial presentation, the patient developed a marked worsening—increased numbness and weakness to ankle dorsiflexion—of his original symptoms. A repeat EMG/nerve conduction study of the lower extremity showed a persistent peroneal nerve neuropathy with a persistent denervation of the extensor hallucis longus, tibialis anterior, and extensor digitorum brevis muscles.

Because of continuing symptoms and increasing pain, the patient had surgery 8 months after his initial presentation. At that time, a markedly thickened peroneal nerve was identified. An incision in the epineural sheath released a clear gelatinous fluid consistent with a ganglion cyst. Through the epineural incision, the nerve was decompressed by manually “milking” the fluid from within the sheath. Approximately  30 mL of mucinous fluid was obtained and sent to pathology. No cells were identified.

Postoperatively, the patient noted a marked improvement in his pain. By 2 weeks postoperatively, the numbness in his foot had resolved. At 6 weeks after surgery, the strength of his tibialis anterior and extensor hallucis longus muscles had improved from 3+ to 4-, and he was free of pain.

At 2 months postoperatively, the patient redeveloped pain and numbness, and noted progressive weakness of his left foot and ankle. A repeat MRI of the left knee showed a dilated tubular structure corresponding to the course of the CPN. Comparison of this MRI with the initial MRI showed that the “prominent vein” was actually the dilated CPN.

He was taken to the operating room again 5 months after his first operation. At this time, the CPN was again noted to be markedly dilated (Figure 2). The nerve was explored and a recurrent branch to the proximal tibiofibular joint was identified and divided (Figures 3, 4). Through the divided branch, the CPN could be decompressed by manually “milking” the nerve in a proximal-to-distal direction, expressing clear gelatinous fluid consistent with a ganglion cyst (Figure 5). Pathology of the excised portion of the recurrent nerve was consistent with an intraneural ganglion cyst.

By 2 weeks postoperatively, the numbness of the patient’s left foot had completely resolved, as did his pain. By 3 months after surgery, his extensor hallucis longus strength was 5/5, and ankle dorsiflexion was 4-/5. At 6 months, his ankle dorsiflexion strength was 5/5, and he was completely asymptomatic. At 2 years postoperatively, he remained completely asymptomatic. A follow-up MRI of the left knee showed a ganglion cyst present at the proximal tibiofibular joint with resolution of the intraneural ganglion cyst within the CPN (Figure 6).

Discussion

Intraneural ganglia of peripheral nerves are relatively rare, most commonly occurring in the CPN.^6,8,9 A literature search reveals that this condition is only sparsely reported in orthopedic journals. This report, therefore, describes this rare, yet curable, condition. As noted, without appropriate intervention, the condition has a high likelihood of recurrence with only a brief interruption of symptoms.^6,8,9,12

The operative technique delineated in this report relies heavily on research demonstrating that peroneal intraneural ganglia develop from the superior tibiofibular joint and gain access to the CPN via the recurrent articular branch.^8,13 Research indicates that such ganglia preferentially proceed proximally along the deep portion of the CPN, within the epineurium.⁶ This hypothesis was corroborated in our case by the swollen appearance of the CPN proximal to its bifurcation.

Currently, there is no consensus on treatment of intraneural ganglion cysts of the CPN. However, evidence suggests that disconnection of the recurrent branch of the CPN may be important in successfully treating the condition.^6,9,14 This unified articular theory was initially proposed by Spinner and colleagues¹² in 2003 and recommends that surgical treatment focus on the articular branch as the source of cyst fluid.^6,9,12,14 This theory by Spinner and coauthors^12,14 was substantiated in our case: Once the articular branch was disconnected, cyst fluid was easily expressed via antegrade massage through the disconnected end. Pathologic analysis of a portion of the detached articular branch is also recommended to rule out other cystic lesions, such as cystic shwannomas.¹⁴

The history of the unified articular theory began in the mid-1990s, when Dr. Robert Spinner, board certified in both orthopedic and neurologic surgery, began researching causes of intraneural ganglion cysts. At the time, such ganglia were often treated by radical resection of the nerve and the cyst. Based on his review of literature, and his own cases, Spinner¹⁵ developed the theory that, just as with extraneural ganglia, these cysts are fed by fluid from the joint. According to Spinner,⁹ the sources of such connections were very small articular nerve branches that connect the nerve to the joint. His research led him to the original citation of such an intraneural ganglion of the ulnar nerve, first described by Dr. M. Beauchene, a French physician, in 1810.¹⁶ Spinner also discovered that Beauchene’s original dissection specimen had been preserved and was displayed in a medical museum in Paris. When Spinner went to France to view the specimen, he indeed found an intraneural ganglion of the ulnar nerve. On closer inspection, Spinner also discovered a small articular nerve branch containing a “hollow lumen” that would have been capable of allowing the passage of fluid into the nerve and leading to the development of a cyst.¹⁶

In our case, in the first operation, a simple incisional decompression of the CPN was performed. Unfortunately, the ganglion cyst quickly recurred, as did the patient’s symptoms. In the second surgical procedure, the articular branch connecting the peroneal nerve to the proximal tibiofibular joint was incised and disconnected from the nerve. This allowed the nerve to be decompressed and prevented a recurrence of the ganglion cyst within the nerve with complete resolution of the patient’s symptoms. This difference alone most likely accounts for the rapid recurrence of symptoms after the initial operation, since the fluid was simply drained, but the source was not detached, allowing the ganglion to recur.^6,12,14 This is similar in theory to excising the attachment of a ganglion cyst at the wrist from the underlying joint capsule rather than performing a needle aspiration or puncturing of the cyst.¹²

Regarding the imaging techniques used to identify intraneural ganglia, it is essential that the surgeon be aware of the unified articular theory and the likely presence of an articular branch. Such branches are extremely small and may be easily missed on imaging and intraoperatively.^17,18 MRI is the best method to image these cysts because of its superior ability to visualize soft-tissue lesions.^18,19 Intraneural ganglion cysts typically appear as homogenous, lobulated, well-circumscribed masses that are hyperintense on T2-weighted MRI.^3,19 Gadolinium may also offer diagnostic utility, because these masses do not enhance with its use on T1-weighted MRI.^3,17,19 By employing these techniques, one may easily view most of the ganglion cyst. To image the small articular branch, Spinner and colleagues¹⁷ recommend thin-section images with high–spatial resolution T2-imaging. They also advocate obtaining multiple image views and planes to increase the likelihood of successful imaging.¹⁷ 

The applications of the unified articular theory also extend beyond intraneural ganglia of the CPN. While the CPN is the most common location for intraneural ganglion occurrence,^6,17,20 cases have also been described of intraneural ganglion cysts of the tibial nerve at the proximal tibiofibular joint, as well as via the posterior tibial and medial plantar nerves at the subtalar joint within the tarsal tunnel.^11,18-23 Most cases involving the posterior tibial and medial plantar nerves were found in patients presenting with signs of tarsal tunnel syndrome.^22,23 Intraneural ganglia have also been found within the superficial peroneal nerve arising from the inferior tibiofibular joint.²⁰ In certain cases, these ganglia have also been noted to connect to the joint via a small articular branch.^19,22 In 1 case of an intraneural ganglion of the tibial nerve at the superior tibiofibular joint, initial conservative surgery led to early recurrence of symptoms.¹⁹ Just as in our case, the patient returned to the operating room and, after isolation and ligation of an articular branch, the patient experienced long-term resolution of both the symptoms and the cyst.¹⁹

Given the overwhelming evidence in support of the unified articular theory, we agree with the recommendation by Spinner and colleagues¹⁹ to search for an articular branch both via preoperative imaging and during the operation itself in all cases of intraneural ganglia. Assuming the mechanism of cyst formation is the same in most cases of intraneural ganglia, one could reasonably apply the same surgical techniques used in our case to the management of all intraneural ganglia, drastically reducing recurrence rates.

Conclusion

Based on research and corroborated by this case, the key to successful operative treatment of a common peroneal intraneural ganglion is division of the recurrent articular branch, which connects the proximal tibiofibular joint to the CPN.^6,9,11,12,14 Evidence has shown that disconnecting the articular branch and disrupting the source of the intraneural ganglion can resolve the condition and dramatically diminish the chance of recurrence.^6,8,12,14 This has become known as the unified articular theory.^6,12,14 Reports also suggest that, without disconnecting this articular branch, intraneural ganglion recurrence rates may be higher than 30%.^6,12,14,19 This case, therefore, supports the findings of previous authors^9-11,14 and provides an example of successful utilization of the treatment protocol delineated by Spinner and colleagues.^10,11

Intraneural ganglion cysts of peripheral nerves occurring within the epineural sheath are rare.^1-7 Case reports exist primarily within the neurosurgical literature, but very little in the orthopedic literature describes this condition. The peripheral nerve most commonly affected by an intraneural ganglion is the common peroneal nerve (CPN).^2,8,9 Such ganglia most often afflict middle-aged men with a history of micro- or macro-trauma and present with typical clinical manifestations of calf pain and progressive symptoms of ipsilateral foot drop and lower leg paresthesia.^2-5,10-12 The mechanism by which these ganglia form is not well understood and, as a result, treatment options are debated.⁶ Recent development of a “unified articular theory,” suggests that such intraneural ganglia of the CPN are fed by a small, recurrent articular branch of the CPN.^6,12,13 Cadaveric studies indicate that this branch originates from the deep peroneal nerve, just millimeters distal to the bifurcation of the CPN, and extends to the superior tibiofibular joint, providing direct access for cyst fluid to enter the CPN following the path of least resistance.^7,8,12,14 Therefore, according to the unified articular theory, the recommended treatment involves division of the articular branch, allowing the ganglion to be decompressed.⁶

We present a case of a 41-year-old man with an intraneural ganglion cyst of the CPN who was successfully treated, according to the recommendations of the unified articular theory. It is important for orthopedic surgeons to read about and recognize this condition, because knowledge of the operative technique outlined in our report allows it to be treated quite effectively. The patient provided written informed consent for print and electronic publication of this case report.

Case Report

A 41-year-old man presented with a 2-month history of traumatic left lateral knee pain with numbness and weakness to the left foot and ankle. Initial examination showed a mild restriction of lumbosacral range of motion, with no complaints of lower back pain. Sciatic root stretch signs were negative. Strength testing of the lower extremities revealed 3+/5 strength of ankle dorsiflexion and great toe extension on the left side. There was a mild alteration in sensation to light touch on the lateral side of the left foot. Tenderness, without swelling, was present around the left fibular head. There was a positive Tinel sign over the peroneal nerve at the level of the fibular neck.

The patient was initially treated with anti-inflammatories and activity modification. An electromyogram (EMG)/nerve conduction study of the lower extremity showed a left peroneal nerve neurapraxia at the level of the fibular head. Noncontrast magnetic resonance imaging (MRI) of the left knee showed a “slightly prominent vein coursing posterior to the fibular head near the expected location of the common peroneal nerve,” according to the radiologist’s notes (Figure 1). The patient exhibited improvement with use of anti-inflammatories over several months. There was an increase in his ankle dorsiflexion strength to 4/5 and improvement in his pain and numbness.

Approximately 7 months after his initial presentation, the patient developed a marked worsening—increased numbness and weakness to ankle dorsiflexion—of his original symptoms. A repeat EMG/nerve conduction study of the lower extremity showed a persistent peroneal nerve neuropathy with a persistent denervation of the extensor hallucis longus, tibialis anterior, and extensor digitorum brevis muscles.

Because of continuing symptoms and increasing pain, the patient had surgery 8 months after his initial presentation. At that time, a markedly thickened peroneal nerve was identified. An incision in the epineural sheath released a clear gelatinous fluid consistent with a ganglion cyst. Through the epineural incision, the nerve was decompressed by manually “milking” the fluid from within the sheath. Approximately  30 mL of mucinous fluid was obtained and sent to pathology. No cells were identified.

Postoperatively, the patient noted a marked improvement in his pain. By 2 weeks postoperatively, the numbness in his foot had resolved. At 6 weeks after surgery, the strength of his tibialis anterior and extensor hallucis longus muscles had improved from 3+ to 4-, and he was free of pain.

At 2 months postoperatively, the patient redeveloped pain and numbness, and noted progressive weakness of his left foot and ankle. A repeat MRI of the left knee showed a dilated tubular structure corresponding to the course of the CPN. Comparison of this MRI with the initial MRI showed that the “prominent vein” was actually the dilated CPN.

He was taken to the operating room again 5 months after his first operation. At this time, the CPN was again noted to be markedly dilated (Figure 2). The nerve was explored and a recurrent branch to the proximal tibiofibular joint was identified and divided (Figures 3, 4). Through the divided branch, the CPN could be decompressed by manually “milking” the nerve in a proximal-to-distal direction, expressing clear gelatinous fluid consistent with a ganglion cyst (Figure 5). Pathology of the excised portion of the recurrent nerve was consistent with an intraneural ganglion cyst.

By 2 weeks postoperatively, the numbness of the patient’s left foot had completely resolved, as did his pain. By 3 months after surgery, his extensor hallucis longus strength was 5/5, and ankle dorsiflexion was 4-/5. At 6 months, his ankle dorsiflexion strength was 5/5, and he was completely asymptomatic. At 2 years postoperatively, he remained completely asymptomatic. A follow-up MRI of the left knee showed a ganglion cyst present at the proximal tibiofibular joint with resolution of the intraneural ganglion cyst within the CPN (Figure 6).

Discussion

Intraneural ganglia of peripheral nerves are relatively rare, most commonly occurring in the CPN.^6,8,9 A literature search reveals that this condition is only sparsely reported in orthopedic journals. This report, therefore, describes this rare, yet curable, condition. As noted, without appropriate intervention, the condition has a high likelihood of recurrence with only a brief interruption of symptoms.^6,8,9,12

The operative technique delineated in this report relies heavily on research demonstrating that peroneal intraneural ganglia develop from the superior tibiofibular joint and gain access to the CPN via the recurrent articular branch.^8,13 Research indicates that such ganglia preferentially proceed proximally along the deep portion of the CPN, within the epineurium.⁶ This hypothesis was corroborated in our case by the swollen appearance of the CPN proximal to its bifurcation.

Currently, there is no consensus on treatment of intraneural ganglion cysts of the CPN. However, evidence suggests that disconnection of the recurrent branch of the CPN may be important in successfully treating the condition.^6,9,14 This unified articular theory was initially proposed by Spinner and colleagues¹² in 2003 and recommends that surgical treatment focus on the articular branch as the source of cyst fluid.^6,9,12,14 This theory by Spinner and coauthors^12,14 was substantiated in our case: Once the articular branch was disconnected, cyst fluid was easily expressed via antegrade massage through the disconnected end. Pathologic analysis of a portion of the detached articular branch is also recommended to rule out other cystic lesions, such as cystic shwannomas.¹⁴

The history of the unified articular theory began in the mid-1990s, when Dr. Robert Spinner, board certified in both orthopedic and neurologic surgery, began researching causes of intraneural ganglion cysts. At the time, such ganglia were often treated by radical resection of the nerve and the cyst. Based on his review of literature, and his own cases, Spinner¹⁵ developed the theory that, just as with extraneural ganglia, these cysts are fed by fluid from the joint. According to Spinner,⁹ the sources of such connections were very small articular nerve branches that connect the nerve to the joint. His research led him to the original citation of such an intraneural ganglion of the ulnar nerve, first described by Dr. M. Beauchene, a French physician, in 1810.¹⁶ Spinner also discovered that Beauchene’s original dissection specimen had been preserved and was displayed in a medical museum in Paris. When Spinner went to France to view the specimen, he indeed found an intraneural ganglion of the ulnar nerve. On closer inspection, Spinner also discovered a small articular nerve branch containing a “hollow lumen” that would have been capable of allowing the passage of fluid into the nerve and leading to the development of a cyst.¹⁶

In our case, in the first operation, a simple incisional decompression of the CPN was performed. Unfortunately, the ganglion cyst quickly recurred, as did the patient’s symptoms. In the second surgical procedure, the articular branch connecting the peroneal nerve to the proximal tibiofibular joint was incised and disconnected from the nerve. This allowed the nerve to be decompressed and prevented a recurrence of the ganglion cyst within the nerve with complete resolution of the patient’s symptoms. This difference alone most likely accounts for the rapid recurrence of symptoms after the initial operation, since the fluid was simply drained, but the source was not detached, allowing the ganglion to recur.^6,12,14 This is similar in theory to excising the attachment of a ganglion cyst at the wrist from the underlying joint capsule rather than performing a needle aspiration or puncturing of the cyst.¹²

Regarding the imaging techniques used to identify intraneural ganglia, it is essential that the surgeon be aware of the unified articular theory and the likely presence of an articular branch. Such branches are extremely small and may be easily missed on imaging and intraoperatively.^17,18 MRI is the best method to image these cysts because of its superior ability to visualize soft-tissue lesions.^18,19 Intraneural ganglion cysts typically appear as homogenous, lobulated, well-circumscribed masses that are hyperintense on T2-weighted MRI.^3,19 Gadolinium may also offer diagnostic utility, because these masses do not enhance with its use on T1-weighted MRI.^3,17,19 By employing these techniques, one may easily view most of the ganglion cyst. To image the small articular branch, Spinner and colleagues¹⁷ recommend thin-section images with high–spatial resolution T2-imaging. They also advocate obtaining multiple image views and planes to increase the likelihood of successful imaging.¹⁷ 

The applications of the unified articular theory also extend beyond intraneural ganglia of the CPN. While the CPN is the most common location for intraneural ganglion occurrence,^6,17,20 cases have also been described of intraneural ganglion cysts of the tibial nerve at the proximal tibiofibular joint, as well as via the posterior tibial and medial plantar nerves at the subtalar joint within the tarsal tunnel.^11,18-23 Most cases involving the posterior tibial and medial plantar nerves were found in patients presenting with signs of tarsal tunnel syndrome.^22,23 Intraneural ganglia have also been found within the superficial peroneal nerve arising from the inferior tibiofibular joint.²⁰ In certain cases, these ganglia have also been noted to connect to the joint via a small articular branch.^19,22 In 1 case of an intraneural ganglion of the tibial nerve at the superior tibiofibular joint, initial conservative surgery led to early recurrence of symptoms.¹⁹ Just as in our case, the patient returned to the operating room and, after isolation and ligation of an articular branch, the patient experienced long-term resolution of both the symptoms and the cyst.¹⁹

Given the overwhelming evidence in support of the unified articular theory, we agree with the recommendation by Spinner and colleagues¹⁹ to search for an articular branch both via preoperative imaging and during the operation itself in all cases of intraneural ganglia. Assuming the mechanism of cyst formation is the same in most cases of intraneural ganglia, one could reasonably apply the same surgical techniques used in our case to the management of all intraneural ganglia, drastically reducing recurrence rates.

Conclusion

Based on research and corroborated by this case, the key to successful operative treatment of a common peroneal intraneural ganglion is division of the recurrent articular branch, which connects the proximal tibiofibular joint to the CPN.^6,9,11,12,14 Evidence has shown that disconnecting the articular branch and disrupting the source of the intraneural ganglion can resolve the condition and dramatically diminish the chance of recurrence.^6,8,12,14 This has become known as the unified articular theory.^6,12,14 Reports also suggest that, without disconnecting this articular branch, intraneural ganglion recurrence rates may be higher than 30%.^6,12,14,19 This case, therefore, supports the findings of previous authors^9-11,14 and provides an example of successful utilization of the treatment protocol delineated by Spinner and colleagues.^10,11