Sickle cell disease is a common genetic disorder in the United States that disproportionately affects people of African ancestry. The characteristic sickling of red blood cells under conditions of reduced oxygen tension leads to intravascular hemolysis and vaso-occlusive events, which in turn cause tissue ischemia-reperfusion injury affecting multiple organs, including the genitourinary system.^1–3

In this paper, we review the genitourinary effects of sickle cell disease, focusing on sickle cell nephropathy, priapism, and renal medullary carcinoma.

THE WIDE-RANGING EFFECTS OF SICKLE CELL DISEASE

In the United States, sickle cell disease affects 1 of every 500 blacks and 1 of every 36,000 Hispanics.¹ The term describes hemoglobinopathies associated with sickling of red blood cells.

Sickling of red blood cells results from a single base-pair change in the beta-globin gene from glutamic acid to valine at position 6, causing abnormal hemoglobin (hemoglobin S), which polymerizes under conditions of reduced oxygen tension and alters the biconcave disk shape into a rigid, irregular, unstable cell. The sickle-shaped cells are prone to intravascular hemolysis,² causing intermittent vaso-occlusive events that result in tissue ischemia-reperfusion injury. Genitourinary problems include impaired ability to concentrate urine, hematuria, renal medullary carcinoma, and increased frequency of urinary tract infection.

SICKLE CELL NEPHROPATHY

Signs of kidney involvement may appear in early childhood

The kidney is one of the most frequently affected organs in sickle cell disease. Renal manifestations begin to appear in early childhood, with impaired medullary concentrating ability and ischemic damage to the tubular cells caused by sickling within the vasa recta renis precipitated by the acidic, hypoxic, and hypertonic environment in the renal medulla.

As in early diabetic nephropathy, renal blood flow is enhanced and the glomerular filtration rate (GFR) is increased. Increased cardiac output as a result of anemia, localized release of prostaglandins, and a hypoxia-induced increase in nitric oxide synthesis all play a role in the increase in GFR.^4,5

Oxidative stress, an increase in markers of inflammation, and local activation of the renin-angiotensin system contribute to renal damage in sickle cell disease.^5–7 The resulting hyperfiltration injury leads to microalbuminuria, which occurs in 20% to 40% of children with sickle cell anemia^8,9 and in as many as 60% of adults.

The glomerular lesions associated with sickle cell disease vary from glomerulopathy in the early stages to secondary focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and glomerular thrombotic microangiopathy.¹⁰

Clinical presentations and workup

Clinical presentations are not limited to glomerular disease but include hyperchloremic metabolic acidosis and hyperkalemia resulting from defects in potassium secretion and renal acidification.

Hyperphosphatemia—a result of increased reabsorption of phosphorus, increased secretion of uric acid, and increased creatinine clearance—is seen in patients with sickle cell disease.^11,12 About 10% of patients can develop an acute kidney injury as a result of volume depletion, rhabdomyolysis, renal vein thrombosis, papillary necrosis, and urinary tract obstruction secondary to blood clots.^11,13

Up to 30% of adult patients with sickle cell disease develop chronic kidney disease. Predictors include severe anemia, hypertension, proteinuria, nephrotic syndrome, and microscopic hematuria.¹⁴ From 4% to 12% of patients go on to develop end-stage renal disease, but with a 1-year mortality rate three times higher than in patients without sickle cell disease.¹⁵

In general, patients with sickle cell anemia have blood pressures below those of age- and sex-matched individuals, but elevated blood pressure and low GFR are not uncommon in affected children. In a cohort of 48 children ages 3 to 18, 8.3% had an estimated GFR less than 90 mL/min/1.73 m², and 16.7% had elevated blood pressure (prehypertension and hypertension).¹⁶

In patients with sickle cell disease, evaluation of proteinuria, hematuria, hypertension, and renal failure should take into consideration the unique renal physiologic and pathologic processes involved. Recent evidence^17,18 suggests that the Chronic Kidney Disease Epidemiology Collaboration equation provides a better estimate of GFR than the Modification of Diet in Renal Disease and Cockcroft-Gault equations, although all three creatinine-based methods overestimate GFR in patients with sickle cell disease when compared with GFR measured with technetium-99m-labeled diethylenetriamine penta-acetic acid renal scanning.

Treatment options

Treatment of sickle cell nephropathy includes adequate fluid intake (given the loss of concentrating ability), adequate blood pressure control, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in patients who have microalbuminuria or proteinuria (or both)^9,11,19 and hydroxyurea. Treatment with enalapril has been shown to decrease proteinuria in patients with sickle cell nephropathy.⁹ In a cohort of children with sickle cell disease, four of nine patients treated with an ACE inhibitor developed hyperkalemia, leading to discontinuation of the drug in three patients.⁹

ACE inhibitors and ARBs must be used cautiously in these patients because they have defects in potassium secretion. Hydroxyurea has also been shown to decrease hyperfiltration and microalbuminuria in recent studies,^20,21 and this could protect against the development of overt nephropathy.

Higher mortality rates have been reported in patients with sickle cell disease who developed end-stage renal disease than in patients with end-stage renal disease without sickle cell disease. Sickle cell disease also increases the risk of pulmonary hypertension and the vaso-occlusive complication known as acute chest syndrome, contributing to increased mortality rates. Of note, in a study that looked at the association between mortality rates and pre-end-stage care of renal disease using data from the Centers for Medicare and Medicaid Services, patients with sickle cell disease who had had predialysis nephrology care had lower mortality rates.¹⁵

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and transplantation

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and renal transplantation. Data from the Organ Procurement and Transplantation Network and the United Network for Organ Sharing show that from 2000 to 2011, African American kidney recipients with sickle cell disease had better survival rates than patients who had undergone transplantation from 1988 to 1999, although rates of long-term survival and graft survival were lower than in transplant recipients with other diagnoses.²²

It is important to note that complications as a result of vaso-occlusive events and thrombosis can lead to graft loss; therefore, sickle cell crisis after transplantation requires careful management.

Take-home messages

• Loss of urine-concentrating ability and hyperfiltration are the earliest pathologic changes in sickle cell disease.
• Microalbuminuria as seen in diabetic nephropathy is the earliest manifestation of sickle cell nephropathy, and the prevalence increases as these patients get older and live longer.
• ACE inhibitors or ARBs should be used with caution, given the heightened risk of hyperkalemia in sickle cell disease.
• Recent results with hydroxyurea in decreasing hyperfiltration and microalbuminuria are encouraging.
• Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease.

PRIAPISM IN SICKLE CELL DISEASE

Priapism was formerly defined as a full, painful erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm. But priapism is now recognized as two separate disorders—ischemic (veno-occlusive, low-flow) priapism and nonischemic (arterial, high-flow) priapism. The new definition includes both disorders: ie, a full or partial erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm.

Ischemic priapism

Hematologic disorders are major contributors to ischemic priapism and include sickle cell disease, multiple myeloma, fat emboli (hyperalimentation),²³ glucose-6-phosphate dehydrogenase deficiency, and hemoglobin Olmsted variant.²⁴

Ischemic priapism is often seen in sickle cell disease and is considered an emergency. It is characterized by an abnormally rigid erection not involving the glans penis. Entrapment of blood in the corpora cavernosa leads to hypoxia, hypercarbia, and acidosis, which in turn leads to a painful compartment syndrome that, if untreated, results in smooth muscle necrosis and subsequent fibrosis. The results are a smaller penis and erectile dysfunction that is unresponsive to any treatment other than implantation of a penile prosthesis. However, scarring of the corpora cavernosa can make this procedure exceedingly difficult, requiring advanced techniques such as corporeal excavation.²⁵

Men with a subtype of ischemic priapism called “stuttering” priapism²⁶ suffer recurrent prolonged erections during sleep. The patient awakens with a painful erection that usually subsides, but sometimes only after several hours. Patients with this disorder suffer from sleep deprivation. Stuttering priapism may lead to full-blown ischemic priapism that does not resolve without intervention.

Nonischemic priapism

In nonischemic priapism, the corpora are engorged but not rigid. The condition results from unregulated arterial inflow and thus is not painful and does not result in damage to the corporeal smooth muscle.

Most cases of nonischemic priapism follow blunt perineal trauma or trauma associated with needle insertion into the corpora. This form of priapism is not associated with sickle cell disease. Because tissue damage does not occur, nonischemic or arterial priapism is not considered an emergency.

Treatment guidelines

Differentiating ischemic from nonischemic priapism is usually straightforward, based on the history, physical examination, corporeal blood gases, and duplex ultrasonography.²⁷

Ischemic priapism is an emergency. After needle aspiration of blood from the corpora cavernosa, phenylephrine is diluted with normal saline to a concentration of 100 to 500 µg/mL and is injected in 1-mL amounts repeatedly at 3- to 5-minute intervals until the erection subsides or until a 1-hour time limit is reached. Blood pressure and pulse are monitored during these injections. If aspiration and phenylephrine irrigation fail, surgical shunting is performed.²⁷

Measures to treat sickle cell disease (hydration, oxygen, exchange transfusions) may be employed simultaneously but should never delay aspiration and phenylephrine injections.²⁵

Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease

As nonischemic priapism is not considered an emergency, management begins with observation. Patients eventually become dissatisfied with their constant partial erection, and they then present for treatment. Most cases resolve after selective catheterization of the internal pudendal artery and embolization of the fistula with absorbable material. If this fails, surgical exploration with ligation of the vessels leading to the fistula is indicated.

Prevalence in sickle cell trait vs sickle cell disease

Ischemic priapism is uncommon in men with sickle cell trait, but prevalence rates in men with sickle cell disease are as high as 42%.²⁸ In a study of 130 men with sickle cell disease, 35% had a history of prolonged ischemic priapism, 72% had a history of stuttering priapism, and 75% of men with stuttering priapism had their first episode before age 20.²⁹

Rates of erectile dysfunction increase with the duration of ischemic episodes and range from 20% to 90%.^28,30 In childhood, sickle cell disease accounts for 63% of the cases of ischemic priapism, and in adults it accounts for 23% of cases.³¹

Take-home messages

• Sickle cell disease accounts for two-thirds of cases of ischemic priapism in children, and one-fourth of adult cases.
• Ischemic priapism is a medical emergency.
• Treatment with aspiration and phenylephrine injections should begin immediately and should not await treatment measures for sickle cell disease (hydration, oxygen, exchange transfusions).

OTHER UROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE

Other urologic complications of sickle cell trait and sickle cell disease include microscopic hematuria, gross hematuria, and renal colic. A formal evaluation of any patient with persistent microscopic hematuria or gross hematuria should consist of urinalysis, computed tomography, and cystoscopy. This approach assesses the upper and lower genitourinary system for treatable causes. Renal ultrasonography can be used instead of computed tomography but tends to provide less information.

Special considerations

In patients with sickle cell trait and sickle cell disease, chronic hypoxia and subsequent sickling of erythrocytes in the renal medulla can lead to papillary hypertrophy and papillary necrosis. In papillary hypertrophy, friable blood vessels can rupture, resulting in microscopic and gross hematuria. In papillary necrosis, the papilla can slough off and become lodged in the ureter.

Nevertheless, hematuria and renal colic in patients with sickle cell disease or trait are most often attributable to common causes such as infection and stones. A finding of hydronephrosis in the absence of a stone, however, suggests obstruction due to a clot or a sloughed papilla. Ureteroscopy, fulguration, and ureteral stent placement can stop the bleeding and alleviate obstruction in these cases.

Renal medullary carcinoma

Another important reason to order imaging in patients with sickle cell disease or trait who present with urologic symptoms is to rule out renal medullary carcinoma, a rare but aggressive cancer that arises from the collecting duct epithelium. This cancer is twice as likely to occur in males than in females; it has been reported in patients ranging in age from 10 to 40, with a median age at presentation of 26.³²

When patients present with symptomatic renal medullary cancer, in most cases the cancer has already metastasized.

On computed tomography, the tumor tends to occupy a central location in the kidney and appears to infiltrate and replace adjacent kidney tissue. Retroperitoneal lymphadenopathy and metastasis are common.

Treatment typically entails radical nephrectomy, chemotherapy, and in some circumstances, radiotherapy. Case reports have shown promising tumor responses to carboplatin and paclitaxel regimens.^33,34 Also, a low threshold for imaging in patients with sickle cell disease and trait may increase the odds of early detection of this aggressive cancer.

Sickle cell disease is a common genetic disorder in the United States that disproportionately affects people of African ancestry. The characteristic sickling of red blood cells under conditions of reduced oxygen tension leads to intravascular hemolysis and vaso-occlusive events, which in turn cause tissue ischemia-reperfusion injury affecting multiple organs, including the genitourinary system.^1–3

In this paper, we review the genitourinary effects of sickle cell disease, focusing on sickle cell nephropathy, priapism, and renal medullary carcinoma.

THE WIDE-RANGING EFFECTS OF SICKLE CELL DISEASE

In the United States, sickle cell disease affects 1 of every 500 blacks and 1 of every 36,000 Hispanics.¹ The term describes hemoglobinopathies associated with sickling of red blood cells.

Sickling of red blood cells results from a single base-pair change in the beta-globin gene from glutamic acid to valine at position 6, causing abnormal hemoglobin (hemoglobin S), which polymerizes under conditions of reduced oxygen tension and alters the biconcave disk shape into a rigid, irregular, unstable cell. The sickle-shaped cells are prone to intravascular hemolysis,² causing intermittent vaso-occlusive events that result in tissue ischemia-reperfusion injury. Genitourinary problems include impaired ability to concentrate urine, hematuria, renal medullary carcinoma, and increased frequency of urinary tract infection.

SICKLE CELL NEPHROPATHY

Signs of kidney involvement may appear in early childhood

The kidney is one of the most frequently affected organs in sickle cell disease. Renal manifestations begin to appear in early childhood, with impaired medullary concentrating ability and ischemic damage to the tubular cells caused by sickling within the vasa recta renis precipitated by the acidic, hypoxic, and hypertonic environment in the renal medulla.

As in early diabetic nephropathy, renal blood flow is enhanced and the glomerular filtration rate (GFR) is increased. Increased cardiac output as a result of anemia, localized release of prostaglandins, and a hypoxia-induced increase in nitric oxide synthesis all play a role in the increase in GFR.^4,5

Oxidative stress, an increase in markers of inflammation, and local activation of the renin-angiotensin system contribute to renal damage in sickle cell disease.^5–7 The resulting hyperfiltration injury leads to microalbuminuria, which occurs in 20% to 40% of children with sickle cell anemia^8,9 and in as many as 60% of adults.

The glomerular lesions associated with sickle cell disease vary from glomerulopathy in the early stages to secondary focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and glomerular thrombotic microangiopathy.¹⁰

Clinical presentations and workup

Clinical presentations are not limited to glomerular disease but include hyperchloremic metabolic acidosis and hyperkalemia resulting from defects in potassium secretion and renal acidification.

Hyperphosphatemia—a result of increased reabsorption of phosphorus, increased secretion of uric acid, and increased creatinine clearance—is seen in patients with sickle cell disease.^11,12 About 10% of patients can develop an acute kidney injury as a result of volume depletion, rhabdomyolysis, renal vein thrombosis, papillary necrosis, and urinary tract obstruction secondary to blood clots.^11,13

Up to 30% of adult patients with sickle cell disease develop chronic kidney disease. Predictors include severe anemia, hypertension, proteinuria, nephrotic syndrome, and microscopic hematuria.¹⁴ From 4% to 12% of patients go on to develop end-stage renal disease, but with a 1-year mortality rate three times higher than in patients without sickle cell disease.¹⁵

In general, patients with sickle cell anemia have blood pressures below those of age- and sex-matched individuals, but elevated blood pressure and low GFR are not uncommon in affected children. In a cohort of 48 children ages 3 to 18, 8.3% had an estimated GFR less than 90 mL/min/1.73 m², and 16.7% had elevated blood pressure (prehypertension and hypertension).¹⁶

In patients with sickle cell disease, evaluation of proteinuria, hematuria, hypertension, and renal failure should take into consideration the unique renal physiologic and pathologic processes involved. Recent evidence^17,18 suggests that the Chronic Kidney Disease Epidemiology Collaboration equation provides a better estimate of GFR than the Modification of Diet in Renal Disease and Cockcroft-Gault equations, although all three creatinine-based methods overestimate GFR in patients with sickle cell disease when compared with GFR measured with technetium-99m-labeled diethylenetriamine penta-acetic acid renal scanning.

Treatment options

Treatment of sickle cell nephropathy includes adequate fluid intake (given the loss of concentrating ability), adequate blood pressure control, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in patients who have microalbuminuria or proteinuria (or both)^9,11,19 and hydroxyurea. Treatment with enalapril has been shown to decrease proteinuria in patients with sickle cell nephropathy.⁹ In a cohort of children with sickle cell disease, four of nine patients treated with an ACE inhibitor developed hyperkalemia, leading to discontinuation of the drug in three patients.⁹

ACE inhibitors and ARBs must be used cautiously in these patients because they have defects in potassium secretion. Hydroxyurea has also been shown to decrease hyperfiltration and microalbuminuria in recent studies,^20,21 and this could protect against the development of overt nephropathy.

Higher mortality rates have been reported in patients with sickle cell disease who developed end-stage renal disease than in patients with end-stage renal disease without sickle cell disease. Sickle cell disease also increases the risk of pulmonary hypertension and the vaso-occlusive complication known as acute chest syndrome, contributing to increased mortality rates. Of note, in a study that looked at the association between mortality rates and pre-end-stage care of renal disease using data from the Centers for Medicare and Medicaid Services, patients with sickle cell disease who had had predialysis nephrology care had lower mortality rates.¹⁵

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and transplantation

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and renal transplantation. Data from the Organ Procurement and Transplantation Network and the United Network for Organ Sharing show that from 2000 to 2011, African American kidney recipients with sickle cell disease had better survival rates than patients who had undergone transplantation from 1988 to 1999, although rates of long-term survival and graft survival were lower than in transplant recipients with other diagnoses.²²

It is important to note that complications as a result of vaso-occlusive events and thrombosis can lead to graft loss; therefore, sickle cell crisis after transplantation requires careful management.

Take-home messages

• Loss of urine-concentrating ability and hyperfiltration are the earliest pathologic changes in sickle cell disease.
• Microalbuminuria as seen in diabetic nephropathy is the earliest manifestation of sickle cell nephropathy, and the prevalence increases as these patients get older and live longer.
• ACE inhibitors or ARBs should be used with caution, given the heightened risk of hyperkalemia in sickle cell disease.
• Recent results with hydroxyurea in decreasing hyperfiltration and microalbuminuria are encouraging.
• Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease.

PRIAPISM IN SICKLE CELL DISEASE

Priapism was formerly defined as a full, painful erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm. But priapism is now recognized as two separate disorders—ischemic (veno-occlusive, low-flow) priapism and nonischemic (arterial, high-flow) priapism. The new definition includes both disorders: ie, a full or partial erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm.

Ischemic priapism

Hematologic disorders are major contributors to ischemic priapism and include sickle cell disease, multiple myeloma, fat emboli (hyperalimentation),²³ glucose-6-phosphate dehydrogenase deficiency, and hemoglobin Olmsted variant.²⁴

Ischemic priapism is often seen in sickle cell disease and is considered an emergency. It is characterized by an abnormally rigid erection not involving the glans penis. Entrapment of blood in the corpora cavernosa leads to hypoxia, hypercarbia, and acidosis, which in turn leads to a painful compartment syndrome that, if untreated, results in smooth muscle necrosis and subsequent fibrosis. The results are a smaller penis and erectile dysfunction that is unresponsive to any treatment other than implantation of a penile prosthesis. However, scarring of the corpora cavernosa can make this procedure exceedingly difficult, requiring advanced techniques such as corporeal excavation.²⁵

Men with a subtype of ischemic priapism called “stuttering” priapism²⁶ suffer recurrent prolonged erections during sleep. The patient awakens with a painful erection that usually subsides, but sometimes only after several hours. Patients with this disorder suffer from sleep deprivation. Stuttering priapism may lead to full-blown ischemic priapism that does not resolve without intervention.

Nonischemic priapism

In nonischemic priapism, the corpora are engorged but not rigid. The condition results from unregulated arterial inflow and thus is not painful and does not result in damage to the corporeal smooth muscle.

Most cases of nonischemic priapism follow blunt perineal trauma or trauma associated with needle insertion into the corpora. This form of priapism is not associated with sickle cell disease. Because tissue damage does not occur, nonischemic or arterial priapism is not considered an emergency.

Treatment guidelines

Differentiating ischemic from nonischemic priapism is usually straightforward, based on the history, physical examination, corporeal blood gases, and duplex ultrasonography.²⁷

Ischemic priapism is an emergency. After needle aspiration of blood from the corpora cavernosa, phenylephrine is diluted with normal saline to a concentration of 100 to 500 µg/mL and is injected in 1-mL amounts repeatedly at 3- to 5-minute intervals until the erection subsides or until a 1-hour time limit is reached. Blood pressure and pulse are monitored during these injections. If aspiration and phenylephrine irrigation fail, surgical shunting is performed.²⁷

Measures to treat sickle cell disease (hydration, oxygen, exchange transfusions) may be employed simultaneously but should never delay aspiration and phenylephrine injections.²⁵

Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease

As nonischemic priapism is not considered an emergency, management begins with observation. Patients eventually become dissatisfied with their constant partial erection, and they then present for treatment. Most cases resolve after selective catheterization of the internal pudendal artery and embolization of the fistula with absorbable material. If this fails, surgical exploration with ligation of the vessels leading to the fistula is indicated.

Prevalence in sickle cell trait vs sickle cell disease

Ischemic priapism is uncommon in men with sickle cell trait, but prevalence rates in men with sickle cell disease are as high as 42%.²⁸ In a study of 130 men with sickle cell disease, 35% had a history of prolonged ischemic priapism, 72% had a history of stuttering priapism, and 75% of men with stuttering priapism had their first episode before age 20.²⁹

Rates of erectile dysfunction increase with the duration of ischemic episodes and range from 20% to 90%.^28,30 In childhood, sickle cell disease accounts for 63% of the cases of ischemic priapism, and in adults it accounts for 23% of cases.³¹

Take-home messages

• Sickle cell disease accounts for two-thirds of cases of ischemic priapism in children, and one-fourth of adult cases.
• Ischemic priapism is a medical emergency.
• Treatment with aspiration and phenylephrine injections should begin immediately and should not await treatment measures for sickle cell disease (hydration, oxygen, exchange transfusions).

OTHER UROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE

Other urologic complications of sickle cell trait and sickle cell disease include microscopic hematuria, gross hematuria, and renal colic. A formal evaluation of any patient with persistent microscopic hematuria or gross hematuria should consist of urinalysis, computed tomography, and cystoscopy. This approach assesses the upper and lower genitourinary system for treatable causes. Renal ultrasonography can be used instead of computed tomography but tends to provide less information.

Special considerations

In patients with sickle cell trait and sickle cell disease, chronic hypoxia and subsequent sickling of erythrocytes in the renal medulla can lead to papillary hypertrophy and papillary necrosis. In papillary hypertrophy, friable blood vessels can rupture, resulting in microscopic and gross hematuria. In papillary necrosis, the papilla can slough off and become lodged in the ureter.

Nevertheless, hematuria and renal colic in patients with sickle cell disease or trait are most often attributable to common causes such as infection and stones. A finding of hydronephrosis in the absence of a stone, however, suggests obstruction due to a clot or a sloughed papilla. Ureteroscopy, fulguration, and ureteral stent placement can stop the bleeding and alleviate obstruction in these cases.

Renal medullary carcinoma

Another important reason to order imaging in patients with sickle cell disease or trait who present with urologic symptoms is to rule out renal medullary carcinoma, a rare but aggressive cancer that arises from the collecting duct epithelium. This cancer is twice as likely to occur in males than in females; it has been reported in patients ranging in age from 10 to 40, with a median age at presentation of 26.³²

When patients present with symptomatic renal medullary cancer, in most cases the cancer has already metastasized.

On computed tomography, the tumor tends to occupy a central location in the kidney and appears to infiltrate and replace adjacent kidney tissue. Retroperitoneal lymphadenopathy and metastasis are common.

Treatment typically entails radical nephrectomy, chemotherapy, and in some circumstances, radiotherapy. Case reports have shown promising tumor responses to carboplatin and paclitaxel regimens.^33,34 Also, a low threshold for imaging in patients with sickle cell disease and trait may increase the odds of early detection of this aggressive cancer.

Sickle cell disease is a common genetic disorder in the United States that disproportionately affects people of African ancestry. The characteristic sickling of red blood cells under conditions of reduced oxygen tension leads to intravascular hemolysis and vaso-occlusive events, which in turn cause tissue ischemia-reperfusion injury affecting multiple organs, including the genitourinary system.^1–3

In this paper, we review the genitourinary effects of sickle cell disease, focusing on sickle cell nephropathy, priapism, and renal medullary carcinoma.

THE WIDE-RANGING EFFECTS OF SICKLE CELL DISEASE

In the United States, sickle cell disease affects 1 of every 500 blacks and 1 of every 36,000 Hispanics.¹ The term describes hemoglobinopathies associated with sickling of red blood cells.

Sickling of red blood cells results from a single base-pair change in the beta-globin gene from glutamic acid to valine at position 6, causing abnormal hemoglobin (hemoglobin S), which polymerizes under conditions of reduced oxygen tension and alters the biconcave disk shape into a rigid, irregular, unstable cell. The sickle-shaped cells are prone to intravascular hemolysis,² causing intermittent vaso-occlusive events that result in tissue ischemia-reperfusion injury. Genitourinary problems include impaired ability to concentrate urine, hematuria, renal medullary carcinoma, and increased frequency of urinary tract infection.

SICKLE CELL NEPHROPATHY

Signs of kidney involvement may appear in early childhood

The kidney is one of the most frequently affected organs in sickle cell disease. Renal manifestations begin to appear in early childhood, with impaired medullary concentrating ability and ischemic damage to the tubular cells caused by sickling within the vasa recta renis precipitated by the acidic, hypoxic, and hypertonic environment in the renal medulla.

As in early diabetic nephropathy, renal blood flow is enhanced and the glomerular filtration rate (GFR) is increased. Increased cardiac output as a result of anemia, localized release of prostaglandins, and a hypoxia-induced increase in nitric oxide synthesis all play a role in the increase in GFR.^4,5

Oxidative stress, an increase in markers of inflammation, and local activation of the renin-angiotensin system contribute to renal damage in sickle cell disease.^5–7 The resulting hyperfiltration injury leads to microalbuminuria, which occurs in 20% to 40% of children with sickle cell anemia^8,9 and in as many as 60% of adults.

The glomerular lesions associated with sickle cell disease vary from glomerulopathy in the early stages to secondary focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and glomerular thrombotic microangiopathy.¹⁰

Clinical presentations and workup

Clinical presentations are not limited to glomerular disease but include hyperchloremic metabolic acidosis and hyperkalemia resulting from defects in potassium secretion and renal acidification.

Hyperphosphatemia—a result of increased reabsorption of phosphorus, increased secretion of uric acid, and increased creatinine clearance—is seen in patients with sickle cell disease.^11,12 About 10% of patients can develop an acute kidney injury as a result of volume depletion, rhabdomyolysis, renal vein thrombosis, papillary necrosis, and urinary tract obstruction secondary to blood clots.^11,13

Up to 30% of adult patients with sickle cell disease develop chronic kidney disease. Predictors include severe anemia, hypertension, proteinuria, nephrotic syndrome, and microscopic hematuria.¹⁴ From 4% to 12% of patients go on to develop end-stage renal disease, but with a 1-year mortality rate three times higher than in patients without sickle cell disease.¹⁵

In general, patients with sickle cell anemia have blood pressures below those of age- and sex-matched individuals, but elevated blood pressure and low GFR are not uncommon in affected children. In a cohort of 48 children ages 3 to 18, 8.3% had an estimated GFR less than 90 mL/min/1.73 m², and 16.7% had elevated blood pressure (prehypertension and hypertension).¹⁶

In patients with sickle cell disease, evaluation of proteinuria, hematuria, hypertension, and renal failure should take into consideration the unique renal physiologic and pathologic processes involved. Recent evidence^17,18 suggests that the Chronic Kidney Disease Epidemiology Collaboration equation provides a better estimate of GFR than the Modification of Diet in Renal Disease and Cockcroft-Gault equations, although all three creatinine-based methods overestimate GFR in patients with sickle cell disease when compared with GFR measured with technetium-99m-labeled diethylenetriamine penta-acetic acid renal scanning.

Treatment options

Treatment of sickle cell nephropathy includes adequate fluid intake (given the loss of concentrating ability), adequate blood pressure control, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in patients who have microalbuminuria or proteinuria (or both)^9,11,19 and hydroxyurea. Treatment with enalapril has been shown to decrease proteinuria in patients with sickle cell nephropathy.⁹ In a cohort of children with sickle cell disease, four of nine patients treated with an ACE inhibitor developed hyperkalemia, leading to discontinuation of the drug in three patients.⁹

ACE inhibitors and ARBs must be used cautiously in these patients because they have defects in potassium secretion. Hydroxyurea has also been shown to decrease hyperfiltration and microalbuminuria in recent studies,^20,21 and this could protect against the development of overt nephropathy.

Higher mortality rates have been reported in patients with sickle cell disease who developed end-stage renal disease than in patients with end-stage renal disease without sickle cell disease. Sickle cell disease also increases the risk of pulmonary hypertension and the vaso-occlusive complication known as acute chest syndrome, contributing to increased mortality rates. Of note, in a study that looked at the association between mortality rates and pre-end-stage care of renal disease using data from the Centers for Medicare and Medicaid Services, patients with sickle cell disease who had had predialysis nephrology care had lower mortality rates.¹⁵

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and transplantation

Treatments for end-stage renal disease are also effective in patients with sickle cell disease and include hemodialysis, peritoneal dialysis, and renal transplantation. Data from the Organ Procurement and Transplantation Network and the United Network for Organ Sharing show that from 2000 to 2011, African American kidney recipients with sickle cell disease had better survival rates than patients who had undergone transplantation from 1988 to 1999, although rates of long-term survival and graft survival were lower than in transplant recipients with other diagnoses.²²

It is important to note that complications as a result of vaso-occlusive events and thrombosis can lead to graft loss; therefore, sickle cell crisis after transplantation requires careful management.

Take-home messages

• Loss of urine-concentrating ability and hyperfiltration are the earliest pathologic changes in sickle cell disease.
• Microalbuminuria as seen in diabetic nephropathy is the earliest manifestation of sickle cell nephropathy, and the prevalence increases as these patients get older and live longer.
• ACE inhibitors or ARBs should be used with caution, given the heightened risk of hyperkalemia in sickle cell disease.
• Recent results with hydroxyurea in decreasing hyperfiltration and microalbuminuria are encouraging.
• Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease.

PRIAPISM IN SICKLE CELL DISEASE

Priapism was formerly defined as a full, painful erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm. But priapism is now recognized as two separate disorders—ischemic (veno-occlusive, low-flow) priapism and nonischemic (arterial, high-flow) priapism. The new definition includes both disorders: ie, a full or partial erection lasting more than 4 hours and unrelated to sexual stimulation or orgasm.

Ischemic priapism

Hematologic disorders are major contributors to ischemic priapism and include sickle cell disease, multiple myeloma, fat emboli (hyperalimentation),²³ glucose-6-phosphate dehydrogenase deficiency, and hemoglobin Olmsted variant.²⁴

Ischemic priapism is often seen in sickle cell disease and is considered an emergency. It is characterized by an abnormally rigid erection not involving the glans penis. Entrapment of blood in the corpora cavernosa leads to hypoxia, hypercarbia, and acidosis, which in turn leads to a painful compartment syndrome that, if untreated, results in smooth muscle necrosis and subsequent fibrosis. The results are a smaller penis and erectile dysfunction that is unresponsive to any treatment other than implantation of a penile prosthesis. However, scarring of the corpora cavernosa can make this procedure exceedingly difficult, requiring advanced techniques such as corporeal excavation.²⁵

Men with a subtype of ischemic priapism called “stuttering” priapism²⁶ suffer recurrent prolonged erections during sleep. The patient awakens with a painful erection that usually subsides, but sometimes only after several hours. Patients with this disorder suffer from sleep deprivation. Stuttering priapism may lead to full-blown ischemic priapism that does not resolve without intervention.

Nonischemic priapism

In nonischemic priapism, the corpora are engorged but not rigid. The condition results from unregulated arterial inflow and thus is not painful and does not result in damage to the corporeal smooth muscle.

Most cases of nonischemic priapism follow blunt perineal trauma or trauma associated with needle insertion into the corpora. This form of priapism is not associated with sickle cell disease. Because tissue damage does not occur, nonischemic or arterial priapism is not considered an emergency.

Treatment guidelines

Differentiating ischemic from nonischemic priapism is usually straightforward, based on the history, physical examination, corporeal blood gases, and duplex ultrasonography.²⁷

Ischemic priapism is an emergency. After needle aspiration of blood from the corpora cavernosa, phenylephrine is diluted with normal saline to a concentration of 100 to 500 µg/mL and is injected in 1-mL amounts repeatedly at 3- to 5-minute intervals until the erection subsides or until a 1-hour time limit is reached. Blood pressure and pulse are monitored during these injections. If aspiration and phenylephrine irrigation fail, surgical shunting is performed.²⁷

Measures to treat sickle cell disease (hydration, oxygen, exchange transfusions) may be employed simultaneously but should never delay aspiration and phenylephrine injections.²⁵

Early referral for predialysis nephrologic care is needed in sickle cell patients with chronic kidney disease

As nonischemic priapism is not considered an emergency, management begins with observation. Patients eventually become dissatisfied with their constant partial erection, and they then present for treatment. Most cases resolve after selective catheterization of the internal pudendal artery and embolization of the fistula with absorbable material. If this fails, surgical exploration with ligation of the vessels leading to the fistula is indicated.

Prevalence in sickle cell trait vs sickle cell disease

Ischemic priapism is uncommon in men with sickle cell trait, but prevalence rates in men with sickle cell disease are as high as 42%.²⁸ In a study of 130 men with sickle cell disease, 35% had a history of prolonged ischemic priapism, 72% had a history of stuttering priapism, and 75% of men with stuttering priapism had their first episode before age 20.²⁹

Rates of erectile dysfunction increase with the duration of ischemic episodes and range from 20% to 90%.^28,30 In childhood, sickle cell disease accounts for 63% of the cases of ischemic priapism, and in adults it accounts for 23% of cases.³¹

Take-home messages

• Sickle cell disease accounts for two-thirds of cases of ischemic priapism in children, and one-fourth of adult cases.
• Ischemic priapism is a medical emergency.
• Treatment with aspiration and phenylephrine injections should begin immediately and should not await treatment measures for sickle cell disease (hydration, oxygen, exchange transfusions).

OTHER UROLOGIC COMPLICATIONS OF SICKLE CELL DISEASE

Other urologic complications of sickle cell trait and sickle cell disease include microscopic hematuria, gross hematuria, and renal colic. A formal evaluation of any patient with persistent microscopic hematuria or gross hematuria should consist of urinalysis, computed tomography, and cystoscopy. This approach assesses the upper and lower genitourinary system for treatable causes. Renal ultrasonography can be used instead of computed tomography but tends to provide less information.

Special considerations

In patients with sickle cell trait and sickle cell disease, chronic hypoxia and subsequent sickling of erythrocytes in the renal medulla can lead to papillary hypertrophy and papillary necrosis. In papillary hypertrophy, friable blood vessels can rupture, resulting in microscopic and gross hematuria. In papillary necrosis, the papilla can slough off and become lodged in the ureter.

Nevertheless, hematuria and renal colic in patients with sickle cell disease or trait are most often attributable to common causes such as infection and stones. A finding of hydronephrosis in the absence of a stone, however, suggests obstruction due to a clot or a sloughed papilla. Ureteroscopy, fulguration, and ureteral stent placement can stop the bleeding and alleviate obstruction in these cases.

Renal medullary carcinoma

Another important reason to order imaging in patients with sickle cell disease or trait who present with urologic symptoms is to rule out renal medullary carcinoma, a rare but aggressive cancer that arises from the collecting duct epithelium. This cancer is twice as likely to occur in males than in females; it has been reported in patients ranging in age from 10 to 40, with a median age at presentation of 26.³²

When patients present with symptomatic renal medullary cancer, in most cases the cancer has already metastasized.

On computed tomography, the tumor tends to occupy a central location in the kidney and appears to infiltrate and replace adjacent kidney tissue. Retroperitoneal lymphadenopathy and metastasis are common.

Treatment typically entails radical nephrectomy, chemotherapy, and in some circumstances, radiotherapy. Case reports have shown promising tumor responses to carboplatin and paclitaxel regimens.^33,34 Also, a low threshold for imaging in patients with sickle cell disease and trait may increase the odds of early detection of this aggressive cancer.

A 63-year-old physician is referred for preoperative evaluation before arthroscopic repair of a torn medial meniscus. Her exercise tolerance was excellent before the knee injury, including running without cardiopulmonary symptoms. She is otherwise healthy except for hypertension that is well controlled on amlodipine. She has no known history of liver or kidney disease, bleeding disorder, recent illness, or complications with anesthesia. She inquires as to whether “routine blood testing” is needed before the procedure.

See related editorial

What laboratory studies, if any, should be ordered?

UNLIKELY TO BE OF BENEFIT

Preoperative laboratory testing is not necessary in this otherwise healthy, asymptomatic patient. In the absence of clinical indications, routine testing before elective, low-risk procedures often increases both the cost of care and the potential anxiety caused by abnormal results that provide no substantial benefit to the patient or the clinician.

Preoperative diagnostic tests should be ordered only to identify and optimize disorders that alter the likelihood of perioperative and postoperative adverse outcomes and to establish a baseline assessment. Yet clinicians often perceive that laboratory testing is required by their organization or by other providers.

A comprehensive history and physical examination are the cornerstones of the effective preoperative evaluation. Preferably, the history and examination should guide further testing rather than ordering a battery of standard tests for all patients. However, selective preoperative laboratory testing may be useful in certain situations, such as in patients undergoing high-risk procedures and those with known underlying conditions or factors that may affect operative management (Table 1).

Unfortunately, high-quality evidence for this selective approach is lacking. According to one observational study,¹ when laboratory testing is appropriate, it is reasonable to use test results already obtained and normal within the preceding 4 months unless the patient has had an interim change in health status.

Definitions of risk stratification (eg, urgency of surgical procedure, graded risk according to type of operation) and tools such as the Revised Cardiac Risk Index can be found in the 2014 American College of Cardiology/American Heart Association guidelines² and may be useful to distinguish healthy patients from those with significant comorbidities, as well as to distinguish low-risk, elective procedures from those that impart higher risk.

Professional societies and guidelines in many countries have criticized the habitual practice of extensive, nonselective laboratory testing.^3–6 Yet despite lack of evidence of benefit, routine preoperative testing is still often done. At an estimated cost of more than $18 billion in the United States annually,⁷ preoperative testing deserves attention, especially in this time of ballooning healthcare costs and increased focus on effective and efficient care.

EVIDENCE AND GUIDELINES

Numerous studies have established that routine laboratory testing rarely changes the preoperative management of the patient or improves surgical outcomes. Narr et al⁸ found that 160 (4%) of 3,782 patients who underwent ambulatory surgery had abnormal test results, and only 10 required treatment. In this study, there was no association between abnormal test results and perioperative management or postoperative adverse events.

In a systematic review, Smetana and Macpherson⁹ noted that the incidence of laboratory test abnormalities that led to a change in management ranged from 0.1% to 2.6%. Notably, clinicians ignore 30% to 60% of abnormal preoperative laboratory results, a practice that may create additional medicolegal risk.⁷

Most guidelines on preoperative testing are based on expert opinion, case series, or consensus

Little evidence exists that helps in the development of guidelines for preoperative laboratory testing. Most guidelines are based on expert opinion, case series, and consensus. As an example of the heterogeneity this creates, the American Society of Anesthesiologists, the Ontario Preoperative Testing Group, and the Canadian Anesthesiologists’ Society provide different recommended indications for preoperative laboratory testing in patients with “advanced age” but do not define a clear minimum age for this cohort.¹⁰

However, one area that does have substantial data is cataract surgery. Patients in their usual state of health who are to undergo this procedure do not require preoperative testing, a claim supported by high-quality evidence including a 2012 Cochrane systematic review.¹¹

Munro et al⁵ performed a systematic review of the evidence behind preoperative laboratory testing, concluding that the power of preoperative tests to predict adverse postoperative outcomes in asymptomatic patients is either weak or nonexistent. The National Institute for Health and Clinical Excellence guidelines of 2003,⁶ the Practice Advisory for Preanesthesia Evaluation of the American Society of Anesthesiologists of 2012,¹² the Institute for Clinical Systems Improvement guideline of 2012,¹³ and a systematic review conducted by Johansson et al¹⁴ found no evidence from high-quality studies to support the claim that routine preoperative testing is beneficial in healthy adults undergoing noncardiac surgery, but that certain patient populations may benefit from selective testing.

A randomized controlled trial evaluated the elimination of preoperative testing in patients undergoing low-risk ambulatory surgery and found no difference in perioperative adverse events in the control and intervention arms.¹⁵ Similar studies achieved the same results.

The Choosing Wisely campaign

The American Board of Internal Medicine Foundation has partnered with medical specialty societies to create lists of common practice patterns that should be questioned and possibly discontinued. These lists are collectively called the Choosing Wisely campaign (www.choosingwisely.org). Avoiding routine preoperative laboratory testing in patients undergoing low-risk surgery without clinical indications can be found in the lists for the American Society of Anesthesiologists, the American Society for Clinical Pathology, and the Society of General Internal Medicine.

THE POSSIBLE HARMS OF TESTING

The prevalence of unrecognized disease that influences the risk of surgery in healthy patients is low, and thus the predictive value of abnormal test values in these patients is low. This leads to substantial false-positivity, which is of uncertain clinical significance and which may in turn cause a cascade of further testing. Not surprisingly, the probability of an abnormal test result increases dramatically with the number of tests ordered, a fact that magnifies the problem of false-positive results.

The costs and harms associated with testing are both direct and indirect. Direct effects include increased healthcare costs of further testing or potentially unnecessary treatment as well as risk associated with additional testing, though these are not common, as there is a low (< 3%) incidence of a change in preoperative management based on an abnormal test result. Likewise, normal results do not appear to substantially reduce the likelihood of postoperative complications.⁹

Indirect effects, which are particularly challenging to measure, may include time lost from employment to pursue further evaluation and anxiety surrounding abnormal results.

THE CLINICAL BOTTOM LINE

Based on over 2 decades of data, our 63-year-old patient should not undergo “routine” preoperative laboratory testing before her upcoming elective, low-risk, noncardiac procedure. Her hypertension is well controlled, and she is taking no medications that may lead to clinically significant metabolic derangements or significant changes in surgical outcome. There are no convincing clinical indications for further laboratory investigation. Further, the results are unlikely to affect the preoperative management and rate of adverse events; the direct and indirect costs may be substantial; and there is a small but tangible risk of harm.

Given the myriad factors that influence unnecessary preoperative testing, a focus on systems-level solutions is paramount. Key steps may include creation and adoption of clear and consistent guidelines, development of clinical care pathways, physician education and modification of practice, interdisciplinary communication and information sharing, economic analysis, and outcomes assessment.

A 63-year-old physician is referred for preoperative evaluation before arthroscopic repair of a torn medial meniscus. Her exercise tolerance was excellent before the knee injury, including running without cardiopulmonary symptoms. She is otherwise healthy except for hypertension that is well controlled on amlodipine. She has no known history of liver or kidney disease, bleeding disorder, recent illness, or complications with anesthesia. She inquires as to whether “routine blood testing” is needed before the procedure.

See related editorial

What laboratory studies, if any, should be ordered?

UNLIKELY TO BE OF BENEFIT

Preoperative laboratory testing is not necessary in this otherwise healthy, asymptomatic patient. In the absence of clinical indications, routine testing before elective, low-risk procedures often increases both the cost of care and the potential anxiety caused by abnormal results that provide no substantial benefit to the patient or the clinician.

Preoperative diagnostic tests should be ordered only to identify and optimize disorders that alter the likelihood of perioperative and postoperative adverse outcomes and to establish a baseline assessment. Yet clinicians often perceive that laboratory testing is required by their organization or by other providers.

A comprehensive history and physical examination are the cornerstones of the effective preoperative evaluation. Preferably, the history and examination should guide further testing rather than ordering a battery of standard tests for all patients. However, selective preoperative laboratory testing may be useful in certain situations, such as in patients undergoing high-risk procedures and those with known underlying conditions or factors that may affect operative management (Table 1).

Unfortunately, high-quality evidence for this selective approach is lacking. According to one observational study,¹ when laboratory testing is appropriate, it is reasonable to use test results already obtained and normal within the preceding 4 months unless the patient has had an interim change in health status.

Definitions of risk stratification (eg, urgency of surgical procedure, graded risk according to type of operation) and tools such as the Revised Cardiac Risk Index can be found in the 2014 American College of Cardiology/American Heart Association guidelines² and may be useful to distinguish healthy patients from those with significant comorbidities, as well as to distinguish low-risk, elective procedures from those that impart higher risk.

Professional societies and guidelines in many countries have criticized the habitual practice of extensive, nonselective laboratory testing.^3–6 Yet despite lack of evidence of benefit, routine preoperative testing is still often done. At an estimated cost of more than $18 billion in the United States annually,⁷ preoperative testing deserves attention, especially in this time of ballooning healthcare costs and increased focus on effective and efficient care.

EVIDENCE AND GUIDELINES

Numerous studies have established that routine laboratory testing rarely changes the preoperative management of the patient or improves surgical outcomes. Narr et al⁸ found that 160 (4%) of 3,782 patients who underwent ambulatory surgery had abnormal test results, and only 10 required treatment. In this study, there was no association between abnormal test results and perioperative management or postoperative adverse events.

In a systematic review, Smetana and Macpherson⁹ noted that the incidence of laboratory test abnormalities that led to a change in management ranged from 0.1% to 2.6%. Notably, clinicians ignore 30% to 60% of abnormal preoperative laboratory results, a practice that may create additional medicolegal risk.⁷

Most guidelines on preoperative testing are based on expert opinion, case series, or consensus

Little evidence exists that helps in the development of guidelines for preoperative laboratory testing. Most guidelines are based on expert opinion, case series, and consensus. As an example of the heterogeneity this creates, the American Society of Anesthesiologists, the Ontario Preoperative Testing Group, and the Canadian Anesthesiologists’ Society provide different recommended indications for preoperative laboratory testing in patients with “advanced age” but do not define a clear minimum age for this cohort.¹⁰

However, one area that does have substantial data is cataract surgery. Patients in their usual state of health who are to undergo this procedure do not require preoperative testing, a claim supported by high-quality evidence including a 2012 Cochrane systematic review.¹¹

Munro et al⁵ performed a systematic review of the evidence behind preoperative laboratory testing, concluding that the power of preoperative tests to predict adverse postoperative outcomes in asymptomatic patients is either weak or nonexistent. The National Institute for Health and Clinical Excellence guidelines of 2003,⁶ the Practice Advisory for Preanesthesia Evaluation of the American Society of Anesthesiologists of 2012,¹² the Institute for Clinical Systems Improvement guideline of 2012,¹³ and a systematic review conducted by Johansson et al¹⁴ found no evidence from high-quality studies to support the claim that routine preoperative testing is beneficial in healthy adults undergoing noncardiac surgery, but that certain patient populations may benefit from selective testing.

A randomized controlled trial evaluated the elimination of preoperative testing in patients undergoing low-risk ambulatory surgery and found no difference in perioperative adverse events in the control and intervention arms.¹⁵ Similar studies achieved the same results.

The Choosing Wisely campaign

The American Board of Internal Medicine Foundation has partnered with medical specialty societies to create lists of common practice patterns that should be questioned and possibly discontinued. These lists are collectively called the Choosing Wisely campaign (www.choosingwisely.org). Avoiding routine preoperative laboratory testing in patients undergoing low-risk surgery without clinical indications can be found in the lists for the American Society of Anesthesiologists, the American Society for Clinical Pathology, and the Society of General Internal Medicine.

THE POSSIBLE HARMS OF TESTING

The prevalence of unrecognized disease that influences the risk of surgery in healthy patients is low, and thus the predictive value of abnormal test values in these patients is low. This leads to substantial false-positivity, which is of uncertain clinical significance and which may in turn cause a cascade of further testing. Not surprisingly, the probability of an abnormal test result increases dramatically with the number of tests ordered, a fact that magnifies the problem of false-positive results.

The costs and harms associated with testing are both direct and indirect. Direct effects include increased healthcare costs of further testing or potentially unnecessary treatment as well as risk associated with additional testing, though these are not common, as there is a low (< 3%) incidence of a change in preoperative management based on an abnormal test result. Likewise, normal results do not appear to substantially reduce the likelihood of postoperative complications.⁹

Indirect effects, which are particularly challenging to measure, may include time lost from employment to pursue further evaluation and anxiety surrounding abnormal results.

THE CLINICAL BOTTOM LINE

Based on over 2 decades of data, our 63-year-old patient should not undergo “routine” preoperative laboratory testing before her upcoming elective, low-risk, noncardiac procedure. Her hypertension is well controlled, and she is taking no medications that may lead to clinically significant metabolic derangements or significant changes in surgical outcome. There are no convincing clinical indications for further laboratory investigation. Further, the results are unlikely to affect the preoperative management and rate of adverse events; the direct and indirect costs may be substantial; and there is a small but tangible risk of harm.

Given the myriad factors that influence unnecessary preoperative testing, a focus on systems-level solutions is paramount. Key steps may include creation and adoption of clear and consistent guidelines, development of clinical care pathways, physician education and modification of practice, interdisciplinary communication and information sharing, economic analysis, and outcomes assessment.

A 63-year-old physician is referred for preoperative evaluation before arthroscopic repair of a torn medial meniscus. Her exercise tolerance was excellent before the knee injury, including running without cardiopulmonary symptoms. She is otherwise healthy except for hypertension that is well controlled on amlodipine. She has no known history of liver or kidney disease, bleeding disorder, recent illness, or complications with anesthesia. She inquires as to whether “routine blood testing” is needed before the procedure.

See related editorial

What laboratory studies, if any, should be ordered?

UNLIKELY TO BE OF BENEFIT

Preoperative laboratory testing is not necessary in this otherwise healthy, asymptomatic patient. In the absence of clinical indications, routine testing before elective, low-risk procedures often increases both the cost of care and the potential anxiety caused by abnormal results that provide no substantial benefit to the patient or the clinician.

Preoperative diagnostic tests should be ordered only to identify and optimize disorders that alter the likelihood of perioperative and postoperative adverse outcomes and to establish a baseline assessment. Yet clinicians often perceive that laboratory testing is required by their organization or by other providers.

A comprehensive history and physical examination are the cornerstones of the effective preoperative evaluation. Preferably, the history and examination should guide further testing rather than ordering a battery of standard tests for all patients. However, selective preoperative laboratory testing may be useful in certain situations, such as in patients undergoing high-risk procedures and those with known underlying conditions or factors that may affect operative management (Table 1).

Unfortunately, high-quality evidence for this selective approach is lacking. According to one observational study,¹ when laboratory testing is appropriate, it is reasonable to use test results already obtained and normal within the preceding 4 months unless the patient has had an interim change in health status.

Definitions of risk stratification (eg, urgency of surgical procedure, graded risk according to type of operation) and tools such as the Revised Cardiac Risk Index can be found in the 2014 American College of Cardiology/American Heart Association guidelines² and may be useful to distinguish healthy patients from those with significant comorbidities, as well as to distinguish low-risk, elective procedures from those that impart higher risk.

Professional societies and guidelines in many countries have criticized the habitual practice of extensive, nonselective laboratory testing.^3–6 Yet despite lack of evidence of benefit, routine preoperative testing is still often done. At an estimated cost of more than $18 billion in the United States annually,⁷ preoperative testing deserves attention, especially in this time of ballooning healthcare costs and increased focus on effective and efficient care.

EVIDENCE AND GUIDELINES

Numerous studies have established that routine laboratory testing rarely changes the preoperative management of the patient or improves surgical outcomes. Narr et al⁸ found that 160 (4%) of 3,782 patients who underwent ambulatory surgery had abnormal test results, and only 10 required treatment. In this study, there was no association between abnormal test results and perioperative management or postoperative adverse events.

In a systematic review, Smetana and Macpherson⁹ noted that the incidence of laboratory test abnormalities that led to a change in management ranged from 0.1% to 2.6%. Notably, clinicians ignore 30% to 60% of abnormal preoperative laboratory results, a practice that may create additional medicolegal risk.⁷

Most guidelines on preoperative testing are based on expert opinion, case series, or consensus

Little evidence exists that helps in the development of guidelines for preoperative laboratory testing. Most guidelines are based on expert opinion, case series, and consensus. As an example of the heterogeneity this creates, the American Society of Anesthesiologists, the Ontario Preoperative Testing Group, and the Canadian Anesthesiologists’ Society provide different recommended indications for preoperative laboratory testing in patients with “advanced age” but do not define a clear minimum age for this cohort.¹⁰

However, one area that does have substantial data is cataract surgery. Patients in their usual state of health who are to undergo this procedure do not require preoperative testing, a claim supported by high-quality evidence including a 2012 Cochrane systematic review.¹¹

Munro et al⁵ performed a systematic review of the evidence behind preoperative laboratory testing, concluding that the power of preoperative tests to predict adverse postoperative outcomes in asymptomatic patients is either weak or nonexistent. The National Institute for Health and Clinical Excellence guidelines of 2003,⁶ the Practice Advisory for Preanesthesia Evaluation of the American Society of Anesthesiologists of 2012,¹² the Institute for Clinical Systems Improvement guideline of 2012,¹³ and a systematic review conducted by Johansson et al¹⁴ found no evidence from high-quality studies to support the claim that routine preoperative testing is beneficial in healthy adults undergoing noncardiac surgery, but that certain patient populations may benefit from selective testing.

A randomized controlled trial evaluated the elimination of preoperative testing in patients undergoing low-risk ambulatory surgery and found no difference in perioperative adverse events in the control and intervention arms.¹⁵ Similar studies achieved the same results.

The Choosing Wisely campaign

The American Board of Internal Medicine Foundation has partnered with medical specialty societies to create lists of common practice patterns that should be questioned and possibly discontinued. These lists are collectively called the Choosing Wisely campaign (www.choosingwisely.org). Avoiding routine preoperative laboratory testing in patients undergoing low-risk surgery without clinical indications can be found in the lists for the American Society of Anesthesiologists, the American Society for Clinical Pathology, and the Society of General Internal Medicine.

THE POSSIBLE HARMS OF TESTING

The prevalence of unrecognized disease that influences the risk of surgery in healthy patients is low, and thus the predictive value of abnormal test values in these patients is low. This leads to substantial false-positivity, which is of uncertain clinical significance and which may in turn cause a cascade of further testing. Not surprisingly, the probability of an abnormal test result increases dramatically with the number of tests ordered, a fact that magnifies the problem of false-positive results.

The costs and harms associated with testing are both direct and indirect. Direct effects include increased healthcare costs of further testing or potentially unnecessary treatment as well as risk associated with additional testing, though these are not common, as there is a low (< 3%) incidence of a change in preoperative management based on an abnormal test result. Likewise, normal results do not appear to substantially reduce the likelihood of postoperative complications.⁹

Indirect effects, which are particularly challenging to measure, may include time lost from employment to pursue further evaluation and anxiety surrounding abnormal results.

THE CLINICAL BOTTOM LINE

Based on over 2 decades of data, our 63-year-old patient should not undergo “routine” preoperative laboratory testing before her upcoming elective, low-risk, noncardiac procedure. Her hypertension is well controlled, and she is taking no medications that may lead to clinically significant metabolic derangements or significant changes in surgical outcome. There are no convincing clinical indications for further laboratory investigation. Further, the results are unlikely to affect the preoperative management and rate of adverse events; the direct and indirect costs may be substantial; and there is a small but tangible risk of harm.

Given the myriad factors that influence unnecessary preoperative testing, a focus on systems-level solutions is paramount. Key steps may include creation and adoption of clear and consistent guidelines, development of clinical care pathways, physician education and modification of practice, interdisciplinary communication and information sharing, economic analysis, and outcomes assessment.

Guidelines and practice advisories issued by several medical societies, including the American Society of Anesthesiologists,¹ American Heart Association (AHA) and American College of Cardiology (ACC),² and Society of General Internal Medicine,³ advise against routine preoperative testing for patients undergoing low-risk surgical procedures. Such testing often includes routine blood chemistry, complete blood cell counts, measures of the clotting system, and cardiac stress testing.

See related article

In this issue of the Cleveland Clinic Journal of Medicine, Dr. Nathan Houchens reviews the evidence against these measures.⁴

Despite a substantial body of evidence going back more than 2 decades that includes prospective randomized controlled trials,^5–10 physicians continue to order unnecessary, ineffective, and costly tests in the perioperative period.¹¹ The process of abandoning current medical practice—a phenomenon known as medical reversal¹²—often takes years,¹³ because it is more difficult to convince physicians to discontinue a current behavior than to implement a new one.¹⁴ The study of what makes physicians accept new therapies and abandon old ones began more than half a century ago.¹⁵

More recently, Cabana et al¹⁶ created a framework to understand why physicians do not follow clinical practice guidelines. Among the reasons are lack of familiarity or agreement with the contents of the guideline, lack of outcome expectancy, inertia of previous practice, and external barriers to implementation.

It is harder to convince physicians to discontinue a current behavior than to implement a new one

The rapid proliferation of guidelines in the past 20 years has led to numerous conflicting recommendations, many of which are based primarily on expert opinion.¹⁷ Guidelines based solely on randomized trials have also come under fire.^18,19

In the case of preoperative testing, the recommendations are generally evidence-based and consistent. Why then do physicians appear to disregard the evidence? We propose several reasons why they might do so.

SOME PHYSICIANS ARE UNFAMILIAR WITH THE EVIDENCE

The complexity of the evidence summarized in guidelines has increased exponentially in the last decade, but physician time to assess the evidence has not increased. For example, the number of references in the executive summary of the ACC/AHA perioperative guidelines increased from 96 in 2002 to 252 in 2014. Most of the recommendations are backed by substantial amounts of high-quality evidence. For example, there are 17 prospective and 13 retrospective studies demonstrating that routine testing with the prothrombin time and the partial thromboplastin time is not helpful in asymptomatic patients.²⁰

Although compliance with medical evidence varies among specialties,²¹ most physicians do not have time to keep up with the ever-increasing amount of information. Specifically in the area of cardiac risk assessment, there has been a rapid proliferation of tests that can be used to assess cardiac risk.^22–28 In a Harris Interactive survey from 2008, physicians reported not applying medical evidence routinely. One-third believed they would do it more if they had the time.²⁹ Without information technology support to provide medical information at the point of care,³⁰ especially in small practices, using evidence may not be practical. Simply making the information available online and not promoting it actively does not improve utilization.³¹

As a consequence, physicians continue to order unnecessary tests, even though they may not feel confident interpreting the results.³²

PHYSICIANS MAY NOT BELIEVE THE EVIDENCE

A lack of transparency in evidence-based guidelines and, sometimes, a lack of flexibility and relevance to clinical practice are important barriers to physicians’ acceptance of and adherence to evidence-based clinical practice guidelines.³⁰

Most physicians do not have time to keep up with the ever-increasing amount of information

Even experts who write guidelines may not be swayed by the evidence. For example, a randomized prospective trial of almost 6,000 patients reported that coronary artery revascularization before elective major vascular surgery does not affect long-term mortality rates.³³ Based on this study, the 2014 ACC/AHA guidelines² advised against revascularization before noncardiac surgery exclusively to reduce perioperative cardiac events. Yet the same guidelines do recommend assessing for myocardial ischemia in patients with elevated risk and poor or unknown functional capacity, using a pharmacologic stress test. Based on the extent of the stress test abnormalities, coronary angiography and revascularization are then suggested for patients willing to undergo coronary artery bypass grafting (CABG) or percutaneous coronary intervention.²

The 2014 European Society of Cardiology and European Society of Anaesthesiology guidelines directly recommend revascularization before high-risk surgery, depending on the extent of a stress-induced perfusion defect.³⁴ This recommendation relies on data from the Coronary Artery Surgery Study registry, which included almost 25,000 patients who underwent coronary angiography from 1975 through 1979. At a mean follow-up of 4.1 years, 1,961 patients underwent high-risk surgery. In this observational cohort, patients who underwent CABG had a lower risk of death and myocardial infarction after surgery.³⁵ The reliance of medical societies³⁴ on data that are more than 30 years old—when operative mortality rates and the treatment of coronary artery disease have changed substantially in the interim and despite the fact that this study did not test whether preoperative revascularization can reduce postoperative mortality—reflects a certain resistance to accept the results of the more recent and relevant randomized trial.³³

Other physicians may also prefer to rely on selective data or to simply defer to guidelines that support their beliefs. Some physicians find that evidence-based guidelines are impractical and rigid and reduce their autonomy.³⁶ For many physicians, trials that use surrogate end points and short-term outcomes are not sufficiently compelling to make them abandon current practice.³⁷ Finally, when members of the guideline committees have financial associations with the pharmaceutical industry, or when corporations interested in the outcomes provide financial support for a trial’s development, the likelihood of a recommendation being trusted and used by physicians is drastically reduced.³⁸

PRACTICING DEFENSIVELY

Even if physicians are familiar with the evidence and believe it, they may choose not to act on it. One reason is fear of litigation.

In court, attorneys can use guidelines as well as articles from medical journals as both exculpatory and inculpatory evidence. But they more frequently rely on the standard of care, or what most physicians would do under similar circumstances. If a patient has a bad outcome, such as a perioperative myocardial infarction or life-threatening bleeding, the defendant may assert that testing was unwarranted because guidelines do not recommend it or because the probability of such an outcome was low. However, because the outcome occurred, the jury may not believe that the probability was low enough not to consider, especially if expert witnesses testify that the standard of care would be to order the test.

In areas of controversy, physicians generally believe that erring on the side of more testing is more defensible in court.³⁹ Indeed, following established practice traditions, learned during residency,^11,40 may absolve physicians in negligence claims if the way medical care was delivered is supported by recognized and respected physicians.⁴¹

Even physicians who write the guidelines may be unswayed by the evidence

As a consequence, physicians prefer to practice the same way their peers do rather than follow the evidence. Unfortunately, the more procedures physicians perform for low-risk patients, the more likely these tests will become accepted as the legal standard of care.⁴² In this vicious circle, the new standard of care can increase the risk of litigation for others.⁴³ Although unnecessary testing that leads to harmful invasive tests or procedures can also result in malpractice litigation, physicians may not consider this possibility.

FINANCIAL INCENTIVES

The threat of malpractice litigation provides a negative financial incentive to keep performing unnecessary tests, but there are a number of positive incentives as well.

First, physicians often feel compelled to order tests when they believe that physicians referring the patients want the tests done, or when they fear that not completing the tests could delay or cancel the scheduled surgery.⁴⁰ Refusing to order the test could result in a loss of future referrals. In contrast, ordering tests allows them to meet expectations, preserve trust, and appear more valuable to referring physicians and their patients.

Insurance companies are complicit in these practices. Paying for unnecessary tests can create direct financial incentives for physicians or institutions that own on-site laboratories or diagnostic imaging equipment. Evidence shows that under those circumstances physicians do order more tests. Self-referral and referral to facilities where physicians have a financial interest is associated with increased healthcare costs.⁴⁴ In addition to direct revenues for the tests performed, physicians may also bill for test interpretation, follow-up visits, and additional procedures generated from test results.

This may be one explanation why the ordering of cardiac tests (stress testing, echocardiography, vascular ultrasonography) by US physicians varies widely from state to state.⁴⁵

RECOMMENDATIONS TO REDUCE INAPPROPRIATE TESTING

To counter these influences, we propose a multifaceted intervention that includes the following:

• Establish preoperative clinics staffed by experts. Despite the large volume of potentially relevant evidence, the number of articles directly supporting or refuting preoperative laboratory testing is small enough that physicians who routinely engage in preoperative assessment should easily master the evidence.
• Identify local leaders who can convince colleagues of the evidence. Distribute evidence summaries or guidelines with references to major articles that support each recommendation.
• Work with clinical practice committees to establish new standards of care within the hospital. Establish hospital care paths to dictate and support local standards of care. Measure individual physician performance and offer feedback with the goal of reducing utilization.
• National societies should recommend that insurance companies remove inappropriate financial incentives. If companies deny payment for inappropriate testing, physicians will stop ordering it. Even requirements for preauthorization of tests should reduce utilization. The Choosing Wisely campaign (www.choosingwisely.org) would be a good place to start.

Guidelines and practice advisories issued by several medical societies, including the American Society of Anesthesiologists,¹ American Heart Association (AHA) and American College of Cardiology (ACC),² and Society of General Internal Medicine,³ advise against routine preoperative testing for patients undergoing low-risk surgical procedures. Such testing often includes routine blood chemistry, complete blood cell counts, measures of the clotting system, and cardiac stress testing.

See related article

In this issue of the Cleveland Clinic Journal of Medicine, Dr. Nathan Houchens reviews the evidence against these measures.⁴

Despite a substantial body of evidence going back more than 2 decades that includes prospective randomized controlled trials,^5–10 physicians continue to order unnecessary, ineffective, and costly tests in the perioperative period.¹¹ The process of abandoning current medical practice—a phenomenon known as medical reversal¹²—often takes years,¹³ because it is more difficult to convince physicians to discontinue a current behavior than to implement a new one.¹⁴ The study of what makes physicians accept new therapies and abandon old ones began more than half a century ago.¹⁵

More recently, Cabana et al¹⁶ created a framework to understand why physicians do not follow clinical practice guidelines. Among the reasons are lack of familiarity or agreement with the contents of the guideline, lack of outcome expectancy, inertia of previous practice, and external barriers to implementation.

It is harder to convince physicians to discontinue a current behavior than to implement a new one

The rapid proliferation of guidelines in the past 20 years has led to numerous conflicting recommendations, many of which are based primarily on expert opinion.¹⁷ Guidelines based solely on randomized trials have also come under fire.^18,19

In the case of preoperative testing, the recommendations are generally evidence-based and consistent. Why then do physicians appear to disregard the evidence? We propose several reasons why they might do so.

SOME PHYSICIANS ARE UNFAMILIAR WITH THE EVIDENCE

The complexity of the evidence summarized in guidelines has increased exponentially in the last decade, but physician time to assess the evidence has not increased. For example, the number of references in the executive summary of the ACC/AHA perioperative guidelines increased from 96 in 2002 to 252 in 2014. Most of the recommendations are backed by substantial amounts of high-quality evidence. For example, there are 17 prospective and 13 retrospective studies demonstrating that routine testing with the prothrombin time and the partial thromboplastin time is not helpful in asymptomatic patients.²⁰

Although compliance with medical evidence varies among specialties,²¹ most physicians do not have time to keep up with the ever-increasing amount of information. Specifically in the area of cardiac risk assessment, there has been a rapid proliferation of tests that can be used to assess cardiac risk.^22–28 In a Harris Interactive survey from 2008, physicians reported not applying medical evidence routinely. One-third believed they would do it more if they had the time.²⁹ Without information technology support to provide medical information at the point of care,³⁰ especially in small practices, using evidence may not be practical. Simply making the information available online and not promoting it actively does not improve utilization.³¹

As a consequence, physicians continue to order unnecessary tests, even though they may not feel confident interpreting the results.³²

PHYSICIANS MAY NOT BELIEVE THE EVIDENCE

A lack of transparency in evidence-based guidelines and, sometimes, a lack of flexibility and relevance to clinical practice are important barriers to physicians’ acceptance of and adherence to evidence-based clinical practice guidelines.³⁰

Most physicians do not have time to keep up with the ever-increasing amount of information

Even experts who write guidelines may not be swayed by the evidence. For example, a randomized prospective trial of almost 6,000 patients reported that coronary artery revascularization before elective major vascular surgery does not affect long-term mortality rates.³³ Based on this study, the 2014 ACC/AHA guidelines² advised against revascularization before noncardiac surgery exclusively to reduce perioperative cardiac events. Yet the same guidelines do recommend assessing for myocardial ischemia in patients with elevated risk and poor or unknown functional capacity, using a pharmacologic stress test. Based on the extent of the stress test abnormalities, coronary angiography and revascularization are then suggested for patients willing to undergo coronary artery bypass grafting (CABG) or percutaneous coronary intervention.²

The 2014 European Society of Cardiology and European Society of Anaesthesiology guidelines directly recommend revascularization before high-risk surgery, depending on the extent of a stress-induced perfusion defect.³⁴ This recommendation relies on data from the Coronary Artery Surgery Study registry, which included almost 25,000 patients who underwent coronary angiography from 1975 through 1979. At a mean follow-up of 4.1 years, 1,961 patients underwent high-risk surgery. In this observational cohort, patients who underwent CABG had a lower risk of death and myocardial infarction after surgery.³⁵ The reliance of medical societies³⁴ on data that are more than 30 years old—when operative mortality rates and the treatment of coronary artery disease have changed substantially in the interim and despite the fact that this study did not test whether preoperative revascularization can reduce postoperative mortality—reflects a certain resistance to accept the results of the more recent and relevant randomized trial.³³

Other physicians may also prefer to rely on selective data or to simply defer to guidelines that support their beliefs. Some physicians find that evidence-based guidelines are impractical and rigid and reduce their autonomy.³⁶ For many physicians, trials that use surrogate end points and short-term outcomes are not sufficiently compelling to make them abandon current practice.³⁷ Finally, when members of the guideline committees have financial associations with the pharmaceutical industry, or when corporations interested in the outcomes provide financial support for a trial’s development, the likelihood of a recommendation being trusted and used by physicians is drastically reduced.³⁸

PRACTICING DEFENSIVELY

Even if physicians are familiar with the evidence and believe it, they may choose not to act on it. One reason is fear of litigation.

In court, attorneys can use guidelines as well as articles from medical journals as both exculpatory and inculpatory evidence. But they more frequently rely on the standard of care, or what most physicians would do under similar circumstances. If a patient has a bad outcome, such as a perioperative myocardial infarction or life-threatening bleeding, the defendant may assert that testing was unwarranted because guidelines do not recommend it or because the probability of such an outcome was low. However, because the outcome occurred, the jury may not believe that the probability was low enough not to consider, especially if expert witnesses testify that the standard of care would be to order the test.

In areas of controversy, physicians generally believe that erring on the side of more testing is more defensible in court.³⁹ Indeed, following established practice traditions, learned during residency,^11,40 may absolve physicians in negligence claims if the way medical care was delivered is supported by recognized and respected physicians.⁴¹

Even physicians who write the guidelines may be unswayed by the evidence

As a consequence, physicians prefer to practice the same way their peers do rather than follow the evidence. Unfortunately, the more procedures physicians perform for low-risk patients, the more likely these tests will become accepted as the legal standard of care.⁴² In this vicious circle, the new standard of care can increase the risk of litigation for others.⁴³ Although unnecessary testing that leads to harmful invasive tests or procedures can also result in malpractice litigation, physicians may not consider this possibility.

FINANCIAL INCENTIVES

The threat of malpractice litigation provides a negative financial incentive to keep performing unnecessary tests, but there are a number of positive incentives as well.

First, physicians often feel compelled to order tests when they believe that physicians referring the patients want the tests done, or when they fear that not completing the tests could delay or cancel the scheduled surgery.⁴⁰ Refusing to order the test could result in a loss of future referrals. In contrast, ordering tests allows them to meet expectations, preserve trust, and appear more valuable to referring physicians and their patients.

Insurance companies are complicit in these practices. Paying for unnecessary tests can create direct financial incentives for physicians or institutions that own on-site laboratories or diagnostic imaging equipment. Evidence shows that under those circumstances physicians do order more tests. Self-referral and referral to facilities where physicians have a financial interest is associated with increased healthcare costs.⁴⁴ In addition to direct revenues for the tests performed, physicians may also bill for test interpretation, follow-up visits, and additional procedures generated from test results.

This may be one explanation why the ordering of cardiac tests (stress testing, echocardiography, vascular ultrasonography) by US physicians varies widely from state to state.⁴⁵

RECOMMENDATIONS TO REDUCE INAPPROPRIATE TESTING

To counter these influences, we propose a multifaceted intervention that includes the following:

• Establish preoperative clinics staffed by experts. Despite the large volume of potentially relevant evidence, the number of articles directly supporting or refuting preoperative laboratory testing is small enough that physicians who routinely engage in preoperative assessment should easily master the evidence.
• Identify local leaders who can convince colleagues of the evidence. Distribute evidence summaries or guidelines with references to major articles that support each recommendation.
• Work with clinical practice committees to establish new standards of care within the hospital. Establish hospital care paths to dictate and support local standards of care. Measure individual physician performance and offer feedback with the goal of reducing utilization.
• National societies should recommend that insurance companies remove inappropriate financial incentives. If companies deny payment for inappropriate testing, physicians will stop ordering it. Even requirements for preauthorization of tests should reduce utilization. The Choosing Wisely campaign (www.choosingwisely.org) would be a good place to start.

Guidelines and practice advisories issued by several medical societies, including the American Society of Anesthesiologists,¹ American Heart Association (AHA) and American College of Cardiology (ACC),² and Society of General Internal Medicine,³ advise against routine preoperative testing for patients undergoing low-risk surgical procedures. Such testing often includes routine blood chemistry, complete blood cell counts, measures of the clotting system, and cardiac stress testing.

See related article

In this issue of the Cleveland Clinic Journal of Medicine, Dr. Nathan Houchens reviews the evidence against these measures.⁴

Despite a substantial body of evidence going back more than 2 decades that includes prospective randomized controlled trials,^5–10 physicians continue to order unnecessary, ineffective, and costly tests in the perioperative period.¹¹ The process of abandoning current medical practice—a phenomenon known as medical reversal¹²—often takes years,¹³ because it is more difficult to convince physicians to discontinue a current behavior than to implement a new one.¹⁴ The study of what makes physicians accept new therapies and abandon old ones began more than half a century ago.¹⁵

More recently, Cabana et al¹⁶ created a framework to understand why physicians do not follow clinical practice guidelines. Among the reasons are lack of familiarity or agreement with the contents of the guideline, lack of outcome expectancy, inertia of previous practice, and external barriers to implementation.

It is harder to convince physicians to discontinue a current behavior than to implement a new one

The rapid proliferation of guidelines in the past 20 years has led to numerous conflicting recommendations, many of which are based primarily on expert opinion.¹⁷ Guidelines based solely on randomized trials have also come under fire.^18,19

In the case of preoperative testing, the recommendations are generally evidence-based and consistent. Why then do physicians appear to disregard the evidence? We propose several reasons why they might do so.

SOME PHYSICIANS ARE UNFAMILIAR WITH THE EVIDENCE

The complexity of the evidence summarized in guidelines has increased exponentially in the last decade, but physician time to assess the evidence has not increased. For example, the number of references in the executive summary of the ACC/AHA perioperative guidelines increased from 96 in 2002 to 252 in 2014. Most of the recommendations are backed by substantial amounts of high-quality evidence. For example, there are 17 prospective and 13 retrospective studies demonstrating that routine testing with the prothrombin time and the partial thromboplastin time is not helpful in asymptomatic patients.²⁰

Although compliance with medical evidence varies among specialties,²¹ most physicians do not have time to keep up with the ever-increasing amount of information. Specifically in the area of cardiac risk assessment, there has been a rapid proliferation of tests that can be used to assess cardiac risk.^22–28 In a Harris Interactive survey from 2008, physicians reported not applying medical evidence routinely. One-third believed they would do it more if they had the time.²⁹ Without information technology support to provide medical information at the point of care,³⁰ especially in small practices, using evidence may not be practical. Simply making the information available online and not promoting it actively does not improve utilization.³¹

As a consequence, physicians continue to order unnecessary tests, even though they may not feel confident interpreting the results.³²

PHYSICIANS MAY NOT BELIEVE THE EVIDENCE

A lack of transparency in evidence-based guidelines and, sometimes, a lack of flexibility and relevance to clinical practice are important barriers to physicians’ acceptance of and adherence to evidence-based clinical practice guidelines.³⁰

Most physicians do not have time to keep up with the ever-increasing amount of information

Even experts who write guidelines may not be swayed by the evidence. For example, a randomized prospective trial of almost 6,000 patients reported that coronary artery revascularization before elective major vascular surgery does not affect long-term mortality rates.³³ Based on this study, the 2014 ACC/AHA guidelines² advised against revascularization before noncardiac surgery exclusively to reduce perioperative cardiac events. Yet the same guidelines do recommend assessing for myocardial ischemia in patients with elevated risk and poor or unknown functional capacity, using a pharmacologic stress test. Based on the extent of the stress test abnormalities, coronary angiography and revascularization are then suggested for patients willing to undergo coronary artery bypass grafting (CABG) or percutaneous coronary intervention.²

The 2014 European Society of Cardiology and European Society of Anaesthesiology guidelines directly recommend revascularization before high-risk surgery, depending on the extent of a stress-induced perfusion defect.³⁴ This recommendation relies on data from the Coronary Artery Surgery Study registry, which included almost 25,000 patients who underwent coronary angiography from 1975 through 1979. At a mean follow-up of 4.1 years, 1,961 patients underwent high-risk surgery. In this observational cohort, patients who underwent CABG had a lower risk of death and myocardial infarction after surgery.³⁵ The reliance of medical societies³⁴ on data that are more than 30 years old—when operative mortality rates and the treatment of coronary artery disease have changed substantially in the interim and despite the fact that this study did not test whether preoperative revascularization can reduce postoperative mortality—reflects a certain resistance to accept the results of the more recent and relevant randomized trial.³³

Other physicians may also prefer to rely on selective data or to simply defer to guidelines that support their beliefs. Some physicians find that evidence-based guidelines are impractical and rigid and reduce their autonomy.³⁶ For many physicians, trials that use surrogate end points and short-term outcomes are not sufficiently compelling to make them abandon current practice.³⁷ Finally, when members of the guideline committees have financial associations with the pharmaceutical industry, or when corporations interested in the outcomes provide financial support for a trial’s development, the likelihood of a recommendation being trusted and used by physicians is drastically reduced.³⁸

PRACTICING DEFENSIVELY

Even if physicians are familiar with the evidence and believe it, they may choose not to act on it. One reason is fear of litigation.

In court, attorneys can use guidelines as well as articles from medical journals as both exculpatory and inculpatory evidence. But they more frequently rely on the standard of care, or what most physicians would do under similar circumstances. If a patient has a bad outcome, such as a perioperative myocardial infarction or life-threatening bleeding, the defendant may assert that testing was unwarranted because guidelines do not recommend it or because the probability of such an outcome was low. However, because the outcome occurred, the jury may not believe that the probability was low enough not to consider, especially if expert witnesses testify that the standard of care would be to order the test.

In areas of controversy, physicians generally believe that erring on the side of more testing is more defensible in court.³⁹ Indeed, following established practice traditions, learned during residency,^11,40 may absolve physicians in negligence claims if the way medical care was delivered is supported by recognized and respected physicians.⁴¹

Even physicians who write the guidelines may be unswayed by the evidence

As a consequence, physicians prefer to practice the same way their peers do rather than follow the evidence. Unfortunately, the more procedures physicians perform for low-risk patients, the more likely these tests will become accepted as the legal standard of care.⁴² In this vicious circle, the new standard of care can increase the risk of litigation for others.⁴³ Although unnecessary testing that leads to harmful invasive tests or procedures can also result in malpractice litigation, physicians may not consider this possibility.

FINANCIAL INCENTIVES

The threat of malpractice litigation provides a negative financial incentive to keep performing unnecessary tests, but there are a number of positive incentives as well.

First, physicians often feel compelled to order tests when they believe that physicians referring the patients want the tests done, or when they fear that not completing the tests could delay or cancel the scheduled surgery.⁴⁰ Refusing to order the test could result in a loss of future referrals. In contrast, ordering tests allows them to meet expectations, preserve trust, and appear more valuable to referring physicians and their patients.

Insurance companies are complicit in these practices. Paying for unnecessary tests can create direct financial incentives for physicians or institutions that own on-site laboratories or diagnostic imaging equipment. Evidence shows that under those circumstances physicians do order more tests. Self-referral and referral to facilities where physicians have a financial interest is associated with increased healthcare costs.⁴⁴ In addition to direct revenues for the tests performed, physicians may also bill for test interpretation, follow-up visits, and additional procedures generated from test results.

This may be one explanation why the ordering of cardiac tests (stress testing, echocardiography, vascular ultrasonography) by US physicians varies widely from state to state.⁴⁵

RECOMMENDATIONS TO REDUCE INAPPROPRIATE TESTING

To counter these influences, we propose a multifaceted intervention that includes the following:

• Establish preoperative clinics staffed by experts. Despite the large volume of potentially relevant evidence, the number of articles directly supporting or refuting preoperative laboratory testing is small enough that physicians who routinely engage in preoperative assessment should easily master the evidence.
• Identify local leaders who can convince colleagues of the evidence. Distribute evidence summaries or guidelines with references to major articles that support each recommendation.
• Work with clinical practice committees to establish new standards of care within the hospital. Establish hospital care paths to dictate and support local standards of care. Measure individual physician performance and offer feedback with the goal of reducing utilization.
• National societies should recommend that insurance companies remove inappropriate financial incentives. If companies deny payment for inappropriate testing, physicians will stop ordering it. Even requirements for preauthorization of tests should reduce utilization. The Choosing Wisely campaign (www.choosingwisely.org) would be a good place to start.

A 56-year-old man presents to the emergency department with nausea, weakness, and exertional dyspnea, which have been going on for 1 week. He is sent by his primary care physician after being noted to be hypotensive with a weak, thready pulse.

He has had diarrhea with intermittent abdominal pain over the past year, with 10 stools daily, including 3 or 4 at night. The stools are described as large, nonbloody, sticky, greasy, and occasionally watery. Stools are fewer when he curtails his food intake. The diarrhea is associated with occasional diffuse abdominal pain he describes as a burning sensation. He has no incontinence or tenesmus. He reports that he has unintentionally lost 137 lb (62 kg) over the past year. He has not taken over-the-counter antidiarrheal agents.

CHRONIC DIARRHEA

1. Chronic diarrhea is defined as lasting for at least how long?

• 1 week
• 2 weeks
• 3 weeks
• 4 weeks

Chronic diarrhea is defined as looser stools for more than 4 weeks,¹ a period that allows most cases of acute, self-limited, infectious diarrhea to resolve.

Because individuals perceive diarrhea differently, reported prevalence rates of chronic diarrhea vary.² Based on the definition of having excessive stool frequency, the prevalence in the United States is about 5%.¹

In developing countries, the most common cause of chronic diarrhea is infection. In developed nations, irritable bowel syndrome, inflammatory bowel disease, malabsorption syndrome, and chronic infection predominate.¹

Once chronicity is established, diarrhea should be characterized as inflammatory, fatty, or watery (Table 1).³

CASE CONTINUED: HISTORY OF HYPERTENSION, DIABETES

Our patient reports that he has never traveled outside the United States. He has a history of hypertension and type 2 diabetes mellitus that is controlled on oral agents. He has had surgery for a radial fracture and for reconstruction of his knees. He uses no tobacco, alcohol, or illicit drugs and works as a train engineer. He has no pets. He knows of no family history of inflammatory bowel disease or chronic diarrhea.

Comment. Patients with diabetes are at increased risk of gastrointestinal problems, with severity increasing with poorer control.⁴ Although our patient’s diabetes puts him at risk of diabetic autonomic neuropathy, his blood glucose control has been consistently good since his diagnosis, and his last measured hemoglobin A_1c was 7.3% (reference range 4%–7%). His description of greasy stools in conjunction with his marked weight loss puts fatty diarrhea higher on the differential diagnosis.

DRUG-INDUCED DIARRHEA

His medications include glimepiride 1 mg twice daily, lisinopril 10 mg daily, metformin 500 mg twice daily, omeprazole 40 mg daily, and naproxen 220 mg daily. He has been taking metformin for at least 2 years. He is allergic to pentobarbital.

2. Which of his medications is least likely to be associated with his diarrhea?

• Lisinopril
• Metformin
• Glimepiride
• Naproxen

More than 700 drugs are known to cause diarrhea, often through the interplay of simultaneous mechanisms.⁵ The diagnosis of drug-induced diarrhea requires taking a careful medication history and establishing a temporal relationship between the drug and the diarrheal symptoms. Treatment consists of withdrawing the offending agent.

Nonsteroidal anti-inflammatory drugs (eg, naproxen) are associated with collagenous colitis that occurs mostly after long-term use (> 6 months). Metformin-induced diarrhea is related to fat malabsorption. Olmesartan, an angiotensin II receptor antagonist, has been associated with severe sprue-like enteropathy. On the other hand, the incidence of diarrhea with lisinopril is similar to that with placebo.⁷

CASE CONTINUED: EXAMINATION AND LABORATORY VALUES

The patient’s primary care physician had recently referred him to a gastroenterologist, and 4 days before presenting to the emergency department he had undergone abdominal and pelvic computed tomography (CT) with iodinated contrast, which had showed hepatic steatosis and pancreatic atrophy.

On examination now, the patient’s temperature is 97.5°F (36.4°C), heart rate 90 beats per minute, respirations 18 breaths per minute, oxygen saturation 99% on room air, and blood pressure 85/55 mm Hg. His body mass index is 32.5 kg/m2. His oral mucosa is dry. The rest of the examination is normal. No rash or ulcers are noted.

His laboratory values (Table 2) are notable for sodium 130 mmol/L, potassium 2.2 mmol/L, bicarbonate 9 mmol/L, blood urea nitrogen 32 mg/dL, creatinine 4.18 mg/dL, and international normalized ratio 5.4. Arterial blood gases drawn on admission reveal pH 7.32 and pCO₂ 19 mm Hg.

ACID-BASE DISTURBANCES

3. The patient’s acidosis is most likely related to which of the following?

• Sepsis
• Diarrhea
• Metformin
• Acute kidney injury

It is most likely related to diarrhea. The patient has a non-anion-gap metabolic acidosis. (The anion gap can be calculated by subtracting the sum of the serum bicarbonate and chloride values from the sodium—here, 130 – [112 + 9] = 9—and most textbooks list the reference range as 10–12 mmol/L.) Non-anion-gap metabolic acidosis results from excessive loss of bicarbonate or impaired ability of the kidney to excrete acid. Bicarbonate losses can occur in diarrhea or in ureteral diversion to the colon. Impairment in urinary acidification can occur in renal tubular acidosis.

To determine the cause of non-anion-gap acidosis, calculating the urine anion gap can be useful (Table 3), as it reflects the ability of the kidneys to excrete acid and is an indirect measure of ammonium excretion. Our patient’s urine anion gap is –45 mmol/L ([62 + 8] – 115), which supports diarrhea as the cause of his non-anion-gap acidosis. Sepsis, metformin use, or acute kidney injury would result in an anion-gap acidosis.

To manage acid-base disturbances, it is important to first determine whether there is a single primary disturbance with compensation or a mixed disorder. In the case of metabolic acidosis, for every 1-mmol/L decrease in bicarbonate, there should be a corresponding 1.3-mm Hg decrease in pCO₂. Our patient’s laboratory data show that he had a pure non-anion-gap metabolic acidosis.⁸ His sensation of dyspnea was likely related to respiratory compensation as evidenced by an appropriately low pCO₂.

CASE CONTINUED: HIS LABORATORY VALUES IMPROVE

The patient is admitted to the hospital for fluid resuscitation with normal saline and potassium and magnesium replacement.

Renal ultrasonography reveals normal-appearing kidneys without obstruction. The calculated fractional excretion of sodium is 3.4%. Urine microscopy reveals two to five hyaline casts per low-power field. His urine output remains adequate, and 3 days after hospitalization, his renal function starts to improve, as reflected in falling serum creatinine and blood urea nitrogen levels: his creatinine level has declined to 1.91 mg/dL and his blood urea nitrogen level has declined to 24 mg/dL. His acute kidney injury is attributed to intravenous contrast given for computed tomography, as well as to volume depletion and hypotension.

Stool studies for ova, parasites, and Clostridium difficile are negative. Fecal calprotectin and lactoferrin are useful noninvasive markers of intestinal inflammation but were not checked in this case.

Loperamide, taken as needed, is started for his diarrhea, along with empiric pancreatic enzyme replacement. After 3 days of treatment with oral vitamin K 10 mg, his international normalized ratio comes down to 1.4, from his admission value of 5.4. Given the clinical concern for fat malabsorption, vitamin D levels are also checked: his 25-hydroxyvitamin D level is less than 10 ng/mL (lower limit of normal 20). His fecal neutral fats are reported as normal, but split fats are increased.

STOOL FAT STUDIES

4. What does increased fecal split fats but normal fecal neutral fats imply?

• Pancreatic insufficiency
• Intestinal malabsorption
• Does not differentiate between the two

The finding does not differentiate between pancreatic insufficiency and intestinal malabsorption. The two-step Sudan stain has been used to differentiate maldigestion (eg, caused by pancreatic insufficiency) from malabsorption. Although patients with impaired digestion were once thought to excrete excessive amounts of intact triglyceride whereas those with malabsorption excrete more of the lipolytic or “split” product, the Sudan stain does not differentiate between the two.¹⁰ Stool fecal-elastase 1 testing correlates well with pancreatic exocrine function but was not performed in our patient.¹¹

CASE CONTINUED: CELIAC DISEASE IS DIAGNOSED

Given the description of his stools, unintentional weight loss, and improvement of stool frequency with fasting, serologic testing for celiac disease is performed (Table 4). The patient undergoes esophagogastroduodenoscopy, which shows mild duodenitis. Small-bowel biopsy reveals blunted villous architecture and increased mixed inflammatory cells of the epithelium and lamina propria, suggestive of celiac disease.

The patient is diagnosed with celiac disease and is counseled to follow a gluten-free diet. He is discharged home and scheduled to follow up with a gastroenterologist and nephrologist. His liver function test abnormalities are attributed to a combination of nonalcoholic steatohepatitis and celiac disease.

CELIAC DISEASE AND MALABSORPTION

Celiac disease is an immune-mediated disorder that causes mucosal injury to the small intestine, leading to malabsorption. It is triggered by gluten intake in genetically susceptible individuals. The HLA-DQ2 haplotype is expressed in nearly 90% of patients with the disease.

The worldwide prevalence of celiac disease is about 0.6% to 1%. Those with an affected first-degree relative, type 1 diabetes, Hashimoto thyroiditis, an autoimmune disease, Down syndrome, Turner syndrome, or IgA deficiency have an increased risk.

Celiac disease presents with chronic diarrhea, weight loss, and abdominal distention and pain. Sequelae of nutrient malabsorption such as iron-deficiency anemia, short stature, and osteopenia may be evident. Liver function may also be impaired. Dermatitis herpetiformis and gluten ataxia are rarer presentations of celiac disease.¹²

In the absence of immunoglobulin (Ig) A deficiency, measurement of serum IgA anti-tissue transglutaminase antibodies is recommended for initial testing. IgG antitissue transglutaminase antibodies can be measured in those with IgA deficiency.¹²

Duodenal biopsies to confirm the diagnosis are recommended in adults unless they have previously had biopsy-proven dermatitis herpetiformis.

Gluten-free diet

The treatment for celiac disease is avoidance of gluten. Patients who consult with a nutritionist and participate in an advocacy group are more likely to adhere to a gluten-free diet, and the physician should strongly encourage and facilitate these activities.¹³

Untreated disease can lead to osteoporosis, impaired splenic function with increased risk of infection with encapsulated organisms, infertility or recurrent abortion, ulcerative jejunoileitis, and lymphoma.¹² Patients should be monitored annually for adherence to the gluten-free diet and for the development of any associated condition. Despite adherence to a gluten-free diet, calcium absorption and bone mineral density are lower in patients with celiac disease than in controls.¹⁴ Careful monitoring of fracture risk and adequate calcium and vitamin D replacement are also important.

Our patient undergoes dual-emission x-ray absorptiometry after discharge, with results consistent with osteopenia. His T scores range from –0.2 at the right hip to –1.1 in the left femoral neck.

Recurrence or persistently abnormal levels of IgA anti-tissue transglutaminase antibodies usually indicates poor dietary compliance.¹²

5. In patients whose symptoms do not improve on gluten restriction, there should be concern for which of the following?

• Lymphoma
• Nonadherence to gluten restriction
• Microscopic colitis
• All of the above

The answer is all of the above. Up to 30% of patients have persistent symptoms on a gluten-free diet. Persistent exposure to gluten is the most common reason for lack of clinical improvement. In addition, bacterial overgrowth of the small bowel, lactose intolerance, pancreatic insufficiency, and microscopic colitis may coexist with celiac disease and may contribute to ongoing symptoms. In a small subset of patients with persistent villous atrophy and symptoms despite strict adherence to a gluten-free diet for 12 months, the disease is deemed “refractory.” Refractory celiac disease can be a precursor to enteropathy-associated T-cell lymphoma.¹³

CASE CONCLUDED

On telephone follow-up 3 weeks after discharge, the patient reports complete resolution of diarrhea and stabilization of his weight. He reports strict adherence to a gluten-free diet and feels he is coping well.

Diagnoses

• Presenting weakness secondary to dehydration and hypokalemia
• Dyspnea secondary to respiratory compensation for metabolic acidosis
• Non-anion-gap metabolic acidosis secondary to diarrhea
• Acute kidney injury secondary to iodinated contrast, volume depletion, hypotension
• Chronic diarrhea secondary to celiac disease
• Coagulopathy secondary to fat malabsorption secondary to celiac disease.

A 56-year-old man presents to the emergency department with nausea, weakness, and exertional dyspnea, which have been going on for 1 week. He is sent by his primary care physician after being noted to be hypotensive with a weak, thready pulse.

He has had diarrhea with intermittent abdominal pain over the past year, with 10 stools daily, including 3 or 4 at night. The stools are described as large, nonbloody, sticky, greasy, and occasionally watery. Stools are fewer when he curtails his food intake. The diarrhea is associated with occasional diffuse abdominal pain he describes as a burning sensation. He has no incontinence or tenesmus. He reports that he has unintentionally lost 137 lb (62 kg) over the past year. He has not taken over-the-counter antidiarrheal agents.

CHRONIC DIARRHEA

1. Chronic diarrhea is defined as lasting for at least how long?

• 1 week
• 2 weeks
• 3 weeks
• 4 weeks

Chronic diarrhea is defined as looser stools for more than 4 weeks,¹ a period that allows most cases of acute, self-limited, infectious diarrhea to resolve.

Because individuals perceive diarrhea differently, reported prevalence rates of chronic diarrhea vary.² Based on the definition of having excessive stool frequency, the prevalence in the United States is about 5%.¹

In developing countries, the most common cause of chronic diarrhea is infection. In developed nations, irritable bowel syndrome, inflammatory bowel disease, malabsorption syndrome, and chronic infection predominate.¹

Once chronicity is established, diarrhea should be characterized as inflammatory, fatty, or watery (Table 1).³

CASE CONTINUED: HISTORY OF HYPERTENSION, DIABETES

Our patient reports that he has never traveled outside the United States. He has a history of hypertension and type 2 diabetes mellitus that is controlled on oral agents. He has had surgery for a radial fracture and for reconstruction of his knees. He uses no tobacco, alcohol, or illicit drugs and works as a train engineer. He has no pets. He knows of no family history of inflammatory bowel disease or chronic diarrhea.

Comment. Patients with diabetes are at increased risk of gastrointestinal problems, with severity increasing with poorer control.⁴ Although our patient’s diabetes puts him at risk of diabetic autonomic neuropathy, his blood glucose control has been consistently good since his diagnosis, and his last measured hemoglobin A_1c was 7.3% (reference range 4%–7%). His description of greasy stools in conjunction with his marked weight loss puts fatty diarrhea higher on the differential diagnosis.

DRUG-INDUCED DIARRHEA

His medications include glimepiride 1 mg twice daily, lisinopril 10 mg daily, metformin 500 mg twice daily, omeprazole 40 mg daily, and naproxen 220 mg daily. He has been taking metformin for at least 2 years. He is allergic to pentobarbital.

2. Which of his medications is least likely to be associated with his diarrhea?

• Lisinopril
• Metformin
• Glimepiride
• Naproxen

More than 700 drugs are known to cause diarrhea, often through the interplay of simultaneous mechanisms.⁵ The diagnosis of drug-induced diarrhea requires taking a careful medication history and establishing a temporal relationship between the drug and the diarrheal symptoms. Treatment consists of withdrawing the offending agent.

Nonsteroidal anti-inflammatory drugs (eg, naproxen) are associated with collagenous colitis that occurs mostly after long-term use (> 6 months). Metformin-induced diarrhea is related to fat malabsorption. Olmesartan, an angiotensin II receptor antagonist, has been associated with severe sprue-like enteropathy. On the other hand, the incidence of diarrhea with lisinopril is similar to that with placebo.⁷

CASE CONTINUED: EXAMINATION AND LABORATORY VALUES

The patient’s primary care physician had recently referred him to a gastroenterologist, and 4 days before presenting to the emergency department he had undergone abdominal and pelvic computed tomography (CT) with iodinated contrast, which had showed hepatic steatosis and pancreatic atrophy.

On examination now, the patient’s temperature is 97.5°F (36.4°C), heart rate 90 beats per minute, respirations 18 breaths per minute, oxygen saturation 99% on room air, and blood pressure 85/55 mm Hg. His body mass index is 32.5 kg/m2. His oral mucosa is dry. The rest of the examination is normal. No rash or ulcers are noted.

His laboratory values (Table 2) are notable for sodium 130 mmol/L, potassium 2.2 mmol/L, bicarbonate 9 mmol/L, blood urea nitrogen 32 mg/dL, creatinine 4.18 mg/dL, and international normalized ratio 5.4. Arterial blood gases drawn on admission reveal pH 7.32 and pCO₂ 19 mm Hg.

ACID-BASE DISTURBANCES

3. The patient’s acidosis is most likely related to which of the following?

• Sepsis
• Diarrhea
• Metformin
• Acute kidney injury

It is most likely related to diarrhea. The patient has a non-anion-gap metabolic acidosis. (The anion gap can be calculated by subtracting the sum of the serum bicarbonate and chloride values from the sodium—here, 130 – [112 + 9] = 9—and most textbooks list the reference range as 10–12 mmol/L.) Non-anion-gap metabolic acidosis results from excessive loss of bicarbonate or impaired ability of the kidney to excrete acid. Bicarbonate losses can occur in diarrhea or in ureteral diversion to the colon. Impairment in urinary acidification can occur in renal tubular acidosis.

To determine the cause of non-anion-gap acidosis, calculating the urine anion gap can be useful (Table 3), as it reflects the ability of the kidneys to excrete acid and is an indirect measure of ammonium excretion. Our patient’s urine anion gap is –45 mmol/L ([62 + 8] – 115), which supports diarrhea as the cause of his non-anion-gap acidosis. Sepsis, metformin use, or acute kidney injury would result in an anion-gap acidosis.

To manage acid-base disturbances, it is important to first determine whether there is a single primary disturbance with compensation or a mixed disorder. In the case of metabolic acidosis, for every 1-mmol/L decrease in bicarbonate, there should be a corresponding 1.3-mm Hg decrease in pCO₂. Our patient’s laboratory data show that he had a pure non-anion-gap metabolic acidosis.⁸ His sensation of dyspnea was likely related to respiratory compensation as evidenced by an appropriately low pCO₂.

CASE CONTINUED: HIS LABORATORY VALUES IMPROVE

The patient is admitted to the hospital for fluid resuscitation with normal saline and potassium and magnesium replacement.

Renal ultrasonography reveals normal-appearing kidneys without obstruction. The calculated fractional excretion of sodium is 3.4%. Urine microscopy reveals two to five hyaline casts per low-power field. His urine output remains adequate, and 3 days after hospitalization, his renal function starts to improve, as reflected in falling serum creatinine and blood urea nitrogen levels: his creatinine level has declined to 1.91 mg/dL and his blood urea nitrogen level has declined to 24 mg/dL. His acute kidney injury is attributed to intravenous contrast given for computed tomography, as well as to volume depletion and hypotension.

Stool studies for ova, parasites, and Clostridium difficile are negative. Fecal calprotectin and lactoferrin are useful noninvasive markers of intestinal inflammation but were not checked in this case.

Loperamide, taken as needed, is started for his diarrhea, along with empiric pancreatic enzyme replacement. After 3 days of treatment with oral vitamin K 10 mg, his international normalized ratio comes down to 1.4, from his admission value of 5.4. Given the clinical concern for fat malabsorption, vitamin D levels are also checked: his 25-hydroxyvitamin D level is less than 10 ng/mL (lower limit of normal 20). His fecal neutral fats are reported as normal, but split fats are increased.

STOOL FAT STUDIES

4. What does increased fecal split fats but normal fecal neutral fats imply?

• Pancreatic insufficiency
• Intestinal malabsorption
• Does not differentiate between the two

The finding does not differentiate between pancreatic insufficiency and intestinal malabsorption. The two-step Sudan stain has been used to differentiate maldigestion (eg, caused by pancreatic insufficiency) from malabsorption. Although patients with impaired digestion were once thought to excrete excessive amounts of intact triglyceride whereas those with malabsorption excrete more of the lipolytic or “split” product, the Sudan stain does not differentiate between the two.¹⁰ Stool fecal-elastase 1 testing correlates well with pancreatic exocrine function but was not performed in our patient.¹¹

CASE CONTINUED: CELIAC DISEASE IS DIAGNOSED

Given the description of his stools, unintentional weight loss, and improvement of stool frequency with fasting, serologic testing for celiac disease is performed (Table 4). The patient undergoes esophagogastroduodenoscopy, which shows mild duodenitis. Small-bowel biopsy reveals blunted villous architecture and increased mixed inflammatory cells of the epithelium and lamina propria, suggestive of celiac disease.

The patient is diagnosed with celiac disease and is counseled to follow a gluten-free diet. He is discharged home and scheduled to follow up with a gastroenterologist and nephrologist. His liver function test abnormalities are attributed to a combination of nonalcoholic steatohepatitis and celiac disease.

CELIAC DISEASE AND MALABSORPTION

Celiac disease is an immune-mediated disorder that causes mucosal injury to the small intestine, leading to malabsorption. It is triggered by gluten intake in genetically susceptible individuals. The HLA-DQ2 haplotype is expressed in nearly 90% of patients with the disease.

The worldwide prevalence of celiac disease is about 0.6% to 1%. Those with an affected first-degree relative, type 1 diabetes, Hashimoto thyroiditis, an autoimmune disease, Down syndrome, Turner syndrome, or IgA deficiency have an increased risk.

Celiac disease presents with chronic diarrhea, weight loss, and abdominal distention and pain. Sequelae of nutrient malabsorption such as iron-deficiency anemia, short stature, and osteopenia may be evident. Liver function may also be impaired. Dermatitis herpetiformis and gluten ataxia are rarer presentations of celiac disease.¹²

In the absence of immunoglobulin (Ig) A deficiency, measurement of serum IgA anti-tissue transglutaminase antibodies is recommended for initial testing. IgG antitissue transglutaminase antibodies can be measured in those with IgA deficiency.¹²

Duodenal biopsies to confirm the diagnosis are recommended in adults unless they have previously had biopsy-proven dermatitis herpetiformis.

Gluten-free diet

The treatment for celiac disease is avoidance of gluten. Patients who consult with a nutritionist and participate in an advocacy group are more likely to adhere to a gluten-free diet, and the physician should strongly encourage and facilitate these activities.¹³

Untreated disease can lead to osteoporosis, impaired splenic function with increased risk of infection with encapsulated organisms, infertility or recurrent abortion, ulcerative jejunoileitis, and lymphoma.¹² Patients should be monitored annually for adherence to the gluten-free diet and for the development of any associated condition. Despite adherence to a gluten-free diet, calcium absorption and bone mineral density are lower in patients with celiac disease than in controls.¹⁴ Careful monitoring of fracture risk and adequate calcium and vitamin D replacement are also important.

Our patient undergoes dual-emission x-ray absorptiometry after discharge, with results consistent with osteopenia. His T scores range from –0.2 at the right hip to –1.1 in the left femoral neck.

Recurrence or persistently abnormal levels of IgA anti-tissue transglutaminase antibodies usually indicates poor dietary compliance.¹²

5. In patients whose symptoms do not improve on gluten restriction, there should be concern for which of the following?

• Lymphoma
• Nonadherence to gluten restriction
• Microscopic colitis
• All of the above

The answer is all of the above. Up to 30% of patients have persistent symptoms on a gluten-free diet. Persistent exposure to gluten is the most common reason for lack of clinical improvement. In addition, bacterial overgrowth of the small bowel, lactose intolerance, pancreatic insufficiency, and microscopic colitis may coexist with celiac disease and may contribute to ongoing symptoms. In a small subset of patients with persistent villous atrophy and symptoms despite strict adherence to a gluten-free diet for 12 months, the disease is deemed “refractory.” Refractory celiac disease can be a precursor to enteropathy-associated T-cell lymphoma.¹³

CASE CONCLUDED

On telephone follow-up 3 weeks after discharge, the patient reports complete resolution of diarrhea and stabilization of his weight. He reports strict adherence to a gluten-free diet and feels he is coping well.

Diagnoses

• Presenting weakness secondary to dehydration and hypokalemia
• Dyspnea secondary to respiratory compensation for metabolic acidosis
• Non-anion-gap metabolic acidosis secondary to diarrhea
• Acute kidney injury secondary to iodinated contrast, volume depletion, hypotension
• Chronic diarrhea secondary to celiac disease
• Coagulopathy secondary to fat malabsorption secondary to celiac disease.

A 56-year-old man presents to the emergency department with nausea, weakness, and exertional dyspnea, which have been going on for 1 week. He is sent by his primary care physician after being noted to be hypotensive with a weak, thready pulse.

He has had diarrhea with intermittent abdominal pain over the past year, with 10 stools daily, including 3 or 4 at night. The stools are described as large, nonbloody, sticky, greasy, and occasionally watery. Stools are fewer when he curtails his food intake. The diarrhea is associated with occasional diffuse abdominal pain he describes as a burning sensation. He has no incontinence or tenesmus. He reports that he has unintentionally lost 137 lb (62 kg) over the past year. He has not taken over-the-counter antidiarrheal agents.

CHRONIC DIARRHEA

1. Chronic diarrhea is defined as lasting for at least how long?

• 1 week
• 2 weeks
• 3 weeks
• 4 weeks

Chronic diarrhea is defined as looser stools for more than 4 weeks,¹ a period that allows most cases of acute, self-limited, infectious diarrhea to resolve.

Because individuals perceive diarrhea differently, reported prevalence rates of chronic diarrhea vary.² Based on the definition of having excessive stool frequency, the prevalence in the United States is about 5%.¹

In developing countries, the most common cause of chronic diarrhea is infection. In developed nations, irritable bowel syndrome, inflammatory bowel disease, malabsorption syndrome, and chronic infection predominate.¹

Once chronicity is established, diarrhea should be characterized as inflammatory, fatty, or watery (Table 1).³

CASE CONTINUED: HISTORY OF HYPERTENSION, DIABETES

Our patient reports that he has never traveled outside the United States. He has a history of hypertension and type 2 diabetes mellitus that is controlled on oral agents. He has had surgery for a radial fracture and for reconstruction of his knees. He uses no tobacco, alcohol, or illicit drugs and works as a train engineer. He has no pets. He knows of no family history of inflammatory bowel disease or chronic diarrhea.

Comment. Patients with diabetes are at increased risk of gastrointestinal problems, with severity increasing with poorer control.⁴ Although our patient’s diabetes puts him at risk of diabetic autonomic neuropathy, his blood glucose control has been consistently good since his diagnosis, and his last measured hemoglobin A_1c was 7.3% (reference range 4%–7%). His description of greasy stools in conjunction with his marked weight loss puts fatty diarrhea higher on the differential diagnosis.

DRUG-INDUCED DIARRHEA

His medications include glimepiride 1 mg twice daily, lisinopril 10 mg daily, metformin 500 mg twice daily, omeprazole 40 mg daily, and naproxen 220 mg daily. He has been taking metformin for at least 2 years. He is allergic to pentobarbital.

2. Which of his medications is least likely to be associated with his diarrhea?

• Lisinopril
• Metformin
• Glimepiride
• Naproxen

More than 700 drugs are known to cause diarrhea, often through the interplay of simultaneous mechanisms.⁵ The diagnosis of drug-induced diarrhea requires taking a careful medication history and establishing a temporal relationship between the drug and the diarrheal symptoms. Treatment consists of withdrawing the offending agent.

Nonsteroidal anti-inflammatory drugs (eg, naproxen) are associated with collagenous colitis that occurs mostly after long-term use (> 6 months). Metformin-induced diarrhea is related to fat malabsorption. Olmesartan, an angiotensin II receptor antagonist, has been associated with severe sprue-like enteropathy. On the other hand, the incidence of diarrhea with lisinopril is similar to that with placebo.⁷

CASE CONTINUED: EXAMINATION AND LABORATORY VALUES

The patient’s primary care physician had recently referred him to a gastroenterologist, and 4 days before presenting to the emergency department he had undergone abdominal and pelvic computed tomography (CT) with iodinated contrast, which had showed hepatic steatosis and pancreatic atrophy.

On examination now, the patient’s temperature is 97.5°F (36.4°C), heart rate 90 beats per minute, respirations 18 breaths per minute, oxygen saturation 99% on room air, and blood pressure 85/55 mm Hg. His body mass index is 32.5 kg/m2. His oral mucosa is dry. The rest of the examination is normal. No rash or ulcers are noted.

His laboratory values (Table 2) are notable for sodium 130 mmol/L, potassium 2.2 mmol/L, bicarbonate 9 mmol/L, blood urea nitrogen 32 mg/dL, creatinine 4.18 mg/dL, and international normalized ratio 5.4. Arterial blood gases drawn on admission reveal pH 7.32 and pCO₂ 19 mm Hg.

ACID-BASE DISTURBANCES

3. The patient’s acidosis is most likely related to which of the following?

• Sepsis
• Diarrhea
• Metformin
• Acute kidney injury

It is most likely related to diarrhea. The patient has a non-anion-gap metabolic acidosis. (The anion gap can be calculated by subtracting the sum of the serum bicarbonate and chloride values from the sodium—here, 130 – [112 + 9] = 9—and most textbooks list the reference range as 10–12 mmol/L.) Non-anion-gap metabolic acidosis results from excessive loss of bicarbonate or impaired ability of the kidney to excrete acid. Bicarbonate losses can occur in diarrhea or in ureteral diversion to the colon. Impairment in urinary acidification can occur in renal tubular acidosis.

To determine the cause of non-anion-gap acidosis, calculating the urine anion gap can be useful (Table 3), as it reflects the ability of the kidneys to excrete acid and is an indirect measure of ammonium excretion. Our patient’s urine anion gap is –45 mmol/L ([62 + 8] – 115), which supports diarrhea as the cause of his non-anion-gap acidosis. Sepsis, metformin use, or acute kidney injury would result in an anion-gap acidosis.

To manage acid-base disturbances, it is important to first determine whether there is a single primary disturbance with compensation or a mixed disorder. In the case of metabolic acidosis, for every 1-mmol/L decrease in bicarbonate, there should be a corresponding 1.3-mm Hg decrease in pCO₂. Our patient’s laboratory data show that he had a pure non-anion-gap metabolic acidosis.⁸ His sensation of dyspnea was likely related to respiratory compensation as evidenced by an appropriately low pCO₂.

CASE CONTINUED: HIS LABORATORY VALUES IMPROVE

The patient is admitted to the hospital for fluid resuscitation with normal saline and potassium and magnesium replacement.

Renal ultrasonography reveals normal-appearing kidneys without obstruction. The calculated fractional excretion of sodium is 3.4%. Urine microscopy reveals two to five hyaline casts per low-power field. His urine output remains adequate, and 3 days after hospitalization, his renal function starts to improve, as reflected in falling serum creatinine and blood urea nitrogen levels: his creatinine level has declined to 1.91 mg/dL and his blood urea nitrogen level has declined to 24 mg/dL. His acute kidney injury is attributed to intravenous contrast given for computed tomography, as well as to volume depletion and hypotension.

Stool studies for ova, parasites, and Clostridium difficile are negative. Fecal calprotectin and lactoferrin are useful noninvasive markers of intestinal inflammation but were not checked in this case.

Loperamide, taken as needed, is started for his diarrhea, along with empiric pancreatic enzyme replacement. After 3 days of treatment with oral vitamin K 10 mg, his international normalized ratio comes down to 1.4, from his admission value of 5.4. Given the clinical concern for fat malabsorption, vitamin D levels are also checked: his 25-hydroxyvitamin D level is less than 10 ng/mL (lower limit of normal 20). His fecal neutral fats are reported as normal, but split fats are increased.

STOOL FAT STUDIES

4. What does increased fecal split fats but normal fecal neutral fats imply?

• Pancreatic insufficiency
• Intestinal malabsorption
• Does not differentiate between the two

The finding does not differentiate between pancreatic insufficiency and intestinal malabsorption. The two-step Sudan stain has been used to differentiate maldigestion (eg, caused by pancreatic insufficiency) from malabsorption. Although patients with impaired digestion were once thought to excrete excessive amounts of intact triglyceride whereas those with malabsorption excrete more of the lipolytic or “split” product, the Sudan stain does not differentiate between the two.¹⁰ Stool fecal-elastase 1 testing correlates well with pancreatic exocrine function but was not performed in our patient.¹¹

CASE CONTINUED: CELIAC DISEASE IS DIAGNOSED

Given the description of his stools, unintentional weight loss, and improvement of stool frequency with fasting, serologic testing for celiac disease is performed (Table 4). The patient undergoes esophagogastroduodenoscopy, which shows mild duodenitis. Small-bowel biopsy reveals blunted villous architecture and increased mixed inflammatory cells of the epithelium and lamina propria, suggestive of celiac disease.

The patient is diagnosed with celiac disease and is counseled to follow a gluten-free diet. He is discharged home and scheduled to follow up with a gastroenterologist and nephrologist. His liver function test abnormalities are attributed to a combination of nonalcoholic steatohepatitis and celiac disease.

CELIAC DISEASE AND MALABSORPTION

Celiac disease is an immune-mediated disorder that causes mucosal injury to the small intestine, leading to malabsorption. It is triggered by gluten intake in genetically susceptible individuals. The HLA-DQ2 haplotype is expressed in nearly 90% of patients with the disease.

The worldwide prevalence of celiac disease is about 0.6% to 1%. Those with an affected first-degree relative, type 1 diabetes, Hashimoto thyroiditis, an autoimmune disease, Down syndrome, Turner syndrome, or IgA deficiency have an increased risk.

Celiac disease presents with chronic diarrhea, weight loss, and abdominal distention and pain. Sequelae of nutrient malabsorption such as iron-deficiency anemia, short stature, and osteopenia may be evident. Liver function may also be impaired. Dermatitis herpetiformis and gluten ataxia are rarer presentations of celiac disease.¹²

In the absence of immunoglobulin (Ig) A deficiency, measurement of serum IgA anti-tissue transglutaminase antibodies is recommended for initial testing. IgG antitissue transglutaminase antibodies can be measured in those with IgA deficiency.¹²

Duodenal biopsies to confirm the diagnosis are recommended in adults unless they have previously had biopsy-proven dermatitis herpetiformis.

Gluten-free diet

The treatment for celiac disease is avoidance of gluten. Patients who consult with a nutritionist and participate in an advocacy group are more likely to adhere to a gluten-free diet, and the physician should strongly encourage and facilitate these activities.¹³

Untreated disease can lead to osteoporosis, impaired splenic function with increased risk of infection with encapsulated organisms, infertility or recurrent abortion, ulcerative jejunoileitis, and lymphoma.¹² Patients should be monitored annually for adherence to the gluten-free diet and for the development of any associated condition. Despite adherence to a gluten-free diet, calcium absorption and bone mineral density are lower in patients with celiac disease than in controls.¹⁴ Careful monitoring of fracture risk and adequate calcium and vitamin D replacement are also important.

Our patient undergoes dual-emission x-ray absorptiometry after discharge, with results consistent with osteopenia. His T scores range from –0.2 at the right hip to –1.1 in the left femoral neck.

Recurrence or persistently abnormal levels of IgA anti-tissue transglutaminase antibodies usually indicates poor dietary compliance.¹²

5. In patients whose symptoms do not improve on gluten restriction, there should be concern for which of the following?

• Lymphoma
• Nonadherence to gluten restriction
• Microscopic colitis
• All of the above

The answer is all of the above. Up to 30% of patients have persistent symptoms on a gluten-free diet. Persistent exposure to gluten is the most common reason for lack of clinical improvement. In addition, bacterial overgrowth of the small bowel, lactose intolerance, pancreatic insufficiency, and microscopic colitis may coexist with celiac disease and may contribute to ongoing symptoms. In a small subset of patients with persistent villous atrophy and symptoms despite strict adherence to a gluten-free diet for 12 months, the disease is deemed “refractory.” Refractory celiac disease can be a precursor to enteropathy-associated T-cell lymphoma.¹³

CASE CONCLUDED

On telephone follow-up 3 weeks after discharge, the patient reports complete resolution of diarrhea and stabilization of his weight. He reports strict adherence to a gluten-free diet and feels he is coping well.

Diagnoses

• Presenting weakness secondary to dehydration and hypokalemia
• Dyspnea secondary to respiratory compensation for metabolic acidosis
• Non-anion-gap metabolic acidosis secondary to diarrhea
• Acute kidney injury secondary to iodinated contrast, volume depletion, hypotension
• Chronic diarrhea secondary to celiac disease
• Coagulopathy secondary to fat malabsorption secondary to celiac disease.

No. According to 2013 guidelines of the US Centers for Disease Control and Prevention (CDC),¹ there is little evidence of benefit for many of the tests commonly mandated by healthcare providers before prescribing hormonal contraception (pill, ring, patch). These tests include breast and pelvic examinations, screening for cervical and sexually transmitted infections, laboratory testing, and mammography.

Only a medical history and blood pressure measurement are needed before prescribing estrogen-containing contraceptives. Patients who have elevated blood pressure but have not been previously diagnosed with hypertension should be preferentially offered other forms of contraception to avoid an additional risk of stroke or myocardial infarction, such as progestin-only products and intrauterine devices (IUDs). Women with blood pressures between 140/90 and 160/100 mm Hg may use estrogen-containing contraceptives only if other options are not appropriate. The CDC guidelines further state that if a patient is unable to come to the office for blood pressure assessment, then a community reading reported by the patient may be used to guide decision-making.

IS A PELVIC EXAMINATION NEEDED?

A pelvic examination (cervical inspection and bimanual examination) will not affect decisions related to prescribing contraceptives, except when prescribing female barrier methods (diaphragm, cervical cap) or IUDs.

Based on a systematic review of the literature between 1946 and 2014, the American College of Physicians now recommends against a screening pelvic examination in asymptomatic, nonpregnant, adult women when a Papanicolaou test is not otherwise indicated.²

The American College of Obstetricians and Gynecologists (ACOG) acknowledges that no current scientific evidence supports or refutes the need for an annual pelvic examination for an asymptomatic, low-risk patient. But ACOG supports pelvic examinations as a way to establish open communication with patients about sexual health and reproduction.³ ACOG also recommends an annual health visit for all women. Whether or not a pelvic examination is performed, women should be counseled annually about birth control and offered contraception.

Patients should also be encouraged to keep their preventive care up-to-date, including cervical cancer screening with a Papanicolaou test or a human papillomavirus test (or both) at appropriate intervals, especially if the patient has cervical abnormalities requiring follow-up. However, falling behind on preventive care should not be a barrier to obtaining contraception.

IMPROVING ADHERENCE, DECREASING UNINTENDED PREGNANCY

One goal of the CDC’s 2013 guidelines was to remove unnecessary barriers to women’s access to contraceptives. In the United States, half of all pregnancies are unintended, and almost half of unintended pregnancies lead to abortion.⁴ Only half of women who have had an abortion used any contraceptive method within the last month.⁵ This suggests high levels of unprotected and underprotected sex.

For most patients, several national societies now recommend long-acting reversible contraceptive (LARC) methods, which include IUDs and progestin-only arm implants, because they have lower failure rates in a real-world setting.^1,6,7 LARC methods offer the advantage of the patient’s not having to remember to take, apply, or insert the contraceptive (ie, they are worry-free), and of not having to rely on a yearly appointment for refills.

Emergency contraception taken orally should be offered without an office visit

The Contraceptive CHOICE Project⁸ was a large prospective cohort study that assessed the impact of offering contraception free of charge in St. Louis, Missouri. Most of the 9,256 women who participated selected a LARC method.⁸ Those taking combined hormonal contraceptives (ie, birth control pill, patch, or ring) had a higher contraceptive failure rate than those using LARC methods (4.55 vs 0.27 per 100 participant-years; hazard ratio after adjustment for age, education, and unintended pregnancy history, 21.8; 95% confidence interval 13.7–34.9). The rate of unintended pregnancy in those under age 21 using combined hormonal contraceptives was almost twice as high as in older participants. Subsequent analyses showed that the abortion rates in the St. Louis region decreased to less than a quarter of the national average after the start of this project.⁹

Given that the failure rate with combined hormonal contraceptives averages 9% per year,¹ it is of the utmost importance that providers not limit access to patients’ prescriptions by requesting unnecessary visits and tests. If oral contraception is selected, women who are dispensed a full year’s supply of pill packs are more likely to continue with their contraceptive in the long term.¹⁰

THE PATIENT WITH A COMPLEX MEDICAL HISTORY

Limiting a woman’s contraceptive choices can increase her odds of experiencing an unintended pregnancy, which is associated with a far greater risk of adverse events than any contraceptive.¹¹ Thus, the CDC developed separate guidelines in 2010 to help determine all available options for the patient with medical comorbidities and with a concerning family history (ie, breast cancer, venous thromboembolism).¹² It can be helpful to consult the 2010 CDC medical eligibility criteria before offering contraception to these patients. Compared with the 2013 guidelines, which provide practical advice on how to use each contraceptive, the 2010 guidelines give guidance on when it is appropriate to prescribe each contraceptive—eg, which contraceptives are preferred based on a patient’s risk factors, medical history, and medication use. In addition to a two-page color summary chart of the 2010 medical eligibility criteria on the CDC website (https://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/legal_summary-chart_english_final_tag508.pdf), a free mobile app is also available to guide decision-making.¹³

Pregnancy should be ruled out before initiating any contraceptive. This can be done through a detailed history. The six-item checklist in Table 1 has a 99.8% negative predictive value, so healthcare providers may be confident that a woman is not pregnant if pregnancy is excluded based on this history.¹⁴ A pregnancy test is needed in those who test positive on the checklist if they wish to start a LARC method such as an IUD or a progestin-only arm implant. However, because the test has a high false-positive rate, initiation of shorter-acting methods such as combined hormonal contraceptives should not be delayed on the basis of a positive checklist screen alone.¹

Emergency contraception taken orally should be offered without an office visit, as its short duration of use allows women with traditional contraindications to hormonal contraceptives to safely use this birth control method.^1,12 Because all emergency contraceptives must be used within 5 days of intercourse (the earlier the better), unnecessary office visits delay access and effectiveness.

Although a levonorgestrel-based emergency contraceptive is available over the counter, ulipristal acetate is more effective, especially in women who are overweight.¹⁵ A copper IUD placed within 5 days of intercourse is the most effective form of emergency contraception¹⁵ but requires an office visit. This method is an option for most women but should be strongly considered for women at highest risk of pregnancy (previous unintended pregnancy, intercourse at midcycle, obesity).

In summary, most women may safely begin their hormonal contraceptive with a detailed medical history alone, without additional office visits, examinations, or screening tests.

No. According to 2013 guidelines of the US Centers for Disease Control and Prevention (CDC),¹ there is little evidence of benefit for many of the tests commonly mandated by healthcare providers before prescribing hormonal contraception (pill, ring, patch). These tests include breast and pelvic examinations, screening for cervical and sexually transmitted infections, laboratory testing, and mammography.

Only a medical history and blood pressure measurement are needed before prescribing estrogen-containing contraceptives. Patients who have elevated blood pressure but have not been previously diagnosed with hypertension should be preferentially offered other forms of contraception to avoid an additional risk of stroke or myocardial infarction, such as progestin-only products and intrauterine devices (IUDs). Women with blood pressures between 140/90 and 160/100 mm Hg may use estrogen-containing contraceptives only if other options are not appropriate. The CDC guidelines further state that if a patient is unable to come to the office for blood pressure assessment, then a community reading reported by the patient may be used to guide decision-making.

IS A PELVIC EXAMINATION NEEDED?

A pelvic examination (cervical inspection and bimanual examination) will not affect decisions related to prescribing contraceptives, except when prescribing female barrier methods (diaphragm, cervical cap) or IUDs.

Based on a systematic review of the literature between 1946 and 2014, the American College of Physicians now recommends against a screening pelvic examination in asymptomatic, nonpregnant, adult women when a Papanicolaou test is not otherwise indicated.²

The American College of Obstetricians and Gynecologists (ACOG) acknowledges that no current scientific evidence supports or refutes the need for an annual pelvic examination for an asymptomatic, low-risk patient. But ACOG supports pelvic examinations as a way to establish open communication with patients about sexual health and reproduction.³ ACOG also recommends an annual health visit for all women. Whether or not a pelvic examination is performed, women should be counseled annually about birth control and offered contraception.

Patients should also be encouraged to keep their preventive care up-to-date, including cervical cancer screening with a Papanicolaou test or a human papillomavirus test (or both) at appropriate intervals, especially if the patient has cervical abnormalities requiring follow-up. However, falling behind on preventive care should not be a barrier to obtaining contraception.

IMPROVING ADHERENCE, DECREASING UNINTENDED PREGNANCY

One goal of the CDC’s 2013 guidelines was to remove unnecessary barriers to women’s access to contraceptives. In the United States, half of all pregnancies are unintended, and almost half of unintended pregnancies lead to abortion.⁴ Only half of women who have had an abortion used any contraceptive method within the last month.⁵ This suggests high levels of unprotected and underprotected sex.

For most patients, several national societies now recommend long-acting reversible contraceptive (LARC) methods, which include IUDs and progestin-only arm implants, because they have lower failure rates in a real-world setting.^1,6,7 LARC methods offer the advantage of the patient’s not having to remember to take, apply, or insert the contraceptive (ie, they are worry-free), and of not having to rely on a yearly appointment for refills.

Emergency contraception taken orally should be offered without an office visit

The Contraceptive CHOICE Project⁸ was a large prospective cohort study that assessed the impact of offering contraception free of charge in St. Louis, Missouri. Most of the 9,256 women who participated selected a LARC method.⁸ Those taking combined hormonal contraceptives (ie, birth control pill, patch, or ring) had a higher contraceptive failure rate than those using LARC methods (4.55 vs 0.27 per 100 participant-years; hazard ratio after adjustment for age, education, and unintended pregnancy history, 21.8; 95% confidence interval 13.7–34.9). The rate of unintended pregnancy in those under age 21 using combined hormonal contraceptives was almost twice as high as in older participants. Subsequent analyses showed that the abortion rates in the St. Louis region decreased to less than a quarter of the national average after the start of this project.⁹

Given that the failure rate with combined hormonal contraceptives averages 9% per year,¹ it is of the utmost importance that providers not limit access to patients’ prescriptions by requesting unnecessary visits and tests. If oral contraception is selected, women who are dispensed a full year’s supply of pill packs are more likely to continue with their contraceptive in the long term.¹⁰

THE PATIENT WITH A COMPLEX MEDICAL HISTORY

Limiting a woman’s contraceptive choices can increase her odds of experiencing an unintended pregnancy, which is associated with a far greater risk of adverse events than any contraceptive.¹¹ Thus, the CDC developed separate guidelines in 2010 to help determine all available options for the patient with medical comorbidities and with a concerning family history (ie, breast cancer, venous thromboembolism).¹² It can be helpful to consult the 2010 CDC medical eligibility criteria before offering contraception to these patients. Compared with the 2013 guidelines, which provide practical advice on how to use each contraceptive, the 2010 guidelines give guidance on when it is appropriate to prescribe each contraceptive—eg, which contraceptives are preferred based on a patient’s risk factors, medical history, and medication use. In addition to a two-page color summary chart of the 2010 medical eligibility criteria on the CDC website (https://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/legal_summary-chart_english_final_tag508.pdf), a free mobile app is also available to guide decision-making.¹³

Pregnancy should be ruled out before initiating any contraceptive. This can be done through a detailed history. The six-item checklist in Table 1 has a 99.8% negative predictive value, so healthcare providers may be confident that a woman is not pregnant if pregnancy is excluded based on this history.¹⁴ A pregnancy test is needed in those who test positive on the checklist if they wish to start a LARC method such as an IUD or a progestin-only arm implant. However, because the test has a high false-positive rate, initiation of shorter-acting methods such as combined hormonal contraceptives should not be delayed on the basis of a positive checklist screen alone.¹

Emergency contraception taken orally should be offered without an office visit, as its short duration of use allows women with traditional contraindications to hormonal contraceptives to safely use this birth control method.^1,12 Because all emergency contraceptives must be used within 5 days of intercourse (the earlier the better), unnecessary office visits delay access and effectiveness.

Although a levonorgestrel-based emergency contraceptive is available over the counter, ulipristal acetate is more effective, especially in women who are overweight.¹⁵ A copper IUD placed within 5 days of intercourse is the most effective form of emergency contraception¹⁵ but requires an office visit. This method is an option for most women but should be strongly considered for women at highest risk of pregnancy (previous unintended pregnancy, intercourse at midcycle, obesity).

In summary, most women may safely begin their hormonal contraceptive with a detailed medical history alone, without additional office visits, examinations, or screening tests.

No. According to 2013 guidelines of the US Centers for Disease Control and Prevention (CDC),¹ there is little evidence of benefit for many of the tests commonly mandated by healthcare providers before prescribing hormonal contraception (pill, ring, patch). These tests include breast and pelvic examinations, screening for cervical and sexually transmitted infections, laboratory testing, and mammography.

Only a medical history and blood pressure measurement are needed before prescribing estrogen-containing contraceptives. Patients who have elevated blood pressure but have not been previously diagnosed with hypertension should be preferentially offered other forms of contraception to avoid an additional risk of stroke or myocardial infarction, such as progestin-only products and intrauterine devices (IUDs). Women with blood pressures between 140/90 and 160/100 mm Hg may use estrogen-containing contraceptives only if other options are not appropriate. The CDC guidelines further state that if a patient is unable to come to the office for blood pressure assessment, then a community reading reported by the patient may be used to guide decision-making.

IS A PELVIC EXAMINATION NEEDED?

A pelvic examination (cervical inspection and bimanual examination) will not affect decisions related to prescribing contraceptives, except when prescribing female barrier methods (diaphragm, cervical cap) or IUDs.

Based on a systematic review of the literature between 1946 and 2014, the American College of Physicians now recommends against a screening pelvic examination in asymptomatic, nonpregnant, adult women when a Papanicolaou test is not otherwise indicated.²

The American College of Obstetricians and Gynecologists (ACOG) acknowledges that no current scientific evidence supports or refutes the need for an annual pelvic examination for an asymptomatic, low-risk patient. But ACOG supports pelvic examinations as a way to establish open communication with patients about sexual health and reproduction.³ ACOG also recommends an annual health visit for all women. Whether or not a pelvic examination is performed, women should be counseled annually about birth control and offered contraception.

Patients should also be encouraged to keep their preventive care up-to-date, including cervical cancer screening with a Papanicolaou test or a human papillomavirus test (or both) at appropriate intervals, especially if the patient has cervical abnormalities requiring follow-up. However, falling behind on preventive care should not be a barrier to obtaining contraception.

IMPROVING ADHERENCE, DECREASING UNINTENDED PREGNANCY

One goal of the CDC’s 2013 guidelines was to remove unnecessary barriers to women’s access to contraceptives. In the United States, half of all pregnancies are unintended, and almost half of unintended pregnancies lead to abortion.⁴ Only half of women who have had an abortion used any contraceptive method within the last month.⁵ This suggests high levels of unprotected and underprotected sex.

For most patients, several national societies now recommend long-acting reversible contraceptive (LARC) methods, which include IUDs and progestin-only arm implants, because they have lower failure rates in a real-world setting.^1,6,7 LARC methods offer the advantage of the patient’s not having to remember to take, apply, or insert the contraceptive (ie, they are worry-free), and of not having to rely on a yearly appointment for refills.

Emergency contraception taken orally should be offered without an office visit

The Contraceptive CHOICE Project⁸ was a large prospective cohort study that assessed the impact of offering contraception free of charge in St. Louis, Missouri. Most of the 9,256 women who participated selected a LARC method.⁸ Those taking combined hormonal contraceptives (ie, birth control pill, patch, or ring) had a higher contraceptive failure rate than those using LARC methods (4.55 vs 0.27 per 100 participant-years; hazard ratio after adjustment for age, education, and unintended pregnancy history, 21.8; 95% confidence interval 13.7–34.9). The rate of unintended pregnancy in those under age 21 using combined hormonal contraceptives was almost twice as high as in older participants. Subsequent analyses showed that the abortion rates in the St. Louis region decreased to less than a quarter of the national average after the start of this project.⁹

Given that the failure rate with combined hormonal contraceptives averages 9% per year,¹ it is of the utmost importance that providers not limit access to patients’ prescriptions by requesting unnecessary visits and tests. If oral contraception is selected, women who are dispensed a full year’s supply of pill packs are more likely to continue with their contraceptive in the long term.¹⁰

THE PATIENT WITH A COMPLEX MEDICAL HISTORY

Limiting a woman’s contraceptive choices can increase her odds of experiencing an unintended pregnancy, which is associated with a far greater risk of adverse events than any contraceptive.¹¹ Thus, the CDC developed separate guidelines in 2010 to help determine all available options for the patient with medical comorbidities and with a concerning family history (ie, breast cancer, venous thromboembolism).¹² It can be helpful to consult the 2010 CDC medical eligibility criteria before offering contraception to these patients. Compared with the 2013 guidelines, which provide practical advice on how to use each contraceptive, the 2010 guidelines give guidance on when it is appropriate to prescribe each contraceptive—eg, which contraceptives are preferred based on a patient’s risk factors, medical history, and medication use. In addition to a two-page color summary chart of the 2010 medical eligibility criteria on the CDC website (https://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/legal_summary-chart_english_final_tag508.pdf), a free mobile app is also available to guide decision-making.¹³

Pregnancy should be ruled out before initiating any contraceptive. This can be done through a detailed history. The six-item checklist in Table 1 has a 99.8% negative predictive value, so healthcare providers may be confident that a woman is not pregnant if pregnancy is excluded based on this history.¹⁴ A pregnancy test is needed in those who test positive on the checklist if they wish to start a LARC method such as an IUD or a progestin-only arm implant. However, because the test has a high false-positive rate, initiation of shorter-acting methods such as combined hormonal contraceptives should not be delayed on the basis of a positive checklist screen alone.¹

Emergency contraception taken orally should be offered without an office visit, as its short duration of use allows women with traditional contraindications to hormonal contraceptives to safely use this birth control method.^1,12 Because all emergency contraceptives must be used within 5 days of intercourse (the earlier the better), unnecessary office visits delay access and effectiveness.

Although a levonorgestrel-based emergency contraceptive is available over the counter, ulipristal acetate is more effective, especially in women who are overweight.¹⁵ A copper IUD placed within 5 days of intercourse is the most effective form of emergency contraception¹⁵ but requires an office visit. This method is an option for most women but should be strongly considered for women at highest risk of pregnancy (previous unintended pregnancy, intercourse at midcycle, obesity).

In summary, most women may safely begin their hormonal contraceptive with a detailed medical history alone, without additional office visits, examinations, or screening tests.

A 43-year-old man with no medical history presented with pain and swelling in his left arm for 2 weeks. He was a regular weight lifter, and his exercise routine included repetitive hyperextension and hyperabduction of his arms while lifting heavy weights.

He had no history of recent trauma or venous cannulation of the left arm. His family history was negative for thrombophilic disorders. Physical examination revealed a swollen and erythematous left arm and visible venous collaterals at the neck, shoulder, and chest. There was no evidence of arterial insufficiency.

Duplex ultrasonography confirmed thrombosis of the left brachial, axillary, and subclavian veins. Further evaluation with computed tomography showed no intrathoracic mass but revealed several subsegmental pulmonary thrombi in the right lung. A screen for thrombophilia was negative. Venography confirmed complete thrombotic occlusion of the subclavian, axillary, and brachial veins (Figure 1).

Catheter-directed thrombolysis with tissue plasminogen activator resulted in complete resolution of the thrombosis, but venography after 3 days of thrombolysis showed 50% residual stenosis of the left subclavian vein where it passes under the first rib (Figure 2). The redness and swelling had markedly improved 2 days after thrombolytic therapy. He was discharged home on rivaroxaban 20 mg daily.

Follow-up venography 2 months later (Figure 3), with the patient performing hyperabduction of the arms, showed a patent subclavian vein with no thrombosis, but dynamic compression and occlusion of the subclavian vein where it passes the first rib. Magnetic resonance imaging (MRI) of the neck showed no cervical (ie, extra) rib and no soft-tissue abnormalities of the scalene triangle.

Following this, the patient underwent resection of the left first rib for decompression of the venous thoracic outlet, which resulted in resolution of his symptoms. He remained asymptomatic at 6-month follow-up.

PAGET-SCHROETTER SYNDROME

Paget-Schroetter syndrome, also referred to as effort-induced or effort thrombosis, is thrombosis of the axillary or subclavian vein associated with strenuous and repetitive activity of the arms. Anatomic abnormalities at the thoracic outlet—cervical rib, congenital bands, hypertrophy of scalene tendons, abnormal insertion of the costoclavicular ligament—and repetitive trauma to the endothelium of the subclavian vein are key factors in its initiation and progression.

The condition is seen primarily in young people who participate in strenuous activities such as rowing, weight lifting, and baseball pitching. It is estimated to be the cause of 40% of cases of primary upper-extremity deep vein thrombosis in the absence of an obvious risk factor or trigger such as a central venous catheter, pacemaker, port, or occult malignancy.¹

A provocative test such as the Adson test or hyperabduction test during MRI or venography helps confirm thoracic outlet obstruction by demonstrating dynamic obstruction.²

TREATMENT CONSIDERATIONS

There are no universal guidelines for the treatment of Paget-Schroetter syndrome. However, the available data^3–5 suggest a multimodal approach that involves early catheter-directed thrombolysis and subsequent surgical decompression of the thoracic outlet. This can restore venous patency and reduce the risk of long-term complications such as rethrombosis and postthrombotic syndrome.^3–5

Surgical treatment includes resection of the first rib and division of the scalene muscles and the costoclavicular ligament. MRI with provocative testing helps guide the surgical approach. Anticoagulation therapy alone—ie, without thrombolysis and surgical decompression—is inadequate as it leads to recurrence of thrombosis and residual symptoms.⁶

Paget-Schroetter syndrome should not be managed the same as lower-extremity deep vein thrombosis because the cause and the exacerbating factors are different.

Unanswered questions

Because we have no data from randomized controlled trials, questions about management remain. What should be the duration of anticoagulation, especially in the absence of coexisting thrombophilia? Is thrombophilia screening useful? What is the optimal timing for starting thrombolytic therapy?

A careful history and heightened suspicion are required to make this diagnosis. If undiagnosed, it carries a risk of significant long-term morbidity and death. Dynamic obstruction during venography, in addition to MRI, can help identify an anatomic obstruction.

A 43-year-old man with no medical history presented with pain and swelling in his left arm for 2 weeks. He was a regular weight lifter, and his exercise routine included repetitive hyperextension and hyperabduction of his arms while lifting heavy weights.

He had no history of recent trauma or venous cannulation of the left arm. His family history was negative for thrombophilic disorders. Physical examination revealed a swollen and erythematous left arm and visible venous collaterals at the neck, shoulder, and chest. There was no evidence of arterial insufficiency.

Duplex ultrasonography confirmed thrombosis of the left brachial, axillary, and subclavian veins. Further evaluation with computed tomography showed no intrathoracic mass but revealed several subsegmental pulmonary thrombi in the right lung. A screen for thrombophilia was negative. Venography confirmed complete thrombotic occlusion of the subclavian, axillary, and brachial veins (Figure 1).

Catheter-directed thrombolysis with tissue plasminogen activator resulted in complete resolution of the thrombosis, but venography after 3 days of thrombolysis showed 50% residual stenosis of the left subclavian vein where it passes under the first rib (Figure 2). The redness and swelling had markedly improved 2 days after thrombolytic therapy. He was discharged home on rivaroxaban 20 mg daily.

Follow-up venography 2 months later (Figure 3), with the patient performing hyperabduction of the arms, showed a patent subclavian vein with no thrombosis, but dynamic compression and occlusion of the subclavian vein where it passes the first rib. Magnetic resonance imaging (MRI) of the neck showed no cervical (ie, extra) rib and no soft-tissue abnormalities of the scalene triangle.

Following this, the patient underwent resection of the left first rib for decompression of the venous thoracic outlet, which resulted in resolution of his symptoms. He remained asymptomatic at 6-month follow-up.

PAGET-SCHROETTER SYNDROME

Paget-Schroetter syndrome, also referred to as effort-induced or effort thrombosis, is thrombosis of the axillary or subclavian vein associated with strenuous and repetitive activity of the arms. Anatomic abnormalities at the thoracic outlet—cervical rib, congenital bands, hypertrophy of scalene tendons, abnormal insertion of the costoclavicular ligament—and repetitive trauma to the endothelium of the subclavian vein are key factors in its initiation and progression.

The condition is seen primarily in young people who participate in strenuous activities such as rowing, weight lifting, and baseball pitching. It is estimated to be the cause of 40% of cases of primary upper-extremity deep vein thrombosis in the absence of an obvious risk factor or trigger such as a central venous catheter, pacemaker, port, or occult malignancy.¹

A provocative test such as the Adson test or hyperabduction test during MRI or venography helps confirm thoracic outlet obstruction by demonstrating dynamic obstruction.²

TREATMENT CONSIDERATIONS

There are no universal guidelines for the treatment of Paget-Schroetter syndrome. However, the available data^3–5 suggest a multimodal approach that involves early catheter-directed thrombolysis and subsequent surgical decompression of the thoracic outlet. This can restore venous patency and reduce the risk of long-term complications such as rethrombosis and postthrombotic syndrome.^3–5

Surgical treatment includes resection of the first rib and division of the scalene muscles and the costoclavicular ligament. MRI with provocative testing helps guide the surgical approach. Anticoagulation therapy alone—ie, without thrombolysis and surgical decompression—is inadequate as it leads to recurrence of thrombosis and residual symptoms.⁶

Paget-Schroetter syndrome should not be managed the same as lower-extremity deep vein thrombosis because the cause and the exacerbating factors are different.

Unanswered questions

Because we have no data from randomized controlled trials, questions about management remain. What should be the duration of anticoagulation, especially in the absence of coexisting thrombophilia? Is thrombophilia screening useful? What is the optimal timing for starting thrombolytic therapy?

A careful history and heightened suspicion are required to make this diagnosis. If undiagnosed, it carries a risk of significant long-term morbidity and death. Dynamic obstruction during venography, in addition to MRI, can help identify an anatomic obstruction.

A 43-year-old man with no medical history presented with pain and swelling in his left arm for 2 weeks. He was a regular weight lifter, and his exercise routine included repetitive hyperextension and hyperabduction of his arms while lifting heavy weights.

He had no history of recent trauma or venous cannulation of the left arm. His family history was negative for thrombophilic disorders. Physical examination revealed a swollen and erythematous left arm and visible venous collaterals at the neck, shoulder, and chest. There was no evidence of arterial insufficiency.

Duplex ultrasonography confirmed thrombosis of the left brachial, axillary, and subclavian veins. Further evaluation with computed tomography showed no intrathoracic mass but revealed several subsegmental pulmonary thrombi in the right lung. A screen for thrombophilia was negative. Venography confirmed complete thrombotic occlusion of the subclavian, axillary, and brachial veins (Figure 1).

Catheter-directed thrombolysis with tissue plasminogen activator resulted in complete resolution of the thrombosis, but venography after 3 days of thrombolysis showed 50% residual stenosis of the left subclavian vein where it passes under the first rib (Figure 2). The redness and swelling had markedly improved 2 days after thrombolytic therapy. He was discharged home on rivaroxaban 20 mg daily.

Follow-up venography 2 months later (Figure 3), with the patient performing hyperabduction of the arms, showed a patent subclavian vein with no thrombosis, but dynamic compression and occlusion of the subclavian vein where it passes the first rib. Magnetic resonance imaging (MRI) of the neck showed no cervical (ie, extra) rib and no soft-tissue abnormalities of the scalene triangle.

Following this, the patient underwent resection of the left first rib for decompression of the venous thoracic outlet, which resulted in resolution of his symptoms. He remained asymptomatic at 6-month follow-up.

PAGET-SCHROETTER SYNDROME

Paget-Schroetter syndrome, also referred to as effort-induced or effort thrombosis, is thrombosis of the axillary or subclavian vein associated with strenuous and repetitive activity of the arms. Anatomic abnormalities at the thoracic outlet—cervical rib, congenital bands, hypertrophy of scalene tendons, abnormal insertion of the costoclavicular ligament—and repetitive trauma to the endothelium of the subclavian vein are key factors in its initiation and progression.

The condition is seen primarily in young people who participate in strenuous activities such as rowing, weight lifting, and baseball pitching. It is estimated to be the cause of 40% of cases of primary upper-extremity deep vein thrombosis in the absence of an obvious risk factor or trigger such as a central venous catheter, pacemaker, port, or occult malignancy.¹

A provocative test such as the Adson test or hyperabduction test during MRI or venography helps confirm thoracic outlet obstruction by demonstrating dynamic obstruction.²

TREATMENT CONSIDERATIONS

There are no universal guidelines for the treatment of Paget-Schroetter syndrome. However, the available data^3–5 suggest a multimodal approach that involves early catheter-directed thrombolysis and subsequent surgical decompression of the thoracic outlet. This can restore venous patency and reduce the risk of long-term complications such as rethrombosis and postthrombotic syndrome.^3–5

Surgical treatment includes resection of the first rib and division of the scalene muscles and the costoclavicular ligament. MRI with provocative testing helps guide the surgical approach. Anticoagulation therapy alone—ie, without thrombolysis and surgical decompression—is inadequate as it leads to recurrence of thrombosis and residual symptoms.⁶

Paget-Schroetter syndrome should not be managed the same as lower-extremity deep vein thrombosis because the cause and the exacerbating factors are different.

Unanswered questions

Because we have no data from randomized controlled trials, questions about management remain. What should be the duration of anticoagulation, especially in the absence of coexisting thrombophilia? Is thrombophilia screening useful? What is the optimal timing for starting thrombolytic therapy?

A careful history and heightened suspicion are required to make this diagnosis. If undiagnosed, it carries a risk of significant long-term morbidity and death. Dynamic obstruction during venography, in addition to MRI, can help identify an anatomic obstruction.

We can promote healthy nutrition, physical activity, socialization, and mental activity. These interventions help stabilize and even improve cognition, as well as enhance quality of life and mood, delay institutionalization, and reduce disruptive behaviors. However, no medication is approved by the US Food and Drug Administration for treating mild cognitive impairment (MCI).

WHAT IS MILD COGNITIVE IMPAIRMENT?

MCI is a dynamic stage between normal aging and dementia. It is diagnosed in patients with an objective cognitive deficit but preserved function.

Population-based studies have found a wide range of rates of MCI incidence (21.5–71.3 per 1,000 person-years) and prevalence (3%–42%).¹ The risk of progression from MCI to dementia ranges from 5% to 25% per year and is highest with MCI that involves memory loss (amnestic MCI).^2,3

MCI can be regarded as a syndrome that is often associated with Alzheimer pathology and that has variable outcomes. In MCI due to Alzheimer disease, the primary complaint is short-term memory loss.⁴ Patients who have multiple impaired cognitive domains with prominent deficits in attention and executive function and relatively unimpaired short-term memory (nonamnestic MCI) are more likely to have vascular or Lewy body pathologies.⁵ Although distinctions between amnestic and nonamnestic MCI can be useful for counseling patients, both subtypes have similar proportions of “pure” Alzheimer disease pathology, vascular infarcts, and other pathologies at autopsy.^5,6

GENERAL MANAGEMENT—IMPROVE OVERALL HEALTH

Primary management of MCI should focus on improving lifestyle factors and treating comorbid conditions that can affect cognition (eg, depression, nutritional deficiencies).

An important goal of management is to preserve working memory, ie, the ability to maintain and manipulate information while ignoring distractions. Preservation of working memory but not short-term memory is associated with slower functional decline in MCI and early Alzheimer disease.⁷ Lifestyle factors including sleep, stress, and exercise affect working memory performance and, thus, functional ability.

Minimizing the risk of traumatic brain injury by reducing the risk of falling is also important. Although the role of alcohol consumption as it relates to cognition is controversial, physicians may counsel older adults with MCI to reduce their alcohol consumption even if they are consuming no more than one standard drink in a 24-hour period, in order to reduce the risk of falls and their sequelae.

Optimally controlling blood pressure, lipids, and blood sugar can reduce cardiovascular risk and may slow progression of MCI to dementia.²

Smoking should be stopped and polypharmacy avoided, with particular emphasis on eliminating medications included in the Beers criteria.⁸

A HEALTHY DIET MAY HELP

Although evidence supporting the benefits of various diets for MCI remains scarce with mixed results, a healthy diet may favorably affect cognition. A 2009 systematic review found that observational studies showed that long-chain omega-3 fatty acids had a positive influence on cognition, but results from clinical trials were equivocal.⁹ Studies investigating the impact on cognition of the Mediterranean diet—rich in vegetables, fruits, whole grains, lean protein, and olive oil—remain mixed (possibly because of dietary and cognitive measurement variations between studies) but suggest that it promotes slower cognitive decline.¹⁰

PHYSICAL ACTIVITY HAS MULTIPLE BENEFITS

Physical activity has many health benefits in the elderly: it reduces muscle loss, increases functional capacity, and decreases the risk of falls.¹¹ Several randomized controlled trials have explored the relationship between physical activity and cognition in patients with varying degrees of cognitive impairment. Although the optimal type and duration of exercise needed to achieve a specific benefit remains unclear, physical activity has been found to be helpful in more studies than not.¹² Baker et al¹³ found that 45 to 60 minutes of high-intensity aerobic activity 4 days a week for 6 months improved executive function.

MAINTAIN SOCIAL ACTIVITIES

Social engagement—which can include a range of activities from conversation to structured group activities—is important for maintaining cognitive function.

A prospective cohort study¹⁴ that followed participants for 1 to 3 years after MCI diagnosis found that those who progressed from mild to severe cognitive impairment were less likely to attend a place of worship, work, or volunteer.

A longitudinal study of 89 elderly people without known dementia evaluated measures of socialization, global cognitive function, and Alzheimer disease pathology seen on brain autopsy. Lower cognitive function was associated with more disease pathology, but social network size modified this relationship: cognitive function was less impaired than expected for those with a large social network, even for those with a high burden of brain pathology.¹⁵

ENCOURAGE BRAIN EXERCISE

Activities can include “cognitive hobbies” such as playing board games, reading, playing a musical instrument, and doing crossword puzzles. Specific cognitive training strategies (eg, mnemonics, calligraphy therapy, computer-based interventions) have shown benefits, although it is unclear if some interventions are more effective than others.¹²

MULTIMODAL STRATEGIES

There are no data supporting strategies that combine multiple interventions compared with a single intervention on cognitive outcome. However, most single interventions likely contain socialization as an unstated intervention. For example, group settings for a cognitive or physical activity may include interactions with an instructor and interactions with other participants. It is thus difficult to identify truly unimodal interventions.

An example of a multimodal approach for cognitive impairment is tai chi. Physical activity in tai chi is used for coordinated movements and balance; attention, visual imagery, and memory provide cognitive stimulation; and it is frequently performed in a group setting or with an instructor. A 1-year trial in 389 MCI patients found that those who practiced tai chi had lower clinical dementia rating scale scores than the control group who participated in stretching and toning exercises.¹⁶

Table 1 summarizes recommendations for patients with MCI. In addition, referral to a geriatrician should be considered for assistance with evaluation and management, particularly if the patient lacks a capable caregiver or if the caregiver is under stress.

We can promote healthy nutrition, physical activity, socialization, and mental activity. These interventions help stabilize and even improve cognition, as well as enhance quality of life and mood, delay institutionalization, and reduce disruptive behaviors. However, no medication is approved by the US Food and Drug Administration for treating mild cognitive impairment (MCI).

WHAT IS MILD COGNITIVE IMPAIRMENT?

MCI is a dynamic stage between normal aging and dementia. It is diagnosed in patients with an objective cognitive deficit but preserved function.

Population-based studies have found a wide range of rates of MCI incidence (21.5–71.3 per 1,000 person-years) and prevalence (3%–42%).¹ The risk of progression from MCI to dementia ranges from 5% to 25% per year and is highest with MCI that involves memory loss (amnestic MCI).^2,3

MCI can be regarded as a syndrome that is often associated with Alzheimer pathology and that has variable outcomes. In MCI due to Alzheimer disease, the primary complaint is short-term memory loss.⁴ Patients who have multiple impaired cognitive domains with prominent deficits in attention and executive function and relatively unimpaired short-term memory (nonamnestic MCI) are more likely to have vascular or Lewy body pathologies.⁵ Although distinctions between amnestic and nonamnestic MCI can be useful for counseling patients, both subtypes have similar proportions of “pure” Alzheimer disease pathology, vascular infarcts, and other pathologies at autopsy.^5,6

GENERAL MANAGEMENT—IMPROVE OVERALL HEALTH

Primary management of MCI should focus on improving lifestyle factors and treating comorbid conditions that can affect cognition (eg, depression, nutritional deficiencies).

An important goal of management is to preserve working memory, ie, the ability to maintain and manipulate information while ignoring distractions. Preservation of working memory but not short-term memory is associated with slower functional decline in MCI and early Alzheimer disease.⁷ Lifestyle factors including sleep, stress, and exercise affect working memory performance and, thus, functional ability.

Minimizing the risk of traumatic brain injury by reducing the risk of falling is also important. Although the role of alcohol consumption as it relates to cognition is controversial, physicians may counsel older adults with MCI to reduce their alcohol consumption even if they are consuming no more than one standard drink in a 24-hour period, in order to reduce the risk of falls and their sequelae.

Optimally controlling blood pressure, lipids, and blood sugar can reduce cardiovascular risk and may slow progression of MCI to dementia.²

Smoking should be stopped and polypharmacy avoided, with particular emphasis on eliminating medications included in the Beers criteria.⁸

A HEALTHY DIET MAY HELP

Although evidence supporting the benefits of various diets for MCI remains scarce with mixed results, a healthy diet may favorably affect cognition. A 2009 systematic review found that observational studies showed that long-chain omega-3 fatty acids had a positive influence on cognition, but results from clinical trials were equivocal.⁹ Studies investigating the impact on cognition of the Mediterranean diet—rich in vegetables, fruits, whole grains, lean protein, and olive oil—remain mixed (possibly because of dietary and cognitive measurement variations between studies) but suggest that it promotes slower cognitive decline.¹⁰

PHYSICAL ACTIVITY HAS MULTIPLE BENEFITS

Physical activity has many health benefits in the elderly: it reduces muscle loss, increases functional capacity, and decreases the risk of falls.¹¹ Several randomized controlled trials have explored the relationship between physical activity and cognition in patients with varying degrees of cognitive impairment. Although the optimal type and duration of exercise needed to achieve a specific benefit remains unclear, physical activity has been found to be helpful in more studies than not.¹² Baker et al¹³ found that 45 to 60 minutes of high-intensity aerobic activity 4 days a week for 6 months improved executive function.

MAINTAIN SOCIAL ACTIVITIES

Social engagement—which can include a range of activities from conversation to structured group activities—is important for maintaining cognitive function.

A prospective cohort study¹⁴ that followed participants for 1 to 3 years after MCI diagnosis found that those who progressed from mild to severe cognitive impairment were less likely to attend a place of worship, work, or volunteer.

A longitudinal study of 89 elderly people without known dementia evaluated measures of socialization, global cognitive function, and Alzheimer disease pathology seen on brain autopsy. Lower cognitive function was associated with more disease pathology, but social network size modified this relationship: cognitive function was less impaired than expected for those with a large social network, even for those with a high burden of brain pathology.¹⁵

ENCOURAGE BRAIN EXERCISE

Activities can include “cognitive hobbies” such as playing board games, reading, playing a musical instrument, and doing crossword puzzles. Specific cognitive training strategies (eg, mnemonics, calligraphy therapy, computer-based interventions) have shown benefits, although it is unclear if some interventions are more effective than others.¹²

MULTIMODAL STRATEGIES

There are no data supporting strategies that combine multiple interventions compared with a single intervention on cognitive outcome. However, most single interventions likely contain socialization as an unstated intervention. For example, group settings for a cognitive or physical activity may include interactions with an instructor and interactions with other participants. It is thus difficult to identify truly unimodal interventions.

An example of a multimodal approach for cognitive impairment is tai chi. Physical activity in tai chi is used for coordinated movements and balance; attention, visual imagery, and memory provide cognitive stimulation; and it is frequently performed in a group setting or with an instructor. A 1-year trial in 389 MCI patients found that those who practiced tai chi had lower clinical dementia rating scale scores than the control group who participated in stretching and toning exercises.¹⁶

Table 1 summarizes recommendations for patients with MCI. In addition, referral to a geriatrician should be considered for assistance with evaluation and management, particularly if the patient lacks a capable caregiver or if the caregiver is under stress.

We can promote healthy nutrition, physical activity, socialization, and mental activity. These interventions help stabilize and even improve cognition, as well as enhance quality of life and mood, delay institutionalization, and reduce disruptive behaviors. However, no medication is approved by the US Food and Drug Administration for treating mild cognitive impairment (MCI).

WHAT IS MILD COGNITIVE IMPAIRMENT?

MCI is a dynamic stage between normal aging and dementia. It is diagnosed in patients with an objective cognitive deficit but preserved function.

Population-based studies have found a wide range of rates of MCI incidence (21.5–71.3 per 1,000 person-years) and prevalence (3%–42%).¹ The risk of progression from MCI to dementia ranges from 5% to 25% per year and is highest with MCI that involves memory loss (amnestic MCI).^2,3

MCI can be regarded as a syndrome that is often associated with Alzheimer pathology and that has variable outcomes. In MCI due to Alzheimer disease, the primary complaint is short-term memory loss.⁴ Patients who have multiple impaired cognitive domains with prominent deficits in attention and executive function and relatively unimpaired short-term memory (nonamnestic MCI) are more likely to have vascular or Lewy body pathologies.⁵ Although distinctions between amnestic and nonamnestic MCI can be useful for counseling patients, both subtypes have similar proportions of “pure” Alzheimer disease pathology, vascular infarcts, and other pathologies at autopsy.^5,6

GENERAL MANAGEMENT—IMPROVE OVERALL HEALTH

Primary management of MCI should focus on improving lifestyle factors and treating comorbid conditions that can affect cognition (eg, depression, nutritional deficiencies).

An important goal of management is to preserve working memory, ie, the ability to maintain and manipulate information while ignoring distractions. Preservation of working memory but not short-term memory is associated with slower functional decline in MCI and early Alzheimer disease.⁷ Lifestyle factors including sleep, stress, and exercise affect working memory performance and, thus, functional ability.

Minimizing the risk of traumatic brain injury by reducing the risk of falling is also important. Although the role of alcohol consumption as it relates to cognition is controversial, physicians may counsel older adults with MCI to reduce their alcohol consumption even if they are consuming no more than one standard drink in a 24-hour period, in order to reduce the risk of falls and their sequelae.

Optimally controlling blood pressure, lipids, and blood sugar can reduce cardiovascular risk and may slow progression of MCI to dementia.²

Smoking should be stopped and polypharmacy avoided, with particular emphasis on eliminating medications included in the Beers criteria.⁸

A HEALTHY DIET MAY HELP

Although evidence supporting the benefits of various diets for MCI remains scarce with mixed results, a healthy diet may favorably affect cognition. A 2009 systematic review found that observational studies showed that long-chain omega-3 fatty acids had a positive influence on cognition, but results from clinical trials were equivocal.⁹ Studies investigating the impact on cognition of the Mediterranean diet—rich in vegetables, fruits, whole grains, lean protein, and olive oil—remain mixed (possibly because of dietary and cognitive measurement variations between studies) but suggest that it promotes slower cognitive decline.¹⁰

PHYSICAL ACTIVITY HAS MULTIPLE BENEFITS

Physical activity has many health benefits in the elderly: it reduces muscle loss, increases functional capacity, and decreases the risk of falls.¹¹ Several randomized controlled trials have explored the relationship between physical activity and cognition in patients with varying degrees of cognitive impairment. Although the optimal type and duration of exercise needed to achieve a specific benefit remains unclear, physical activity has been found to be helpful in more studies than not.¹² Baker et al¹³ found that 45 to 60 minutes of high-intensity aerobic activity 4 days a week for 6 months improved executive function.

MAINTAIN SOCIAL ACTIVITIES

Social engagement—which can include a range of activities from conversation to structured group activities—is important for maintaining cognitive function.

A prospective cohort study¹⁴ that followed participants for 1 to 3 years after MCI diagnosis found that those who progressed from mild to severe cognitive impairment were less likely to attend a place of worship, work, or volunteer.

A longitudinal study of 89 elderly people without known dementia evaluated measures of socialization, global cognitive function, and Alzheimer disease pathology seen on brain autopsy. Lower cognitive function was associated with more disease pathology, but social network size modified this relationship: cognitive function was less impaired than expected for those with a large social network, even for those with a high burden of brain pathology.¹⁵

ENCOURAGE BRAIN EXERCISE

Activities can include “cognitive hobbies” such as playing board games, reading, playing a musical instrument, and doing crossword puzzles. Specific cognitive training strategies (eg, mnemonics, calligraphy therapy, computer-based interventions) have shown benefits, although it is unclear if some interventions are more effective than others.¹²

MULTIMODAL STRATEGIES

There are no data supporting strategies that combine multiple interventions compared with a single intervention on cognitive outcome. However, most single interventions likely contain socialization as an unstated intervention. For example, group settings for a cognitive or physical activity may include interactions with an instructor and interactions with other participants. It is thus difficult to identify truly unimodal interventions.

An example of a multimodal approach for cognitive impairment is tai chi. Physical activity in tai chi is used for coordinated movements and balance; attention, visual imagery, and memory provide cognitive stimulation; and it is frequently performed in a group setting or with an instructor. A 1-year trial in 389 MCI patients found that those who practiced tai chi had lower clinical dementia rating scale scores than the control group who participated in stretching and toning exercises.¹⁶

Table 1 summarizes recommendations for patients with MCI. In addition, referral to a geriatrician should be considered for assistance with evaluation and management, particularly if the patient lacks a capable caregiver or if the caregiver is under stress.

A 75-year-old woman was referred to our pulmonary clinic with a 4-year history of intermittent episodes of persistent cough, occasionally productive of sputum, and mild exertional dyspnea. She had been treated with azithromycin for presumed community-acquired pneumonia, and her symptoms had initially improved. Subsequently, she experienced discrete, recurrent episodes of “bronchitis,” with productive cough and mild exertional dyspnea. Testing for latent tuberculosis had been negative. She reported a 10-pack-year smoking history in the remote past.

Her medical history included asthma, atrial fibrillation, gastroesophageal reflux disorder, hyperlipidemia, osteopenia, hypothyroidism, and allergic rhinitis. Her current medications were metoprolol, propafenone, and warfarin.

ABNORMALITIES ON PREVIOUS IMAGING

Computed tomography (CT) in April 2010 had revealed scattered linear, nodular, and “tree-in-bud” opacities involving the bilateral apices and the upper, middle, and lower lobes of the right lung, suggestive of bronchiolitis. Mild bronchiectasis had also been noted (Figure 1). Chest radiography had demonstrated signs of bronchiectasis and several scattered nodules (Figure 2). These abnormalities were still present on another CT scan in May 2013.

The patient had not undergone bronchoscopy before she was referred to our clinic.

WORKUP AT OUR CLINIC

On examination, the patient was lean, with a body mass index of 20.53 kg/m². She appeared calm, well-groomed, and well-dressed, and had a very polite manner. When she coughed, she tried to suppress it, as if she were self-conscious about it. Her heart rhythm was irregularly irregular with a normal rate.

Expectorated sputum samples were obtained. Stains for acid-fast bacilli were negative, but three cultures were positive for acid-fast bacilli consistent with Mycobacterium avium-intracellulare. Serologic studies were negative for fungal infection and immunoglobulin deficiency.

Based on her symptoms and on the findings of imaging studies and sputum culture, we arrived at the diagnosis of nontuberculous mycobacterial lung infection, specifically, Lady Windermere syndrome.

NONTUBERCULOUS MYOCOBACTERIAL LUNG INFECTION

The diagnosis of nontuberculous mycobacterial lung infection is based on respiratory symptoms, findings on imaging (eg, nodular or cavitary opacities on radiography, or multifocal bronchiectasis and multiple small nodules on CT), and a positive culture for nontuberculous mycobacterial infection in more than two specimens of expectorated sputum or in more than one specimen from bronchoalveolar lavage. Lung biopsy with tissue culture is another way to confirm the diagnosis.

LADY WINDERMERE SYNDROME

Lady Windermere syndrome was described more than 20 years ago.¹ The name derives from the lead character in Oscar Wilde’s play Lady Windermere’s Fan, which satirizes the strict morals and polite manners typical of the Victorian era in Great Britain.²

The patient with Lady Windermere syndrome is typically a thin, lean, well-mannered elderly woman who voluntarily suppresses her cough out of politeness. Suppression of the cough is thought to predispose to lung infection by allowing secretions to collect in the airways, especially in the right middle lobe, which has the longest and narrowest of the lobar bronchi.^3,4

Symptoms of Lady Windermere syndrome include cough, sputum production, and fatigue similar to that of acute or chronic bronchitis. Dyspnea, fever, and hemoptysis are less common.⁵ The differential diagnosis for these symptoms is broad and includes asthma, chronic obstructive pulmonary disease, gastroesophageal reflux disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, postnasal drip, lung cancer, and heart failure.

A prospective cohort study by Kim et al⁶ yielded descriptions of typical patients with Lady Windermere syndrome. Patients were tall and lean, tended to have scoliosis, and more commonly had pectus excavatum or mitral valve prolapse; 95% were women, 91% were white, and the average age was 60. The morphologic features are thought to contribute to impaired clearance of airway secretions by altered mechanics during coughing.

HALLMARKS ON IMAGING

Kim et al⁶ reported that the most common findings on lung imaging in nontuberculous mycobacterial infection were bronchiectasis involving the right middle lobe (90%), nodules involving the right lower lobe (73%) and right middle lobe (71%), and, less commonly, a cavitary infiltrate involving the right upper lobe (17%) or right middle lobe (10%).

Key findings on imaging in Lady Windermere syndrome include opacities and “cylindrical bronchiectasis” predominantly involving the right middle lobe or lingula.⁵ Bronchiolar inflammation in response to nontuberculous mycobacterial infection may cause a nodular appearance, often progressing to a tree-in-bud appearance on CT.

Other diagnostic considerations for tree-in-bud appearance on CT include fungal, viral, or other bacterial infection, aspiration pneumonitis, inhalation of a foreign substance, cystic fibrosis, rheumatoid arthritis, SjÖgren syndrome, bronchiolitis obliterans, and neoplastic disease.

CURRENT TREATMENT OPTIONS

Treatment of nontuberculous mycobacterial lung infection, including Lady Windermere syndrome, is not necessary in every case, given the variability in clinical symptoms and in disease progression. Patients with progressive symptoms or radiographic changes should be considered candidates for treatment.

Management is directed at the underlying infection. M avium-intracellulare is ubiquitous in the environment, including in soil and water, and it has been reported as the most common pathogen in nontuberculous mycobacterial lung infection.⁷

Nodular-bronchiectatic nontuberculous mycobacterial lung disease typically progresses more slowly than fibrocavitary disease. For patients with nodular-bronchiectatic disease, follow-up over months or years may be needed before clinical or radiographic changes become apparent.

When treatment is indicated for nodular-bronchiectatic nontuberculous mycobacterial lung infection, it should include a macrolide antibiotic, ethambutol, and rifampin.^7,8 Monotherapy with a macrolide is not recommended because of the risk of macrolide resistance. Addition of an aminoglycoside may be considered when treating fibrocavitary disease or widespread nodular bronchiectatic disease.

Management of bronchiectasis, when present, includes chest physiotherapy, pulmonary hygiene therapy, and awareness of the predisposition for nonmycobacterial lung infection. The decision to prescribe antimicrobials should take into consideration the risks and benefits for each patient.

Because treatment involves multidrug regimens, drug interactions and adverse effects need to be considered and monitored, especially in elderly patients, who may already be taking multiple medications. Treatment should be continued until a patient has negative sputum cultures for acid-fast bacilli while on therapy, for 1 year.

A 75-year-old woman was referred to our pulmonary clinic with a 4-year history of intermittent episodes of persistent cough, occasionally productive of sputum, and mild exertional dyspnea. She had been treated with azithromycin for presumed community-acquired pneumonia, and her symptoms had initially improved. Subsequently, she experienced discrete, recurrent episodes of “bronchitis,” with productive cough and mild exertional dyspnea. Testing for latent tuberculosis had been negative. She reported a 10-pack-year smoking history in the remote past.

Her medical history included asthma, atrial fibrillation, gastroesophageal reflux disorder, hyperlipidemia, osteopenia, hypothyroidism, and allergic rhinitis. Her current medications were metoprolol, propafenone, and warfarin.

ABNORMALITIES ON PREVIOUS IMAGING

Computed tomography (CT) in April 2010 had revealed scattered linear, nodular, and “tree-in-bud” opacities involving the bilateral apices and the upper, middle, and lower lobes of the right lung, suggestive of bronchiolitis. Mild bronchiectasis had also been noted (Figure 1). Chest radiography had demonstrated signs of bronchiectasis and several scattered nodules (Figure 2). These abnormalities were still present on another CT scan in May 2013.

The patient had not undergone bronchoscopy before she was referred to our clinic.

WORKUP AT OUR CLINIC

On examination, the patient was lean, with a body mass index of 20.53 kg/m². She appeared calm, well-groomed, and well-dressed, and had a very polite manner. When she coughed, she tried to suppress it, as if she were self-conscious about it. Her heart rhythm was irregularly irregular with a normal rate.

Expectorated sputum samples were obtained. Stains for acid-fast bacilli were negative, but three cultures were positive for acid-fast bacilli consistent with Mycobacterium avium-intracellulare. Serologic studies were negative for fungal infection and immunoglobulin deficiency.

Based on her symptoms and on the findings of imaging studies and sputum culture, we arrived at the diagnosis of nontuberculous mycobacterial lung infection, specifically, Lady Windermere syndrome.

NONTUBERCULOUS MYOCOBACTERIAL LUNG INFECTION

The diagnosis of nontuberculous mycobacterial lung infection is based on respiratory symptoms, findings on imaging (eg, nodular or cavitary opacities on radiography, or multifocal bronchiectasis and multiple small nodules on CT), and a positive culture for nontuberculous mycobacterial infection in more than two specimens of expectorated sputum or in more than one specimen from bronchoalveolar lavage. Lung biopsy with tissue culture is another way to confirm the diagnosis.

LADY WINDERMERE SYNDROME

Lady Windermere syndrome was described more than 20 years ago.¹ The name derives from the lead character in Oscar Wilde’s play Lady Windermere’s Fan, which satirizes the strict morals and polite manners typical of the Victorian era in Great Britain.²

The patient with Lady Windermere syndrome is typically a thin, lean, well-mannered elderly woman who voluntarily suppresses her cough out of politeness. Suppression of the cough is thought to predispose to lung infection by allowing secretions to collect in the airways, especially in the right middle lobe, which has the longest and narrowest of the lobar bronchi.^3,4

Symptoms of Lady Windermere syndrome include cough, sputum production, and fatigue similar to that of acute or chronic bronchitis. Dyspnea, fever, and hemoptysis are less common.⁵ The differential diagnosis for these symptoms is broad and includes asthma, chronic obstructive pulmonary disease, gastroesophageal reflux disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, postnasal drip, lung cancer, and heart failure.

A prospective cohort study by Kim et al⁶ yielded descriptions of typical patients with Lady Windermere syndrome. Patients were tall and lean, tended to have scoliosis, and more commonly had pectus excavatum or mitral valve prolapse; 95% were women, 91% were white, and the average age was 60. The morphologic features are thought to contribute to impaired clearance of airway secretions by altered mechanics during coughing.

HALLMARKS ON IMAGING

Kim et al⁶ reported that the most common findings on lung imaging in nontuberculous mycobacterial infection were bronchiectasis involving the right middle lobe (90%), nodules involving the right lower lobe (73%) and right middle lobe (71%), and, less commonly, a cavitary infiltrate involving the right upper lobe (17%) or right middle lobe (10%).

Key findings on imaging in Lady Windermere syndrome include opacities and “cylindrical bronchiectasis” predominantly involving the right middle lobe or lingula.⁵ Bronchiolar inflammation in response to nontuberculous mycobacterial infection may cause a nodular appearance, often progressing to a tree-in-bud appearance on CT.

Other diagnostic considerations for tree-in-bud appearance on CT include fungal, viral, or other bacterial infection, aspiration pneumonitis, inhalation of a foreign substance, cystic fibrosis, rheumatoid arthritis, SjÖgren syndrome, bronchiolitis obliterans, and neoplastic disease.

CURRENT TREATMENT OPTIONS

Treatment of nontuberculous mycobacterial lung infection, including Lady Windermere syndrome, is not necessary in every case, given the variability in clinical symptoms and in disease progression. Patients with progressive symptoms or radiographic changes should be considered candidates for treatment.

Management is directed at the underlying infection. M avium-intracellulare is ubiquitous in the environment, including in soil and water, and it has been reported as the most common pathogen in nontuberculous mycobacterial lung infection.⁷

Nodular-bronchiectatic nontuberculous mycobacterial lung disease typically progresses more slowly than fibrocavitary disease. For patients with nodular-bronchiectatic disease, follow-up over months or years may be needed before clinical or radiographic changes become apparent.

When treatment is indicated for nodular-bronchiectatic nontuberculous mycobacterial lung infection, it should include a macrolide antibiotic, ethambutol, and rifampin.^7,8 Monotherapy with a macrolide is not recommended because of the risk of macrolide resistance. Addition of an aminoglycoside may be considered when treating fibrocavitary disease or widespread nodular bronchiectatic disease.

Management of bronchiectasis, when present, includes chest physiotherapy, pulmonary hygiene therapy, and awareness of the predisposition for nonmycobacterial lung infection. The decision to prescribe antimicrobials should take into consideration the risks and benefits for each patient.

Because treatment involves multidrug regimens, drug interactions and adverse effects need to be considered and monitored, especially in elderly patients, who may already be taking multiple medications. Treatment should be continued until a patient has negative sputum cultures for acid-fast bacilli while on therapy, for 1 year.

A 75-year-old woman was referred to our pulmonary clinic with a 4-year history of intermittent episodes of persistent cough, occasionally productive of sputum, and mild exertional dyspnea. She had been treated with azithromycin for presumed community-acquired pneumonia, and her symptoms had initially improved. Subsequently, she experienced discrete, recurrent episodes of “bronchitis,” with productive cough and mild exertional dyspnea. Testing for latent tuberculosis had been negative. She reported a 10-pack-year smoking history in the remote past.

Her medical history included asthma, atrial fibrillation, gastroesophageal reflux disorder, hyperlipidemia, osteopenia, hypothyroidism, and allergic rhinitis. Her current medications were metoprolol, propafenone, and warfarin.

ABNORMALITIES ON PREVIOUS IMAGING

Computed tomography (CT) in April 2010 had revealed scattered linear, nodular, and “tree-in-bud” opacities involving the bilateral apices and the upper, middle, and lower lobes of the right lung, suggestive of bronchiolitis. Mild bronchiectasis had also been noted (Figure 1). Chest radiography had demonstrated signs of bronchiectasis and several scattered nodules (Figure 2). These abnormalities were still present on another CT scan in May 2013.

The patient had not undergone bronchoscopy before she was referred to our clinic.

WORKUP AT OUR CLINIC

On examination, the patient was lean, with a body mass index of 20.53 kg/m². She appeared calm, well-groomed, and well-dressed, and had a very polite manner. When she coughed, she tried to suppress it, as if she were self-conscious about it. Her heart rhythm was irregularly irregular with a normal rate.

Expectorated sputum samples were obtained. Stains for acid-fast bacilli were negative, but three cultures were positive for acid-fast bacilli consistent with Mycobacterium avium-intracellulare. Serologic studies were negative for fungal infection and immunoglobulin deficiency.

Based on her symptoms and on the findings of imaging studies and sputum culture, we arrived at the diagnosis of nontuberculous mycobacterial lung infection, specifically, Lady Windermere syndrome.

NONTUBERCULOUS MYOCOBACTERIAL LUNG INFECTION

The diagnosis of nontuberculous mycobacterial lung infection is based on respiratory symptoms, findings on imaging (eg, nodular or cavitary opacities on radiography, or multifocal bronchiectasis and multiple small nodules on CT), and a positive culture for nontuberculous mycobacterial infection in more than two specimens of expectorated sputum or in more than one specimen from bronchoalveolar lavage. Lung biopsy with tissue culture is another way to confirm the diagnosis.

LADY WINDERMERE SYNDROME

Lady Windermere syndrome was described more than 20 years ago.¹ The name derives from the lead character in Oscar Wilde’s play Lady Windermere’s Fan, which satirizes the strict morals and polite manners typical of the Victorian era in Great Britain.²

The patient with Lady Windermere syndrome is typically a thin, lean, well-mannered elderly woman who voluntarily suppresses her cough out of politeness. Suppression of the cough is thought to predispose to lung infection by allowing secretions to collect in the airways, especially in the right middle lobe, which has the longest and narrowest of the lobar bronchi.^3,4

Symptoms of Lady Windermere syndrome include cough, sputum production, and fatigue similar to that of acute or chronic bronchitis. Dyspnea, fever, and hemoptysis are less common.⁵ The differential diagnosis for these symptoms is broad and includes asthma, chronic obstructive pulmonary disease, gastroesophageal reflux disease, pneumonia, bronchiectasis, cystic fibrosis, interstitial lung disease, postnasal drip, lung cancer, and heart failure.

A prospective cohort study by Kim et al⁶ yielded descriptions of typical patients with Lady Windermere syndrome. Patients were tall and lean, tended to have scoliosis, and more commonly had pectus excavatum or mitral valve prolapse; 95% were women, 91% were white, and the average age was 60. The morphologic features are thought to contribute to impaired clearance of airway secretions by altered mechanics during coughing.

HALLMARKS ON IMAGING

Kim et al⁶ reported that the most common findings on lung imaging in nontuberculous mycobacterial infection were bronchiectasis involving the right middle lobe (90%), nodules involving the right lower lobe (73%) and right middle lobe (71%), and, less commonly, a cavitary infiltrate involving the right upper lobe (17%) or right middle lobe (10%).

Key findings on imaging in Lady Windermere syndrome include opacities and “cylindrical bronchiectasis” predominantly involving the right middle lobe or lingula.⁵ Bronchiolar inflammation in response to nontuberculous mycobacterial infection may cause a nodular appearance, often progressing to a tree-in-bud appearance on CT.

Other diagnostic considerations for tree-in-bud appearance on CT include fungal, viral, or other bacterial infection, aspiration pneumonitis, inhalation of a foreign substance, cystic fibrosis, rheumatoid arthritis, SjÖgren syndrome, bronchiolitis obliterans, and neoplastic disease.

CURRENT TREATMENT OPTIONS

Treatment of nontuberculous mycobacterial lung infection, including Lady Windermere syndrome, is not necessary in every case, given the variability in clinical symptoms and in disease progression. Patients with progressive symptoms or radiographic changes should be considered candidates for treatment.

Management is directed at the underlying infection. M avium-intracellulare is ubiquitous in the environment, including in soil and water, and it has been reported as the most common pathogen in nontuberculous mycobacterial lung infection.⁷

Nodular-bronchiectatic nontuberculous mycobacterial lung disease typically progresses more slowly than fibrocavitary disease. For patients with nodular-bronchiectatic disease, follow-up over months or years may be needed before clinical or radiographic changes become apparent.

When treatment is indicated for nodular-bronchiectatic nontuberculous mycobacterial lung infection, it should include a macrolide antibiotic, ethambutol, and rifampin.^7,8 Monotherapy with a macrolide is not recommended because of the risk of macrolide resistance. Addition of an aminoglycoside may be considered when treating fibrocavitary disease or widespread nodular bronchiectatic disease.

Management of bronchiectasis, when present, includes chest physiotherapy, pulmonary hygiene therapy, and awareness of the predisposition for nonmycobacterial lung infection. The decision to prescribe antimicrobials should take into consideration the risks and benefits for each patient.

Because treatment involves multidrug regimens, drug interactions and adverse effects need to be considered and monitored, especially in elderly patients, who may already be taking multiple medications. Treatment should be continued until a patient has negative sputum cultures for acid-fast bacilli while on therapy, for 1 year.

Symptoms compatible with gastroesophageal reflux disease (GERD) are incredibly prevalent. The typical ones are common, and the atypical ones are so often attributed to GERD that they too are extremely common. It seems that few patients in my clinic are not taking a proton pump inhibitor (PPI).

Drs. Alzubaidi and Gabbard, in their review of GERD in this issue, note that up to 40% of people experience symptoms of GERD at least once monthly. Since these symptoms can be intermittent, diagnosis poses a problem when the diagnostic algorithm includes a trial of a PPI. It is sometimes unclear whether PPI therapy relieved the symptoms or whether the symptoms abated for other reasons. I suspect that many patients remain on PPI therapy longer than needed (and often longer than initially intended) because of a false sense of improvement and continued need. When patients are diagnosed on clinical grounds, we need to intermittently reassess the continued need for PPI therapy. The authors discuss and place in reasonable perspective a few of the potential complications of chronic PPI use, but not the effects on absorption of iron, calcium, and micronutrients, or PPI-associated gastric polyposis. These can be clinically significant in some patients.

I believe that some atypical symptoms such as cough and hoarseness are overly attributed to GERD, so that PPI therapy is started, continued, and escalated due to premature closure of the diagnosis. I believe that the diagnosis should be reassessed at least once with observed withdrawal of PPI therapy in patients who did not have a firm physiologic diagnosis. Asking the patient to keep a symptom diary may help.

Lack of a significant response to PPI therapy should cast doubt on the diagnosis of GERD and warrant exploration for an alternative cause of the symptoms (eg, eosinophilic esophagitis, bile reflux, sinus disease, dysmotility). The possibility that the patient was not given an optimal trial of a PPI must also be considered: eg, the dose may have been inadequate, the timing of administration may have been suboptimal (not preprandial), or the patient may have been taking over-the-counter NSAIDs.

GERD is so prevalent in the general population that we must train ourselves to consider the possibility that, even if totally relieved by PPI therapy, the symptoms might be associated with aggravating comorbid conditions such as obstructive sleep apnea, Raynaud phenomenon, drugs that can decrease the tone of the lower esophageal sphincter, or even scleroderma.

Finally, in patients who have had a less-than-total response to full-dose PPI therapy and have had other diagnoses excluded, we shouldn’t forget the value of adding appropriately timed histamine 2 receptor antagonist therapy (and asking the patient about use of medications that can exacerbate symptoms).

Even the diseases we deal with every day sometimes warrant a second look.

Symptoms compatible with gastroesophageal reflux disease (GERD) are incredibly prevalent. The typical ones are common, and the atypical ones are so often attributed to GERD that they too are extremely common. It seems that few patients in my clinic are not taking a proton pump inhibitor (PPI).

Drs. Alzubaidi and Gabbard, in their review of GERD in this issue, note that up to 40% of people experience symptoms of GERD at least once monthly. Since these symptoms can be intermittent, diagnosis poses a problem when the diagnostic algorithm includes a trial of a PPI. It is sometimes unclear whether PPI therapy relieved the symptoms or whether the symptoms abated for other reasons. I suspect that many patients remain on PPI therapy longer than needed (and often longer than initially intended) because of a false sense of improvement and continued need. When patients are diagnosed on clinical grounds, we need to intermittently reassess the continued need for PPI therapy. The authors discuss and place in reasonable perspective a few of the potential complications of chronic PPI use, but not the effects on absorption of iron, calcium, and micronutrients, or PPI-associated gastric polyposis. These can be clinically significant in some patients.

I believe that some atypical symptoms such as cough and hoarseness are overly attributed to GERD, so that PPI therapy is started, continued, and escalated due to premature closure of the diagnosis. I believe that the diagnosis should be reassessed at least once with observed withdrawal of PPI therapy in patients who did not have a firm physiologic diagnosis. Asking the patient to keep a symptom diary may help.

Lack of a significant response to PPI therapy should cast doubt on the diagnosis of GERD and warrant exploration for an alternative cause of the symptoms (eg, eosinophilic esophagitis, bile reflux, sinus disease, dysmotility). The possibility that the patient was not given an optimal trial of a PPI must also be considered: eg, the dose may have been inadequate, the timing of administration may have been suboptimal (not preprandial), or the patient may have been taking over-the-counter NSAIDs.

GERD is so prevalent in the general population that we must train ourselves to consider the possibility that, even if totally relieved by PPI therapy, the symptoms might be associated with aggravating comorbid conditions such as obstructive sleep apnea, Raynaud phenomenon, drugs that can decrease the tone of the lower esophageal sphincter, or even scleroderma.

Finally, in patients who have had a less-than-total response to full-dose PPI therapy and have had other diagnoses excluded, we shouldn’t forget the value of adding appropriately timed histamine 2 receptor antagonist therapy (and asking the patient about use of medications that can exacerbate symptoms).

Even the diseases we deal with every day sometimes warrant a second look.

Symptoms compatible with gastroesophageal reflux disease (GERD) are incredibly prevalent. The typical ones are common, and the atypical ones are so often attributed to GERD that they too are extremely common. It seems that few patients in my clinic are not taking a proton pump inhibitor (PPI).

Drs. Alzubaidi and Gabbard, in their review of GERD in this issue, note that up to 40% of people experience symptoms of GERD at least once monthly. Since these symptoms can be intermittent, diagnosis poses a problem when the diagnostic algorithm includes a trial of a PPI. It is sometimes unclear whether PPI therapy relieved the symptoms or whether the symptoms abated for other reasons. I suspect that many patients remain on PPI therapy longer than needed (and often longer than initially intended) because of a false sense of improvement and continued need. When patients are diagnosed on clinical grounds, we need to intermittently reassess the continued need for PPI therapy. The authors discuss and place in reasonable perspective a few of the potential complications of chronic PPI use, but not the effects on absorption of iron, calcium, and micronutrients, or PPI-associated gastric polyposis. These can be clinically significant in some patients.

I believe that some atypical symptoms such as cough and hoarseness are overly attributed to GERD, so that PPI therapy is started, continued, and escalated due to premature closure of the diagnosis. I believe that the diagnosis should be reassessed at least once with observed withdrawal of PPI therapy in patients who did not have a firm physiologic diagnosis. Asking the patient to keep a symptom diary may help.

Lack of a significant response to PPI therapy should cast doubt on the diagnosis of GERD and warrant exploration for an alternative cause of the symptoms (eg, eosinophilic esophagitis, bile reflux, sinus disease, dysmotility). The possibility that the patient was not given an optimal trial of a PPI must also be considered: eg, the dose may have been inadequate, the timing of administration may have been suboptimal (not preprandial), or the patient may have been taking over-the-counter NSAIDs.

GERD is so prevalent in the general population that we must train ourselves to consider the possibility that, even if totally relieved by PPI therapy, the symptoms might be associated with aggravating comorbid conditions such as obstructive sleep apnea, Raynaud phenomenon, drugs that can decrease the tone of the lower esophageal sphincter, or even scleroderma.

Finally, in patients who have had a less-than-total response to full-dose PPI therapy and have had other diagnoses excluded, we shouldn’t forget the value of adding appropriately timed histamine 2 receptor antagonist therapy (and asking the patient about use of medications that can exacerbate symptoms).

Even the diseases we deal with every day sometimes warrant a second look.

Gastroesophageal reflux disease (GERD) is a chronic and common medical problem, with up to 40% of the population experiencing its symptoms at least once per month.¹ The condition develops when the reflux of stomach contents causes troublesome symptoms or complications.²

GERD symptoms can range from heartburn and regurgitation to cough and hoarseness. While many patients’ symptoms respond to medical treatment, the diagnosis and treatment in those whose symptoms do not respond to a proton pump inhibitor (PPI) may be challenging.

This article reviews the diagnosis and treatment options for GERD.

SYMPTOMS: TYPICAL, ATYPICAL, AND ALARM

Symptoms of GERD (Table 1) can be classified as typical (heartburn and regurgitation) or atypical (cough, asthma, hoarseness, chronic laryngitis, throat-clearing, chest pain, dyspepsia, and nausea). Atypical symptoms are more likely to be due to GERD if patients also have typical symptoms and if the symptoms respond to a trial of a PPI.³

Alarm symptoms. Keep in mind that extraesophageal presentations may be multifactorial, and it may be difficult to establish that reflux, even if present, is actually the cause. While chest pain may be due to GERD, it is important to rule out cardiac chest pain before considering GERD as a cause. Similarly, dysphagia along with typical or atypical symptoms warrants investigation for potential complications such as underlying motility disorder, esophageal stricture, esophageal ring, or malignancy.⁴ Other alarm symptoms include odynophagia, bleeding, weight loss, and anemia.

DIAGNOSING GERD: RESPONSE TO A PPI IS DIAGNOSTIC

Patients with typical symptoms that respond to PPI therapy need no further evaluation for a diagnosis of GERD to be made.⁵ On the other hand, further testing should be undertaken in patients with typical symptoms that do not respond to PPI therapy, in patients presenting with atypical symptoms, and in patients in whom antireflux surgery is being considered. Figure 1 shows our proposed algorithm.

Try a PPI for 6–8 weeks

Relief of heartburn and regurgitation after a 6- to 8-week course of a PPI strongly suggests GERD.⁶ However, a negative trial of a PPI does not rule out GERD, as this approach has been found to have a sensitivity of 78% and specificity of 54%.⁶

Despite this limitation, a trial of PPI therapy should be offered to patients presenting with typical symptoms and no alarm features. This approach has been found to be more cost-effective than proceeding directly to diagnostic testing.⁷

Endoscopy

Endoscopic findings in GERD can include erosive esophagitis, peptic stricture, and Barrett esophagus. Esophageal erosions are a highly specific sign of GERD; the Los Angeles classification system, a standardized scale for grading the severity of erosive esophagitis (from A to D, with D the most severe) provides an objective way to assess severity.⁸ However, most patients with heartburn and regurgitation do not have erosive disease, thus limiting the sensitivity of upper endoscopy as an initial diagnostic test in patients with suspected GERD.⁹

We recommend endoscopy for patients who present with alarm symptoms, patients with noncardiac chest pain, PPI nonresponders, and patients with chronic GERD symptoms and multiple risk factors for Barrett esophagus besides GERD, such as older age, male sex, white race, overweight, and smoking.¹⁰

Ambulatory pH and impedance monitoring

Ambulatory pH monitoring is the gold standard test for pathologic acid exposure in the esophagus. pH testing is indicated in PPI nonresponders, patients presenting with atypical symptoms, and before antireflux surgery.

In general, pH testing should be performed after the patient has been off PPI therapy for at least 7 days, as the test is highly unlikely to be abnormal while a patient is on a PPI.¹¹ It is done either with a transnasal catheter for 24 hours, or with a wireless capsule (Bravo pH System, Given Imaging Ltd, Duluth, GA), which collects 48 to 96 hours of data. Studies of the wireless system have shown that its sensitivity increases 12% to 25% when it is performed for 48 hours compared with 24 hours.^12,13

The pH test can be combined with impedance testing to evaluate for nonacid reflux.¹⁴ However, the clinical significance of nonacid reflux remains controversial, and for this reason the Esophageal Diagnostic Advisory Panel recommends that the decision to perform antireflux surgery should not be based on abnormal impedance testing.¹⁵

Ambulatory pH monitoring is the gold-standard test

During pH and impedance testing, special software can calculate how closely the patient’s symptoms correlate with esophageal acid exposure. The symptom index (SI) and symptom association probability (SAP) are the symptom measurements most commonly used in practice. The SI measures the overall strength of the relationship, and an SI greater than 50% is considered positive.¹⁶ The SAP determines whether this relationship could have occurred by chance, and an SAP greater than 95% is statistically significant.¹⁷ In patients with normal levels of esophageal acid exposure, an elevated SI or SAP may indicate a component of esophageal hypersensitivity in symptom generation.

At our institution, we generally perform pH-only transnasal or wireless testing off PPI therapy to establish that the patient has pathologic acid exposure in the distal esophagus. Combined pH-impedance testing is typically reserved for patients with atypical symptoms unresponsive to PPI therapy and abnormal results on previous pH testing, which allows for correlation of nonacid reflux and symptoms.

Other tests

Esophageal manometry and barium esophagography have limited value in the primary diagnosis of GERD. However, they should be considered to rule out achalasia and other esophageal motility disorders in patients whose symptoms do not respond to PPIs. For this reason, esophageal manometry should be performed before considering antireflux surgery.

MANAGING GERD

Table 2 summarizes the various treatments for GERD.

Lifestyle modifications

Lifestyle modifications are the first-line therapy for GERD. Modifications that have been studied include weight loss, head-of-bed elevation, and avoidance of tobacco, alcohol, and late-night meals. Another modification that has been suggested is avoiding foods that can aggravate reflux symptoms—eg, caffeine, coffee, chocolate, spicy foods, highly acidic foods (oranges, tomatoes), and fatty foods. Of these, only weight loss and head-of-bed elevation have been proven effective.¹⁸

Three randomized controlled trials demonstrated that GERD symptoms and esophageal pH values improved with head-of-bed elevation using blocks or incline foam wedges.^19–21 Several cohort studies demonstrated reduction in GERD symptoms with weight loss.^22,23 Recently, a prospective cohort study also found that smoking cessation significantly improved GERD symptoms in patients with normal body mass index and severe symptoms.²⁴

Antacids

Several antacids (eg, sodium bicarbonate, calcium carbonate, magnesium hydroxide, aluminum hydroxide) are available over the counter.

Antacids were thought to control heartburn symptoms by increasing the pH of gastric contents that might subsequently reflux into the esophagus. However, well-controlled studies have shown that they relieve heartburn by neutralizing acid in the esophagus, with no significant effect on gastric pH.^25,26

Antacids provide rapid but short-lived relief from an existing episode of heartburn. Because they do not significantly raise the gastric pH, they do not prevent subsequent reflux episodes from repeatedly exposing the esophagus to gastric acid and causing heartburn. Additionally, antacids have not been shown to contribute to healing of erosive esophagitis.²⁷ Hence, they may not be optimal for treating frequent reflux heartburn.

Sodium alginate

Gastric acid pockets are unbuffered pools of acid that float on top of ingested food.²⁸ They develop as a result of poor mixing of newly secreted acid and food in the proximal stomach, which remains relatively quiescent after a meal compared with the distal stomach.²⁹ In GERD, proximal extension of the acid pocket above the diaphragm increases the risk of acid reflux.³⁰ The acid pocket is therefore an important source of postprandial acid in GERD and, as such, represents a unique therapeutic target.

Emerging evidence suggests that alginates may act directly on the acid pocket. Alginates are natural polysaccharide polymers that, on contact with gastric acid, precipitate within minutes into a low-density viscous gel of near-neutral pH. The change in pH triggers the sodium bicarbonate in the formulation to release carbon dioxide that becomes trapped in the alginate gel, causing it to float to the top of the gastric contents like a raft.³¹

A randomized controlled trial demonstrated that sodium alginate was as effective as omeprazole in relieving symptoms in patients with nonerosive reflux disease.³² Alginate has also been shown to provide more postprandial reflux relief than antacids.³³

Histamine-2 receptor antagonists

Histamine-2 receptor antagonists act more swiftly and increase postprandial gastric pH more rapidly than PPIs, thus making them a good option for prophylaxis against postprandial GERD.³⁴ Taking these drugs at bedtime may help in patients with objective nighttime reflux despite optimal PPI use. However, tachyphylaxis may occur as early as 1 week after starting combination therapy.³⁵

Proton pump inhibitors

There are currently seven available PPIs, including four that can be obtained over the counter (omeprazole, lansoprazole, esomeprazole, and omeprazole-sodium bicarbonate) and three available only by prescription (rabeprazole, pantoprazole, and dexlansoprazole). Studies have shown than a standard 6- to 8-week course of a PPI provides complete symptom relief in 70% to 80% of patients with erosive reflux disease and in 60% of patients with nonerosive reflux disease.^36,37 Clinically, PPIs all appear to be similar in their symptom relief.³⁸

Most PPIs should be taken 30 to 60 minutes before meals. Exceptions are omeprazole-sodium bicarbonate and dexlansoprazole, which can be taken without regard to meals. At our institution, we usually start PPIs in a once-daily standard dose for 6 to 8 weeks and consider increasing to twice-daily dosing if symptoms do not respond completely. Patients with mild intermittent GERD symptoms may benefit from “on-demand” use of PPIs. This approach is best suited for patients with nonerosive reflux disease without evidence of Barrett esophagus on endoscopy.

Safety and adverse effects of PPIs

PPIs are generally safe but can cause adverse effects (Table 3).

Osteoporosis. In 2010, the US Food and Drug Administration issued warnings regarding the potential for wrist, hip, and spine fractures in PPI users.²⁶ Most recent evidence suggests that PPIs may be associated with a small increase in risk of hip fractures in patients already at high risk.^39,40 However, the 2013 American College of Gastroenterology (ACG) guidelines say that patients with known osteoporosis can remain on PPI therapy, and concern for hip fractures and osteoporosis should not affect the decision to use PPIs long-term except in patients with other risk factors for hip fracture.⁴¹

Community-acquired pneumonia. An increased risk of community-acquired pneumonia cannot be clearly documented in association with PPI therapy. Multiple studies, including randomized controlled trials, investigated this potential correlation. However, evidence suggests that short-term but not long-term PPI use may be associated with an overall increased risk of community-acquired pneumonia.^42,43 Current guidelines suggest that in patients who need a PPI, the drug should not be withheld on the basis of a potential risk of community-acquired pneumonia.⁴¹

Clostridium difficile infection. In theory, PPIs may increase the risk of C difficile infection by increasing the ability of the spore to convert to the vegetative form and to survive intraluminally. In fact, studies and meta-analyses have suggested that PPIs do increase the risk of development and recurrence of C difficile infection.^44,45 Therefore, PPIs should be used with care in patients who are at risk.⁴¹

Interaction with clopidogrel. The antiplatelet activity of clopidogrel requires activation by CYP2C19, the same pathway required for metabolism of some PPIs. Concern was raised about decreased antiplatelet activity of clopidogrel in the presence of PPIs. This was extensively studied, and there now appears to be no increased risk of adverse cardiovascular events in patients on PPIs, based on data from well-controlled randomized trials.^46,47 A consensus panel of the American College of Cardiology Foundation, the American Heart Association, and the ACG said that PPIs may be used for appropriate indications in patients taking clopidogrel.⁴⁷

Hypomagnesemia. By an unknown molecular mechanism, PPIs are thought to reduce intestinal magnesium absorption, leading to hypomagnesemia. A meta-analysis published in 2011 showed that PPI-induced hypomagnesemia is a drug-class effect and occurred after a median of 5.5 years of PPI use. Stopping the PPI resulted in magnesium recovery in 4 days, and rechallenge led to recurrence within 4 days.⁴⁸

Hence, to avoid putting patients on long-term PPI therapy at risk, clinicians should anticipate this problem. Our practice is to check the magnesium level before starting a patient on long-term PPI therapy, and then to repeat the measurement every 1 to 2 years.

Baclofen

Transient lower esophageal sphincter relaxation has been shown to be a cause of reflux in healthy people and in patients with GERD.⁴⁹

Baclofen, a muscle relaxant with selective gamma-aminobutyric acid receptor class B agonist properties, reduces transient lower esophageal sphincter relaxation in humans.⁵⁰ In a well-designed, double-blind, randomized controlled trial, baclofen was associated with a significant decrease in upright reflux on 24-hour pH monitoring and significant improvement in belching and overall reflux symptoms.⁵¹ However, baclofen is not approved by the US Food and Drug Administration for the treatment of GERD, and its use may be limited by side effects such as somnolence and dizziness.

Antireflux surgery

Antireflux surgery is a reasonable option for selected patients with chronic GERD. The main types of surgery are laparoscopic fundoplication and, for obese patients, gastric bypass. Reasons to consider antireflux surgery include desire to stop PPI therapy, esophagitis not healed by PPIs, symptomatic hiatal hernia, and refractory reflux documented by pH testing.⁴¹

Clinically, all PPIs appear to be similar in their symptom relief

In general, surgical therapy may be considered in patients who respond to PPIs, but patients who do not respond to PPIs are less likely to respond to antireflux surgery.¹⁵ Other patients less likely to respond are those with symptoms of dyspepsia, such as nausea, vomiting, and epigastric pain.⁴¹

Common adverse effects of antireflux surgery include gas-bloat syndrome (up to 85% of patients), dysphagia (10% to 50% of patients), diarrhea (18% to 33% of patients), and recurrent heartburn (10% to 62% of patients).⁵²

Endoscopic and minimally invasive antireflux procedures include endoscopic plication of the lower esophageal sphincter, radiofrequency augmentation of the lower esophageal sphincter, and sphincter augmentation by a string of titanium beads. While some have shown promise, they are not recommended by the most recent ACG guidelines, given lack of long-term data.⁴¹

REFRACTORY GERD

There is no consensus on the definition of refractory GERD. However, for the sake of simplicity, we can define it as persistence of suspected GERD symptoms despite treatment with a PPI. This may vary from a partial response to PPI therapy to a complete absence of response.

It is extremely important to rule out non-GERD causes of the ongoing symptoms, such as achalasia, gastroparesis, eosinophilic esophagitis, rumination, and aerophagia. PPI nonresponders are more likely to be obese, poorly compliant, and have extraesophageal symptoms.^53–56 As previously discussed, PPIs should be taken 30 to 60 minutes before meals. For patients whose symptoms fail to respond to standard-dose daily PPI therapy, switching to another PPI or doubling the dose is common, although data to support this practice are limited. Of note, omeprazole-sodium bicarbonate has been shown to provide more symptom relief in nocturnal GERD.⁵⁷ Additionally, adding a nighttime histamine-2 receptor antagonist may also help in patients with objective nighttime reflux.⁴¹

After noncompliance and suboptimal PPI dosing have been ruled out, PPI nonresponders with typical symptoms should undergo upper endoscopy and subsequent pH monitoring. Normal esophageal acid exposure on pH testing suggests functional heartburn or functional dyspepsia. Negative pH testing in a patient with atypical symptoms suggests a non-GERD cause of symptoms, and referral to an otolaryngologist, pulmonologist, or allergist is often warranted.

While antireflux surgery can be considered for patients with nonacid reflux on impedance testing, it should again be noted that GERD in patients with no response to PPIs is less likely to respond to antireflux surgery.¹⁵

TAKE-HOME POINTS

• GERD is a common medical condition, affecting up to 40% of US adults at least once monthly.
• GERD can result in a wide variety of symptoms, including typical heartburn and regurgitation as well as atypical symptoms such as cough.
• On the other hand, keep in mind that multiple non-GERD causes of heartburn and regurgitation may exist.
• Testing for GERD includes endoscopy and pH testing as well as functional testing such as esophageal manometry.
• While in most patients GERD will respond to lifestyle changes and antisecretory therapy such as a PPI, careful attention must be given to patients with symptoms refractory to PPI therapy.
• For a subset of patients, antireflux surgery may be a reasonable option, but care must be taken to exclude patients with a lower likelihood of responding to surgery.

Gastroesophageal reflux disease (GERD) is a chronic and common medical problem, with up to 40% of the population experiencing its symptoms at least once per month.¹ The condition develops when the reflux of stomach contents causes troublesome symptoms or complications.²

GERD symptoms can range from heartburn and regurgitation to cough and hoarseness. While many patients’ symptoms respond to medical treatment, the diagnosis and treatment in those whose symptoms do not respond to a proton pump inhibitor (PPI) may be challenging.

This article reviews the diagnosis and treatment options for GERD.

SYMPTOMS: TYPICAL, ATYPICAL, AND ALARM

Symptoms of GERD (Table 1) can be classified as typical (heartburn and regurgitation) or atypical (cough, asthma, hoarseness, chronic laryngitis, throat-clearing, chest pain, dyspepsia, and nausea). Atypical symptoms are more likely to be due to GERD if patients also have typical symptoms and if the symptoms respond to a trial of a PPI.³

Alarm symptoms. Keep in mind that extraesophageal presentations may be multifactorial, and it may be difficult to establish that reflux, even if present, is actually the cause. While chest pain may be due to GERD, it is important to rule out cardiac chest pain before considering GERD as a cause. Similarly, dysphagia along with typical or atypical symptoms warrants investigation for potential complications such as underlying motility disorder, esophageal stricture, esophageal ring, or malignancy.⁴ Other alarm symptoms include odynophagia, bleeding, weight loss, and anemia.

DIAGNOSING GERD: RESPONSE TO A PPI IS DIAGNOSTIC

Patients with typical symptoms that respond to PPI therapy need no further evaluation for a diagnosis of GERD to be made.⁵ On the other hand, further testing should be undertaken in patients with typical symptoms that do not respond to PPI therapy, in patients presenting with atypical symptoms, and in patients in whom antireflux surgery is being considered. Figure 1 shows our proposed algorithm.

Try a PPI for 6–8 weeks

Relief of heartburn and regurgitation after a 6- to 8-week course of a PPI strongly suggests GERD.⁶ However, a negative trial of a PPI does not rule out GERD, as this approach has been found to have a sensitivity of 78% and specificity of 54%.⁶

Despite this limitation, a trial of PPI therapy should be offered to patients presenting with typical symptoms and no alarm features. This approach has been found to be more cost-effective than proceeding directly to diagnostic testing.⁷

Endoscopy

Endoscopic findings in GERD can include erosive esophagitis, peptic stricture, and Barrett esophagus. Esophageal erosions are a highly specific sign of GERD; the Los Angeles classification system, a standardized scale for grading the severity of erosive esophagitis (from A to D, with D the most severe) provides an objective way to assess severity.⁸ However, most patients with heartburn and regurgitation do not have erosive disease, thus limiting the sensitivity of upper endoscopy as an initial diagnostic test in patients with suspected GERD.⁹

We recommend endoscopy for patients who present with alarm symptoms, patients with noncardiac chest pain, PPI nonresponders, and patients with chronic GERD symptoms and multiple risk factors for Barrett esophagus besides GERD, such as older age, male sex, white race, overweight, and smoking.¹⁰

Ambulatory pH and impedance monitoring

Ambulatory pH monitoring is the gold standard test for pathologic acid exposure in the esophagus. pH testing is indicated in PPI nonresponders, patients presenting with atypical symptoms, and before antireflux surgery.

In general, pH testing should be performed after the patient has been off PPI therapy for at least 7 days, as the test is highly unlikely to be abnormal while a patient is on a PPI.¹¹ It is done either with a transnasal catheter for 24 hours, or with a wireless capsule (Bravo pH System, Given Imaging Ltd, Duluth, GA), which collects 48 to 96 hours of data. Studies of the wireless system have shown that its sensitivity increases 12% to 25% when it is performed for 48 hours compared with 24 hours.^12,13

The pH test can be combined with impedance testing to evaluate for nonacid reflux.¹⁴ However, the clinical significance of nonacid reflux remains controversial, and for this reason the Esophageal Diagnostic Advisory Panel recommends that the decision to perform antireflux surgery should not be based on abnormal impedance testing.¹⁵

Ambulatory pH monitoring is the gold-standard test

During pH and impedance testing, special software can calculate how closely the patient’s symptoms correlate with esophageal acid exposure. The symptom index (SI) and symptom association probability (SAP) are the symptom measurements most commonly used in practice. The SI measures the overall strength of the relationship, and an SI greater than 50% is considered positive.¹⁶ The SAP determines whether this relationship could have occurred by chance, and an SAP greater than 95% is statistically significant.¹⁷ In patients with normal levels of esophageal acid exposure, an elevated SI or SAP may indicate a component of esophageal hypersensitivity in symptom generation.

At our institution, we generally perform pH-only transnasal or wireless testing off PPI therapy to establish that the patient has pathologic acid exposure in the distal esophagus. Combined pH-impedance testing is typically reserved for patients with atypical symptoms unresponsive to PPI therapy and abnormal results on previous pH testing, which allows for correlation of nonacid reflux and symptoms.

Other tests

Esophageal manometry and barium esophagography have limited value in the primary diagnosis of GERD. However, they should be considered to rule out achalasia and other esophageal motility disorders in patients whose symptoms do not respond to PPIs. For this reason, esophageal manometry should be performed before considering antireflux surgery.

MANAGING GERD

Table 2 summarizes the various treatments for GERD.

Lifestyle modifications

Lifestyle modifications are the first-line therapy for GERD. Modifications that have been studied include weight loss, head-of-bed elevation, and avoidance of tobacco, alcohol, and late-night meals. Another modification that has been suggested is avoiding foods that can aggravate reflux symptoms—eg, caffeine, coffee, chocolate, spicy foods, highly acidic foods (oranges, tomatoes), and fatty foods. Of these, only weight loss and head-of-bed elevation have been proven effective.¹⁸

Three randomized controlled trials demonstrated that GERD symptoms and esophageal pH values improved with head-of-bed elevation using blocks or incline foam wedges.^19–21 Several cohort studies demonstrated reduction in GERD symptoms with weight loss.^22,23 Recently, a prospective cohort study also found that smoking cessation significantly improved GERD symptoms in patients with normal body mass index and severe symptoms.²⁴

Antacids

Several antacids (eg, sodium bicarbonate, calcium carbonate, magnesium hydroxide, aluminum hydroxide) are available over the counter.

Antacids were thought to control heartburn symptoms by increasing the pH of gastric contents that might subsequently reflux into the esophagus. However, well-controlled studies have shown that they relieve heartburn by neutralizing acid in the esophagus, with no significant effect on gastric pH.^25,26

Antacids provide rapid but short-lived relief from an existing episode of heartburn. Because they do not significantly raise the gastric pH, they do not prevent subsequent reflux episodes from repeatedly exposing the esophagus to gastric acid and causing heartburn. Additionally, antacids have not been shown to contribute to healing of erosive esophagitis.²⁷ Hence, they may not be optimal for treating frequent reflux heartburn.

Sodium alginate

Gastric acid pockets are unbuffered pools of acid that float on top of ingested food.²⁸ They develop as a result of poor mixing of newly secreted acid and food in the proximal stomach, which remains relatively quiescent after a meal compared with the distal stomach.²⁹ In GERD, proximal extension of the acid pocket above the diaphragm increases the risk of acid reflux.³⁰ The acid pocket is therefore an important source of postprandial acid in GERD and, as such, represents a unique therapeutic target.

Emerging evidence suggests that alginates may act directly on the acid pocket. Alginates are natural polysaccharide polymers that, on contact with gastric acid, precipitate within minutes into a low-density viscous gel of near-neutral pH. The change in pH triggers the sodium bicarbonate in the formulation to release carbon dioxide that becomes trapped in the alginate gel, causing it to float to the top of the gastric contents like a raft.³¹

A randomized controlled trial demonstrated that sodium alginate was as effective as omeprazole in relieving symptoms in patients with nonerosive reflux disease.³² Alginate has also been shown to provide more postprandial reflux relief than antacids.³³

Histamine-2 receptor antagonists

Histamine-2 receptor antagonists act more swiftly and increase postprandial gastric pH more rapidly than PPIs, thus making them a good option for prophylaxis against postprandial GERD.³⁴ Taking these drugs at bedtime may help in patients with objective nighttime reflux despite optimal PPI use. However, tachyphylaxis may occur as early as 1 week after starting combination therapy.³⁵

Proton pump inhibitors

There are currently seven available PPIs, including four that can be obtained over the counter (omeprazole, lansoprazole, esomeprazole, and omeprazole-sodium bicarbonate) and three available only by prescription (rabeprazole, pantoprazole, and dexlansoprazole). Studies have shown than a standard 6- to 8-week course of a PPI provides complete symptom relief in 70% to 80% of patients with erosive reflux disease and in 60% of patients with nonerosive reflux disease.^36,37 Clinically, PPIs all appear to be similar in their symptom relief.³⁸

Most PPIs should be taken 30 to 60 minutes before meals. Exceptions are omeprazole-sodium bicarbonate and dexlansoprazole, which can be taken without regard to meals. At our institution, we usually start PPIs in a once-daily standard dose for 6 to 8 weeks and consider increasing to twice-daily dosing if symptoms do not respond completely. Patients with mild intermittent GERD symptoms may benefit from “on-demand” use of PPIs. This approach is best suited for patients with nonerosive reflux disease without evidence of Barrett esophagus on endoscopy.

Safety and adverse effects of PPIs

PPIs are generally safe but can cause adverse effects (Table 3).

Osteoporosis. In 2010, the US Food and Drug Administration issued warnings regarding the potential for wrist, hip, and spine fractures in PPI users.²⁶ Most recent evidence suggests that PPIs may be associated with a small increase in risk of hip fractures in patients already at high risk.^39,40 However, the 2013 American College of Gastroenterology (ACG) guidelines say that patients with known osteoporosis can remain on PPI therapy, and concern for hip fractures and osteoporosis should not affect the decision to use PPIs long-term except in patients with other risk factors for hip fracture.⁴¹

Community-acquired pneumonia. An increased risk of community-acquired pneumonia cannot be clearly documented in association with PPI therapy. Multiple studies, including randomized controlled trials, investigated this potential correlation. However, evidence suggests that short-term but not long-term PPI use may be associated with an overall increased risk of community-acquired pneumonia.^42,43 Current guidelines suggest that in patients who need a PPI, the drug should not be withheld on the basis of a potential risk of community-acquired pneumonia.⁴¹

Clostridium difficile infection. In theory, PPIs may increase the risk of C difficile infection by increasing the ability of the spore to convert to the vegetative form and to survive intraluminally. In fact, studies and meta-analyses have suggested that PPIs do increase the risk of development and recurrence of C difficile infection.^44,45 Therefore, PPIs should be used with care in patients who are at risk.⁴¹

Interaction with clopidogrel. The antiplatelet activity of clopidogrel requires activation by CYP2C19, the same pathway required for metabolism of some PPIs. Concern was raised about decreased antiplatelet activity of clopidogrel in the presence of PPIs. This was extensively studied, and there now appears to be no increased risk of adverse cardiovascular events in patients on PPIs, based on data from well-controlled randomized trials.^46,47 A consensus panel of the American College of Cardiology Foundation, the American Heart Association, and the ACG said that PPIs may be used for appropriate indications in patients taking clopidogrel.⁴⁷

Hypomagnesemia. By an unknown molecular mechanism, PPIs are thought to reduce intestinal magnesium absorption, leading to hypomagnesemia. A meta-analysis published in 2011 showed that PPI-induced hypomagnesemia is a drug-class effect and occurred after a median of 5.5 years of PPI use. Stopping the PPI resulted in magnesium recovery in 4 days, and rechallenge led to recurrence within 4 days.⁴⁸

Hence, to avoid putting patients on long-term PPI therapy at risk, clinicians should anticipate this problem. Our practice is to check the magnesium level before starting a patient on long-term PPI therapy, and then to repeat the measurement every 1 to 2 years.

Baclofen

Transient lower esophageal sphincter relaxation has been shown to be a cause of reflux in healthy people and in patients with GERD.⁴⁹

Baclofen, a muscle relaxant with selective gamma-aminobutyric acid receptor class B agonist properties, reduces transient lower esophageal sphincter relaxation in humans.⁵⁰ In a well-designed, double-blind, randomized controlled trial, baclofen was associated with a significant decrease in upright reflux on 24-hour pH monitoring and significant improvement in belching and overall reflux symptoms.⁵¹ However, baclofen is not approved by the US Food and Drug Administration for the treatment of GERD, and its use may be limited by side effects such as somnolence and dizziness.

Antireflux surgery

Antireflux surgery is a reasonable option for selected patients with chronic GERD. The main types of surgery are laparoscopic fundoplication and, for obese patients, gastric bypass. Reasons to consider antireflux surgery include desire to stop PPI therapy, esophagitis not healed by PPIs, symptomatic hiatal hernia, and refractory reflux documented by pH testing.⁴¹

Clinically, all PPIs appear to be similar in their symptom relief

In general, surgical therapy may be considered in patients who respond to PPIs, but patients who do not respond to PPIs are less likely to respond to antireflux surgery.¹⁵ Other patients less likely to respond are those with symptoms of dyspepsia, such as nausea, vomiting, and epigastric pain.⁴¹

Common adverse effects of antireflux surgery include gas-bloat syndrome (up to 85% of patients), dysphagia (10% to 50% of patients), diarrhea (18% to 33% of patients), and recurrent heartburn (10% to 62% of patients).⁵²

Endoscopic and minimally invasive antireflux procedures include endoscopic plication of the lower esophageal sphincter, radiofrequency augmentation of the lower esophageal sphincter, and sphincter augmentation by a string of titanium beads. While some have shown promise, they are not recommended by the most recent ACG guidelines, given lack of long-term data.⁴¹

REFRACTORY GERD

There is no consensus on the definition of refractory GERD. However, for the sake of simplicity, we can define it as persistence of suspected GERD symptoms despite treatment with a PPI. This may vary from a partial response to PPI therapy to a complete absence of response.

It is extremely important to rule out non-GERD causes of the ongoing symptoms, such as achalasia, gastroparesis, eosinophilic esophagitis, rumination, and aerophagia. PPI nonresponders are more likely to be obese, poorly compliant, and have extraesophageal symptoms.^53–56 As previously discussed, PPIs should be taken 30 to 60 minutes before meals. For patients whose symptoms fail to respond to standard-dose daily PPI therapy, switching to another PPI or doubling the dose is common, although data to support this practice are limited. Of note, omeprazole-sodium bicarbonate has been shown to provide more symptom relief in nocturnal GERD.⁵⁷ Additionally, adding a nighttime histamine-2 receptor antagonist may also help in patients with objective nighttime reflux.⁴¹

After noncompliance and suboptimal PPI dosing have been ruled out, PPI nonresponders with typical symptoms should undergo upper endoscopy and subsequent pH monitoring. Normal esophageal acid exposure on pH testing suggests functional heartburn or functional dyspepsia. Negative pH testing in a patient with atypical symptoms suggests a non-GERD cause of symptoms, and referral to an otolaryngologist, pulmonologist, or allergist is often warranted.

While antireflux surgery can be considered for patients with nonacid reflux on impedance testing, it should again be noted that GERD in patients with no response to PPIs is less likely to respond to antireflux surgery.¹⁵

TAKE-HOME POINTS

• GERD is a common medical condition, affecting up to 40% of US adults at least once monthly.
• GERD can result in a wide variety of symptoms, including typical heartburn and regurgitation as well as atypical symptoms such as cough.
• On the other hand, keep in mind that multiple non-GERD causes of heartburn and regurgitation may exist.
• Testing for GERD includes endoscopy and pH testing as well as functional testing such as esophageal manometry.
• While in most patients GERD will respond to lifestyle changes and antisecretory therapy such as a PPI, careful attention must be given to patients with symptoms refractory to PPI therapy.
• For a subset of patients, antireflux surgery may be a reasonable option, but care must be taken to exclude patients with a lower likelihood of responding to surgery.

Gastroesophageal reflux disease (GERD) is a chronic and common medical problem, with up to 40% of the population experiencing its symptoms at least once per month.¹ The condition develops when the reflux of stomach contents causes troublesome symptoms or complications.²

GERD symptoms can range from heartburn and regurgitation to cough and hoarseness. While many patients’ symptoms respond to medical treatment, the diagnosis and treatment in those whose symptoms do not respond to a proton pump inhibitor (PPI) may be challenging.

This article reviews the diagnosis and treatment options for GERD.

SYMPTOMS: TYPICAL, ATYPICAL, AND ALARM

Symptoms of GERD (Table 1) can be classified as typical (heartburn and regurgitation) or atypical (cough, asthma, hoarseness, chronic laryngitis, throat-clearing, chest pain, dyspepsia, and nausea). Atypical symptoms are more likely to be due to GERD if patients also have typical symptoms and if the symptoms respond to a trial of a PPI.³

Alarm symptoms. Keep in mind that extraesophageal presentations may be multifactorial, and it may be difficult to establish that reflux, even if present, is actually the cause. While chest pain may be due to GERD, it is important to rule out cardiac chest pain before considering GERD as a cause. Similarly, dysphagia along with typical or atypical symptoms warrants investigation for potential complications such as underlying motility disorder, esophageal stricture, esophageal ring, or malignancy.⁴ Other alarm symptoms include odynophagia, bleeding, weight loss, and anemia.

DIAGNOSING GERD: RESPONSE TO A PPI IS DIAGNOSTIC

Patients with typical symptoms that respond to PPI therapy need no further evaluation for a diagnosis of GERD to be made.⁵ On the other hand, further testing should be undertaken in patients with typical symptoms that do not respond to PPI therapy, in patients presenting with atypical symptoms, and in patients in whom antireflux surgery is being considered. Figure 1 shows our proposed algorithm.

Try a PPI for 6–8 weeks

Relief of heartburn and regurgitation after a 6- to 8-week course of a PPI strongly suggests GERD.⁶ However, a negative trial of a PPI does not rule out GERD, as this approach has been found to have a sensitivity of 78% and specificity of 54%.⁶

Despite this limitation, a trial of PPI therapy should be offered to patients presenting with typical symptoms and no alarm features. This approach has been found to be more cost-effective than proceeding directly to diagnostic testing.⁷

Endoscopy

Endoscopic findings in GERD can include erosive esophagitis, peptic stricture, and Barrett esophagus. Esophageal erosions are a highly specific sign of GERD; the Los Angeles classification system, a standardized scale for grading the severity of erosive esophagitis (from A to D, with D the most severe) provides an objective way to assess severity.⁸ However, most patients with heartburn and regurgitation do not have erosive disease, thus limiting the sensitivity of upper endoscopy as an initial diagnostic test in patients with suspected GERD.⁹

We recommend endoscopy for patients who present with alarm symptoms, patients with noncardiac chest pain, PPI nonresponders, and patients with chronic GERD symptoms and multiple risk factors for Barrett esophagus besides GERD, such as older age, male sex, white race, overweight, and smoking.¹⁰

Ambulatory pH and impedance monitoring

Ambulatory pH monitoring is the gold standard test for pathologic acid exposure in the esophagus. pH testing is indicated in PPI nonresponders, patients presenting with atypical symptoms, and before antireflux surgery.

In general, pH testing should be performed after the patient has been off PPI therapy for at least 7 days, as the test is highly unlikely to be abnormal while a patient is on a PPI.¹¹ It is done either with a transnasal catheter for 24 hours, or with a wireless capsule (Bravo pH System, Given Imaging Ltd, Duluth, GA), which collects 48 to 96 hours of data. Studies of the wireless system have shown that its sensitivity increases 12% to 25% when it is performed for 48 hours compared with 24 hours.^12,13

The pH test can be combined with impedance testing to evaluate for nonacid reflux.¹⁴ However, the clinical significance of nonacid reflux remains controversial, and for this reason the Esophageal Diagnostic Advisory Panel recommends that the decision to perform antireflux surgery should not be based on abnormal impedance testing.¹⁵

Ambulatory pH monitoring is the gold-standard test

During pH and impedance testing, special software can calculate how closely the patient’s symptoms correlate with esophageal acid exposure. The symptom index (SI) and symptom association probability (SAP) are the symptom measurements most commonly used in practice. The SI measures the overall strength of the relationship, and an SI greater than 50% is considered positive.¹⁶ The SAP determines whether this relationship could have occurred by chance, and an SAP greater than 95% is statistically significant.¹⁷ In patients with normal levels of esophageal acid exposure, an elevated SI or SAP may indicate a component of esophageal hypersensitivity in symptom generation.

At our institution, we generally perform pH-only transnasal or wireless testing off PPI therapy to establish that the patient has pathologic acid exposure in the distal esophagus. Combined pH-impedance testing is typically reserved for patients with atypical symptoms unresponsive to PPI therapy and abnormal results on previous pH testing, which allows for correlation of nonacid reflux and symptoms.

Other tests

Esophageal manometry and barium esophagography have limited value in the primary diagnosis of GERD. However, they should be considered to rule out achalasia and other esophageal motility disorders in patients whose symptoms do not respond to PPIs. For this reason, esophageal manometry should be performed before considering antireflux surgery.

MANAGING GERD

Table 2 summarizes the various treatments for GERD.

Lifestyle modifications

Lifestyle modifications are the first-line therapy for GERD. Modifications that have been studied include weight loss, head-of-bed elevation, and avoidance of tobacco, alcohol, and late-night meals. Another modification that has been suggested is avoiding foods that can aggravate reflux symptoms—eg, caffeine, coffee, chocolate, spicy foods, highly acidic foods (oranges, tomatoes), and fatty foods. Of these, only weight loss and head-of-bed elevation have been proven effective.¹⁸

Three randomized controlled trials demonstrated that GERD symptoms and esophageal pH values improved with head-of-bed elevation using blocks or incline foam wedges.^19–21 Several cohort studies demonstrated reduction in GERD symptoms with weight loss.^22,23 Recently, a prospective cohort study also found that smoking cessation significantly improved GERD symptoms in patients with normal body mass index and severe symptoms.²⁴

Antacids

Several antacids (eg, sodium bicarbonate, calcium carbonate, magnesium hydroxide, aluminum hydroxide) are available over the counter.

Antacids were thought to control heartburn symptoms by increasing the pH of gastric contents that might subsequently reflux into the esophagus. However, well-controlled studies have shown that they relieve heartburn by neutralizing acid in the esophagus, with no significant effect on gastric pH.^25,26

Antacids provide rapid but short-lived relief from an existing episode of heartburn. Because they do not significantly raise the gastric pH, they do not prevent subsequent reflux episodes from repeatedly exposing the esophagus to gastric acid and causing heartburn. Additionally, antacids have not been shown to contribute to healing of erosive esophagitis.²⁷ Hence, they may not be optimal for treating frequent reflux heartburn.

Sodium alginate

Gastric acid pockets are unbuffered pools of acid that float on top of ingested food.²⁸ They develop as a result of poor mixing of newly secreted acid and food in the proximal stomach, which remains relatively quiescent after a meal compared with the distal stomach.²⁹ In GERD, proximal extension of the acid pocket above the diaphragm increases the risk of acid reflux.³⁰ The acid pocket is therefore an important source of postprandial acid in GERD and, as such, represents a unique therapeutic target.

Emerging evidence suggests that alginates may act directly on the acid pocket. Alginates are natural polysaccharide polymers that, on contact with gastric acid, precipitate within minutes into a low-density viscous gel of near-neutral pH. The change in pH triggers the sodium bicarbonate in the formulation to release carbon dioxide that becomes trapped in the alginate gel, causing it to float to the top of the gastric contents like a raft.³¹

A randomized controlled trial demonstrated that sodium alginate was as effective as omeprazole in relieving symptoms in patients with nonerosive reflux disease.³² Alginate has also been shown to provide more postprandial reflux relief than antacids.³³

Histamine-2 receptor antagonists

Histamine-2 receptor antagonists act more swiftly and increase postprandial gastric pH more rapidly than PPIs, thus making them a good option for prophylaxis against postprandial GERD.³⁴ Taking these drugs at bedtime may help in patients with objective nighttime reflux despite optimal PPI use. However, tachyphylaxis may occur as early as 1 week after starting combination therapy.³⁵

Proton pump inhibitors

There are currently seven available PPIs, including four that can be obtained over the counter (omeprazole, lansoprazole, esomeprazole, and omeprazole-sodium bicarbonate) and three available only by prescription (rabeprazole, pantoprazole, and dexlansoprazole). Studies have shown than a standard 6- to 8-week course of a PPI provides complete symptom relief in 70% to 80% of patients with erosive reflux disease and in 60% of patients with nonerosive reflux disease.^36,37 Clinically, PPIs all appear to be similar in their symptom relief.³⁸

Most PPIs should be taken 30 to 60 minutes before meals. Exceptions are omeprazole-sodium bicarbonate and dexlansoprazole, which can be taken without regard to meals. At our institution, we usually start PPIs in a once-daily standard dose for 6 to 8 weeks and consider increasing to twice-daily dosing if symptoms do not respond completely. Patients with mild intermittent GERD symptoms may benefit from “on-demand” use of PPIs. This approach is best suited for patients with nonerosive reflux disease without evidence of Barrett esophagus on endoscopy.

Safety and adverse effects of PPIs

PPIs are generally safe but can cause adverse effects (Table 3).

Osteoporosis. In 2010, the US Food and Drug Administration issued warnings regarding the potential for wrist, hip, and spine fractures in PPI users.²⁶ Most recent evidence suggests that PPIs may be associated with a small increase in risk of hip fractures in patients already at high risk.^39,40 However, the 2013 American College of Gastroenterology (ACG) guidelines say that patients with known osteoporosis can remain on PPI therapy, and concern for hip fractures and osteoporosis should not affect the decision to use PPIs long-term except in patients with other risk factors for hip fracture.⁴¹

Community-acquired pneumonia. An increased risk of community-acquired pneumonia cannot be clearly documented in association with PPI therapy. Multiple studies, including randomized controlled trials, investigated this potential correlation. However, evidence suggests that short-term but not long-term PPI use may be associated with an overall increased risk of community-acquired pneumonia.^42,43 Current guidelines suggest that in patients who need a PPI, the drug should not be withheld on the basis of a potential risk of community-acquired pneumonia.⁴¹

Clostridium difficile infection. In theory, PPIs may increase the risk of C difficile infection by increasing the ability of the spore to convert to the vegetative form and to survive intraluminally. In fact, studies and meta-analyses have suggested that PPIs do increase the risk of development and recurrence of C difficile infection.^44,45 Therefore, PPIs should be used with care in patients who are at risk.⁴¹

Interaction with clopidogrel. The antiplatelet activity of clopidogrel requires activation by CYP2C19, the same pathway required for metabolism of some PPIs. Concern was raised about decreased antiplatelet activity of clopidogrel in the presence of PPIs. This was extensively studied, and there now appears to be no increased risk of adverse cardiovascular events in patients on PPIs, based on data from well-controlled randomized trials.^46,47 A consensus panel of the American College of Cardiology Foundation, the American Heart Association, and the ACG said that PPIs may be used for appropriate indications in patients taking clopidogrel.⁴⁷

Hypomagnesemia. By an unknown molecular mechanism, PPIs are thought to reduce intestinal magnesium absorption, leading to hypomagnesemia. A meta-analysis published in 2011 showed that PPI-induced hypomagnesemia is a drug-class effect and occurred after a median of 5.5 years of PPI use. Stopping the PPI resulted in magnesium recovery in 4 days, and rechallenge led to recurrence within 4 days.⁴⁸

Hence, to avoid putting patients on long-term PPI therapy at risk, clinicians should anticipate this problem. Our practice is to check the magnesium level before starting a patient on long-term PPI therapy, and then to repeat the measurement every 1 to 2 years.

Baclofen

Transient lower esophageal sphincter relaxation has been shown to be a cause of reflux in healthy people and in patients with GERD.⁴⁹

Baclofen, a muscle relaxant with selective gamma-aminobutyric acid receptor class B agonist properties, reduces transient lower esophageal sphincter relaxation in humans.⁵⁰ In a well-designed, double-blind, randomized controlled trial, baclofen was associated with a significant decrease in upright reflux on 24-hour pH monitoring and significant improvement in belching and overall reflux symptoms.⁵¹ However, baclofen is not approved by the US Food and Drug Administration for the treatment of GERD, and its use may be limited by side effects such as somnolence and dizziness.

Antireflux surgery

Antireflux surgery is a reasonable option for selected patients with chronic GERD. The main types of surgery are laparoscopic fundoplication and, for obese patients, gastric bypass. Reasons to consider antireflux surgery include desire to stop PPI therapy, esophagitis not healed by PPIs, symptomatic hiatal hernia, and refractory reflux documented by pH testing.⁴¹

Clinically, all PPIs appear to be similar in their symptom relief

In general, surgical therapy may be considered in patients who respond to PPIs, but patients who do not respond to PPIs are less likely to respond to antireflux surgery.¹⁵ Other patients less likely to respond are those with symptoms of dyspepsia, such as nausea, vomiting, and epigastric pain.⁴¹

Common adverse effects of antireflux surgery include gas-bloat syndrome (up to 85% of patients), dysphagia (10% to 50% of patients), diarrhea (18% to 33% of patients), and recurrent heartburn (10% to 62% of patients).⁵²

Endoscopic and minimally invasive antireflux procedures include endoscopic plication of the lower esophageal sphincter, radiofrequency augmentation of the lower esophageal sphincter, and sphincter augmentation by a string of titanium beads. While some have shown promise, they are not recommended by the most recent ACG guidelines, given lack of long-term data.⁴¹

REFRACTORY GERD

There is no consensus on the definition of refractory GERD. However, for the sake of simplicity, we can define it as persistence of suspected GERD symptoms despite treatment with a PPI. This may vary from a partial response to PPI therapy to a complete absence of response.

It is extremely important to rule out non-GERD causes of the ongoing symptoms, such as achalasia, gastroparesis, eosinophilic esophagitis, rumination, and aerophagia. PPI nonresponders are more likely to be obese, poorly compliant, and have extraesophageal symptoms.^53–56 As previously discussed, PPIs should be taken 30 to 60 minutes before meals. For patients whose symptoms fail to respond to standard-dose daily PPI therapy, switching to another PPI or doubling the dose is common, although data to support this practice are limited. Of note, omeprazole-sodium bicarbonate has been shown to provide more symptom relief in nocturnal GERD.⁵⁷ Additionally, adding a nighttime histamine-2 receptor antagonist may also help in patients with objective nighttime reflux.⁴¹

After noncompliance and suboptimal PPI dosing have been ruled out, PPI nonresponders with typical symptoms should undergo upper endoscopy and subsequent pH monitoring. Normal esophageal acid exposure on pH testing suggests functional heartburn or functional dyspepsia. Negative pH testing in a patient with atypical symptoms suggests a non-GERD cause of symptoms, and referral to an otolaryngologist, pulmonologist, or allergist is often warranted.

While antireflux surgery can be considered for patients with nonacid reflux on impedance testing, it should again be noted that GERD in patients with no response to PPIs is less likely to respond to antireflux surgery.¹⁵

TAKE-HOME POINTS

• GERD is a common medical condition, affecting up to 40% of US adults at least once monthly.
• GERD can result in a wide variety of symptoms, including typical heartburn and regurgitation as well as atypical symptoms such as cough.
• On the other hand, keep in mind that multiple non-GERD causes of heartburn and regurgitation may exist.
• Testing for GERD includes endoscopy and pH testing as well as functional testing such as esophageal manometry.
• While in most patients GERD will respond to lifestyle changes and antisecretory therapy such as a PPI, careful attention must be given to patients with symptoms refractory to PPI therapy.
• For a subset of patients, antireflux surgery may be a reasonable option, but care must be taken to exclude patients with a lower likelihood of responding to surgery.