The details about an individual’s search for information tell us a lot about healthcare concerns and uncertainty across the medical universe. For nearly a decade, one of the most “clicked on” papers we have published in the Journal has been a review of small fiber neuropathy—a clinical entity with a prevalence of perhaps 1 in 1,000 to 2,000 people and, to my knowledge, no associated walkathons or arm bracelets. Yet it certainly piques the interest of clinicians from many specialties far broader than neurology. In this issue of the Journal, Dr. Jinny Tavee updates her 2009 review and provides us with a clinical overview of the disorder and the opportunity to assess how much further we need to more fully understand its management and associated comorbid conditions.

The wide interest in this disorder plugs into our current seeming epidemic of patients with chronic pain. It seems that almost half of my new patients have issues related to chronic pain that are not directly explained by active inflammation or anatomic damage. Many of these patients have diffuse body pains with associated fatigue and sleep disorders and are diagnosed with fibromyalgia. But others describe pain with a burning and tingling quality that seems of neurologic origin, yet their neurologic examination is normal. A few describe a predominantly distal symmetric stocking-and-glove distribution, but most do not. In some patients these pains are spatially random and evanescent, which to me are usually the hardest to fathom. Nerve conduction studies, when performed, are unrevealing.

A number of systemic autoimmune disorders, as discussed by Dr. Tavee in her article, are suggested to have an association with these symptoms. Given the chronicity and the frustrating nature of the symptoms, it is no surprise that a panoply of immune serologies are frequently ordered. Invariably, since serologies (eg, ANA, SSA, SSB, rheumatoid factor) are not specific for any single entity, some will return as positive. The strength of many of these associations is weak; even when the clinical diagnosis of lupus, for example, is definite, treatment of the underlying disease does not necessarily improve the dysesthetic pain. In an alternative scenario, the small fiber neuropathy is ascribed to a systemic autoimmune disorder that has been diagnosed because an autoantibody has been detected, but this rarely helps the patient and may in fact worsen symptoms by increasing anxiety and concern over having a systemic disease such as Sjögren syndrome or lupus (both of which sound terrible when reviewed on the Internet).

Some patients describe autonomic symptoms. Given the biologic basis that has been defined for this entity, it is no surprise that some patients have marked symptoms of decreased exocrine gland function, gastrointestinal dysmotility, and orthostasis. These symptoms may not be recognized unless specifically sought out when interviewing the patient.

Given the chronicity and sometimes the vagaries of symptoms, it is often comforting for patients to get an actual diagnosis. Dr. Tavee notes the relative simplicity of diagnostic procedures. But determining the clinical implications of the results may not be straightforward, and devising a fully and uniformly effective therapeutic approach eludes us still. As she points out, a multidisciplinary approach to therapy and diagnosis can be quite helpful.

The details about an individual’s search for information tell us a lot about healthcare concerns and uncertainty across the medical universe. For nearly a decade, one of the most “clicked on” papers we have published in the Journal has been a review of small fiber neuropathy—a clinical entity with a prevalence of perhaps 1 in 1,000 to 2,000 people and, to my knowledge, no associated walkathons or arm bracelets. Yet it certainly piques the interest of clinicians from many specialties far broader than neurology. In this issue of the Journal, Dr. Jinny Tavee updates her 2009 review and provides us with a clinical overview of the disorder and the opportunity to assess how much further we need to more fully understand its management and associated comorbid conditions.

The wide interest in this disorder plugs into our current seeming epidemic of patients with chronic pain. It seems that almost half of my new patients have issues related to chronic pain that are not directly explained by active inflammation or anatomic damage. Many of these patients have diffuse body pains with associated fatigue and sleep disorders and are diagnosed with fibromyalgia. But others describe pain with a burning and tingling quality that seems of neurologic origin, yet their neurologic examination is normal. A few describe a predominantly distal symmetric stocking-and-glove distribution, but most do not. In some patients these pains are spatially random and evanescent, which to me are usually the hardest to fathom. Nerve conduction studies, when performed, are unrevealing.

A number of systemic autoimmune disorders, as discussed by Dr. Tavee in her article, are suggested to have an association with these symptoms. Given the chronicity and the frustrating nature of the symptoms, it is no surprise that a panoply of immune serologies are frequently ordered. Invariably, since serologies (eg, ANA, SSA, SSB, rheumatoid factor) are not specific for any single entity, some will return as positive. The strength of many of these associations is weak; even when the clinical diagnosis of lupus, for example, is definite, treatment of the underlying disease does not necessarily improve the dysesthetic pain. In an alternative scenario, the small fiber neuropathy is ascribed to a systemic autoimmune disorder that has been diagnosed because an autoantibody has been detected, but this rarely helps the patient and may in fact worsen symptoms by increasing anxiety and concern over having a systemic disease such as Sjögren syndrome or lupus (both of which sound terrible when reviewed on the Internet).

Some patients describe autonomic symptoms. Given the biologic basis that has been defined for this entity, it is no surprise that some patients have marked symptoms of decreased exocrine gland function, gastrointestinal dysmotility, and orthostasis. These symptoms may not be recognized unless specifically sought out when interviewing the patient.

Given the chronicity and sometimes the vagaries of symptoms, it is often comforting for patients to get an actual diagnosis. Dr. Tavee notes the relative simplicity of diagnostic procedures. But determining the clinical implications of the results may not be straightforward, and devising a fully and uniformly effective therapeutic approach eludes us still. As she points out, a multidisciplinary approach to therapy and diagnosis can be quite helpful.

The details about an individual’s search for information tell us a lot about healthcare concerns and uncertainty across the medical universe. For nearly a decade, one of the most “clicked on” papers we have published in the Journal has been a review of small fiber neuropathy—a clinical entity with a prevalence of perhaps 1 in 1,000 to 2,000 people and, to my knowledge, no associated walkathons or arm bracelets. Yet it certainly piques the interest of clinicians from many specialties far broader than neurology. In this issue of the Journal, Dr. Jinny Tavee updates her 2009 review and provides us with a clinical overview of the disorder and the opportunity to assess how much further we need to more fully understand its management and associated comorbid conditions.

The wide interest in this disorder plugs into our current seeming epidemic of patients with chronic pain. It seems that almost half of my new patients have issues related to chronic pain that are not directly explained by active inflammation or anatomic damage. Many of these patients have diffuse body pains with associated fatigue and sleep disorders and are diagnosed with fibromyalgia. But others describe pain with a burning and tingling quality that seems of neurologic origin, yet their neurologic examination is normal. A few describe a predominantly distal symmetric stocking-and-glove distribution, but most do not. In some patients these pains are spatially random and evanescent, which to me are usually the hardest to fathom. Nerve conduction studies, when performed, are unrevealing.

A number of systemic autoimmune disorders, as discussed by Dr. Tavee in her article, are suggested to have an association with these symptoms. Given the chronicity and the frustrating nature of the symptoms, it is no surprise that a panoply of immune serologies are frequently ordered. Invariably, since serologies (eg, ANA, SSA, SSB, rheumatoid factor) are not specific for any single entity, some will return as positive. The strength of many of these associations is weak; even when the clinical diagnosis of lupus, for example, is definite, treatment of the underlying disease does not necessarily improve the dysesthetic pain. In an alternative scenario, the small fiber neuropathy is ascribed to a systemic autoimmune disorder that has been diagnosed because an autoantibody has been detected, but this rarely helps the patient and may in fact worsen symptoms by increasing anxiety and concern over having a systemic disease such as Sjögren syndrome or lupus (both of which sound terrible when reviewed on the Internet).

Some patients describe autonomic symptoms. Given the biologic basis that has been defined for this entity, it is no surprise that some patients have marked symptoms of decreased exocrine gland function, gastrointestinal dysmotility, and orthostasis. These symptoms may not be recognized unless specifically sought out when interviewing the patient.

Given the chronicity and sometimes the vagaries of symptoms, it is often comforting for patients to get an actual diagnosis. Dr. Tavee notes the relative simplicity of diagnostic procedures. But determining the clinical implications of the results may not be straightforward, and devising a fully and uniformly effective therapeutic approach eludes us still. As she points out, a multidisciplinary approach to therapy and diagnosis can be quite helpful.

A 54-year-old man presented to our hospital with acute-onset left-sided weakness and right facial droop. Three days earlier he had also had migraine-like headaches, which he had never experienced before. He also reported a change in behavior during the past week, which his family had described as inappropriate laughter.

He had no history of hypertension, diabetes, or dyslipidemia. He did not smoke or drink alcohol. However, he had an extensive family history of stroke. His mother had a stroke at age 50, his brother a stroke at age 57, and his sister had been admitted for a stroke 1 month earlier at the age of 52.

On examination, he had weakness of the left arm and leg, right facial droop, and hyperactive reflexes on the left side. He had no sensory or cerebellar deficits. He had episodes of laughter during the examination.

We learned that the patient’s sister had undergone a workup showing mutations in the NOTCH3 gene and a skin biopsy study consistent with CADASIL.

Our patient was started on antiplatelet and high-intensity statin therapy. His symptoms improved, and he was discharged to an acute inpatient rehabilitation facility. He was referred to a CADASIL registry.

STROKE AND HEREDITY

CADASIL is a rare hereditary vascular disorder inherited in an autosomal dominant manner. It is the most common inherited form of small-vessel disease and results from a mutation in the NOTCH3 gene that leads to degeneration of smooth muscle in cerebral blood vessels. It can manifest as migraine with aura, vascular dementia, cognitive impairment, or ischemic stroke.

The diagnosis is based on a clinical picture that typically includes stroke at a young age (age 40 to 50) in the absence of stroke risk factors, or frequent lacunar infarction episodes that can manifest as migraine, lacunar infarct, or dementia.¹ Some patients, such as ours, may have subtle nonspecific behavioral changes such as inappropriate laughter, which may herald the development of an infarct.

Characteristic findings on MRI are white matter hyperintensities that tend to be bilateral and symmetrical in the periventricular areas. Symmetrical involvement in the temporal lobes has high sensitivity and specificity for CADASIL.² Biopsy study of the skin, muscle, or sural nerve shows small-vessel changes that include thickening of the media, granular material positive on periodic acid-Schiff staining, and narrowing of the lumen. However, the gold standard for diagnosis is confirmation of the NOTCH3 mutation on chromosome 19.^1,2

There is no known treatment for CADASIL.

A 54-year-old man presented to our hospital with acute-onset left-sided weakness and right facial droop. Three days earlier he had also had migraine-like headaches, which he had never experienced before. He also reported a change in behavior during the past week, which his family had described as inappropriate laughter.

He had no history of hypertension, diabetes, or dyslipidemia. He did not smoke or drink alcohol. However, he had an extensive family history of stroke. His mother had a stroke at age 50, his brother a stroke at age 57, and his sister had been admitted for a stroke 1 month earlier at the age of 52.

On examination, he had weakness of the left arm and leg, right facial droop, and hyperactive reflexes on the left side. He had no sensory or cerebellar deficits. He had episodes of laughter during the examination.

We learned that the patient’s sister had undergone a workup showing mutations in the NOTCH3 gene and a skin biopsy study consistent with CADASIL.

Our patient was started on antiplatelet and high-intensity statin therapy. His symptoms improved, and he was discharged to an acute inpatient rehabilitation facility. He was referred to a CADASIL registry.

STROKE AND HEREDITY

CADASIL is a rare hereditary vascular disorder inherited in an autosomal dominant manner. It is the most common inherited form of small-vessel disease and results from a mutation in the NOTCH3 gene that leads to degeneration of smooth muscle in cerebral blood vessels. It can manifest as migraine with aura, vascular dementia, cognitive impairment, or ischemic stroke.

The diagnosis is based on a clinical picture that typically includes stroke at a young age (age 40 to 50) in the absence of stroke risk factors, or frequent lacunar infarction episodes that can manifest as migraine, lacunar infarct, or dementia.¹ Some patients, such as ours, may have subtle nonspecific behavioral changes such as inappropriate laughter, which may herald the development of an infarct.

Characteristic findings on MRI are white matter hyperintensities that tend to be bilateral and symmetrical in the periventricular areas. Symmetrical involvement in the temporal lobes has high sensitivity and specificity for CADASIL.² Biopsy study of the skin, muscle, or sural nerve shows small-vessel changes that include thickening of the media, granular material positive on periodic acid-Schiff staining, and narrowing of the lumen. However, the gold standard for diagnosis is confirmation of the NOTCH3 mutation on chromosome 19.^1,2

There is no known treatment for CADASIL.

A 54-year-old man presented to our hospital with acute-onset left-sided weakness and right facial droop. Three days earlier he had also had migraine-like headaches, which he had never experienced before. He also reported a change in behavior during the past week, which his family had described as inappropriate laughter.

He had no history of hypertension, diabetes, or dyslipidemia. He did not smoke or drink alcohol. However, he had an extensive family history of stroke. His mother had a stroke at age 50, his brother a stroke at age 57, and his sister had been admitted for a stroke 1 month earlier at the age of 52.

On examination, he had weakness of the left arm and leg, right facial droop, and hyperactive reflexes on the left side. He had no sensory or cerebellar deficits. He had episodes of laughter during the examination.

We learned that the patient’s sister had undergone a workup showing mutations in the NOTCH3 gene and a skin biopsy study consistent with CADASIL.

Our patient was started on antiplatelet and high-intensity statin therapy. His symptoms improved, and he was discharged to an acute inpatient rehabilitation facility. He was referred to a CADASIL registry.

STROKE AND HEREDITY

CADASIL is a rare hereditary vascular disorder inherited in an autosomal dominant manner. It is the most common inherited form of small-vessel disease and results from a mutation in the NOTCH3 gene that leads to degeneration of smooth muscle in cerebral blood vessels. It can manifest as migraine with aura, vascular dementia, cognitive impairment, or ischemic stroke.

The diagnosis is based on a clinical picture that typically includes stroke at a young age (age 40 to 50) in the absence of stroke risk factors, or frequent lacunar infarction episodes that can manifest as migraine, lacunar infarct, or dementia.¹ Some patients, such as ours, may have subtle nonspecific behavioral changes such as inappropriate laughter, which may herald the development of an infarct.

Characteristic findings on MRI are white matter hyperintensities that tend to be bilateral and symmetrical in the periventricular areas. Symmetrical involvement in the temporal lobes has high sensitivity and specificity for CADASIL.² Biopsy study of the skin, muscle, or sural nerve shows small-vessel changes that include thickening of the media, granular material positive on periodic acid-Schiff staining, and narrowing of the lumen. However, the gold standard for diagnosis is confirmation of the NOTCH3 mutation on chromosome 19.^1,2

There is no known treatment for CADASIL.

A 55-year-old man presented to the emergency department with 1 week of bilateral lower-extremity joint pain associated with painful skin nodules. He had a history of chronic recurrent alcoholic pancreatitis. He denied abdominal pain, nausea, or vomiting.

Results of initial laboratory testing:

• Alkaline phosphatase 300 IU/L (reference range 36–108)
• Erythrocyte sedimentation rate 81 mm/h (0–15)
• Lipase 20,000 U/L (16–61).

AN ATYPICAL PRESENTATION OF A COMMON DISEASE

Epidemiology and pathophysiology

Pancreatitis, panniculitis, and polyarthritis syndrome is a rare systemic complication of pancreatic disease occurring most often in middle-aged men with an acute exacerbation of chronic pancreatitis and a history of alcohol use disorder.^1,2 It is also associated with pancreatic pseudocyst, pancreas divisum, and pancreatic adenocarcinoma.^3–6 It is characterized by systemic fat necrosis secondary to severe and persistent elevation of pancreatic enzymes. The mortality rate is high; in a case series of 25 patients, 24% died within days to weeks after admission.¹

Clinical presentation and treatment

The diagnosis of pancreatitis, panniculitis, and polyarthritis syndrome is often missed. Abdominal pain is mild or absent in over 60% of patients.¹ Therefore, a high index of suspicion is required for early diagnosis.

The differential diagnosis includes sarcoidosis (including Löfgren syndrome), subcutaneous infection, and vasculitis. “Ghost adipocytes” on skin biopsy are pathognomonic for pancreatic panniculitis and are the result of saponification; they appear to be anuclear, with basophilic material throughout the cytoplasm.⁷ Arthrocentesis of affected joints may reveal thick, creamy material, rich in triglycerides, which is diagnostic of pancreatic arthritis.^1,8

Treatment relies on correction of the underlying pancreatic pathology. Pancreatitis, panniculitis, and polyarthritis syndrome has been successfully treated by cyst gastrostomy, pancreatic duct stenting, and pancreaticoduodenectomy.^7,9–11

TAKE-HOME POINTS

• Pancreatitis, panniculitis, and polyarthritis syndrome mimics rheumatologic disease and often presents without abdominal pain.
• The diagnosis is confirmed by the presence of elevated serum lipase or amylase, pancreatic imaging showing pancreatitis, and ghost adipocytes on skin biopsy.
• Treatment is aimed at correcting the underlying pancreatic abnormality.

A 55-year-old man presented to the emergency department with 1 week of bilateral lower-extremity joint pain associated with painful skin nodules. He had a history of chronic recurrent alcoholic pancreatitis. He denied abdominal pain, nausea, or vomiting.

Results of initial laboratory testing:

• Alkaline phosphatase 300 IU/L (reference range 36–108)
• Erythrocyte sedimentation rate 81 mm/h (0–15)
• Lipase 20,000 U/L (16–61).

AN ATYPICAL PRESENTATION OF A COMMON DISEASE

Epidemiology and pathophysiology

Pancreatitis, panniculitis, and polyarthritis syndrome is a rare systemic complication of pancreatic disease occurring most often in middle-aged men with an acute exacerbation of chronic pancreatitis and a history of alcohol use disorder.^1,2 It is also associated with pancreatic pseudocyst, pancreas divisum, and pancreatic adenocarcinoma.^3–6 It is characterized by systemic fat necrosis secondary to severe and persistent elevation of pancreatic enzymes. The mortality rate is high; in a case series of 25 patients, 24% died within days to weeks after admission.¹

Clinical presentation and treatment

The diagnosis of pancreatitis, panniculitis, and polyarthritis syndrome is often missed. Abdominal pain is mild or absent in over 60% of patients.¹ Therefore, a high index of suspicion is required for early diagnosis.

The differential diagnosis includes sarcoidosis (including Löfgren syndrome), subcutaneous infection, and vasculitis. “Ghost adipocytes” on skin biopsy are pathognomonic for pancreatic panniculitis and are the result of saponification; they appear to be anuclear, with basophilic material throughout the cytoplasm.⁷ Arthrocentesis of affected joints may reveal thick, creamy material, rich in triglycerides, which is diagnostic of pancreatic arthritis.^1,8

Treatment relies on correction of the underlying pancreatic pathology. Pancreatitis, panniculitis, and polyarthritis syndrome has been successfully treated by cyst gastrostomy, pancreatic duct stenting, and pancreaticoduodenectomy.^7,9–11

TAKE-HOME POINTS

• Pancreatitis, panniculitis, and polyarthritis syndrome mimics rheumatologic disease and often presents without abdominal pain.
• The diagnosis is confirmed by the presence of elevated serum lipase or amylase, pancreatic imaging showing pancreatitis, and ghost adipocytes on skin biopsy.
• Treatment is aimed at correcting the underlying pancreatic abnormality.

A 55-year-old man presented to the emergency department with 1 week of bilateral lower-extremity joint pain associated with painful skin nodules. He had a history of chronic recurrent alcoholic pancreatitis. He denied abdominal pain, nausea, or vomiting.

Results of initial laboratory testing:

• Alkaline phosphatase 300 IU/L (reference range 36–108)
• Erythrocyte sedimentation rate 81 mm/h (0–15)
• Lipase 20,000 U/L (16–61).

AN ATYPICAL PRESENTATION OF A COMMON DISEASE

Epidemiology and pathophysiology

Pancreatitis, panniculitis, and polyarthritis syndrome is a rare systemic complication of pancreatic disease occurring most often in middle-aged men with an acute exacerbation of chronic pancreatitis and a history of alcohol use disorder.^1,2 It is also associated with pancreatic pseudocyst, pancreas divisum, and pancreatic adenocarcinoma.^3–6 It is characterized by systemic fat necrosis secondary to severe and persistent elevation of pancreatic enzymes. The mortality rate is high; in a case series of 25 patients, 24% died within days to weeks after admission.¹

Clinical presentation and treatment

The diagnosis of pancreatitis, panniculitis, and polyarthritis syndrome is often missed. Abdominal pain is mild or absent in over 60% of patients.¹ Therefore, a high index of suspicion is required for early diagnosis.

The differential diagnosis includes sarcoidosis (including Löfgren syndrome), subcutaneous infection, and vasculitis. “Ghost adipocytes” on skin biopsy are pathognomonic for pancreatic panniculitis and are the result of saponification; they appear to be anuclear, with basophilic material throughout the cytoplasm.⁷ Arthrocentesis of affected joints may reveal thick, creamy material, rich in triglycerides, which is diagnostic of pancreatic arthritis.^1,8

Treatment relies on correction of the underlying pancreatic pathology. Pancreatitis, panniculitis, and polyarthritis syndrome has been successfully treated by cyst gastrostomy, pancreatic duct stenting, and pancreaticoduodenectomy.^7,9–11

TAKE-HOME POINTS

• Pancreatitis, panniculitis, and polyarthritis syndrome mimics rheumatologic disease and often presents without abdominal pain.
• The diagnosis is confirmed by the presence of elevated serum lipase or amylase, pancreatic imaging showing pancreatitis, and ghost adipocytes on skin biopsy.
• Treatment is aimed at correcting the underlying pancreatic abnormality.

A 54-year-old postmenopausal woman presents with a 3-day history of left lower quadrant pain. Abdominal and pelvic computed tomography confirm the diagnosis of acute diverticulitis, and a left ovarian cyst is incidentally noted. Her abdominal discomfort resolves with antibiotics.

Transvaginal ultrasonography confirms the presence of a 4.5-cm simple left ovarian cyst. The radiologist recommends follow-up ultrasonography in 3 months “if clinically indicated.” The patient feels well and is anxious about having additional testing. What do you recommend?

HOW USEFUL IS ULTRASONOGRAPHY FOR OVARIAN CYSTS?

Ovarian cysts are common and may affect up to 20% of women at some time during their life.¹ In a prospective study of almost 40,000 women enrolled in an ovarian cancer screening program, the prevalence of ovarian cysts was 15.3% in premenopausal women and 8.2% in postmenopausal women.²

Pelvic ultrasonography is the most effective way to evaluate incidentally noted cysts, and the transvaginal approach is preferred.³ The International Ovarian Tumor Analysis group has outlined morphologic features, referred to as “simple rules,” for predicting if a cyst is malignant or benign.⁴ In a prospective validation study, these simple rules were applied in 76% of cases, with a sensitivity of 95% and a specificity of 91%.⁴ However, it should be noted that these rules apply to examinations done by experienced gynecologic ultrasonographers, as accuracy of ultrasonography is both machine- and operator-dependent.

WHAT IS THE MALIGNANCY POTENTIAL OF A SIMPLE OVARIAN CYST?

A simple ovarian cyst is defined as an anechoic round or oval lesion, different from a unilocular cyst, which may contain septations, solid wall irregularities, or internal echoes.⁵ Overall, simple ovarian cysts have a very low likelihood of malignancy. In the large, multi-site Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, simple cysts were observed in 14% of postmenopausal women,6 but no cyst was associated with the development of ovarian cancer over 4 years of follow-up.

HOW OFTEN SHOULD IMAGING BE REPEATED?

In premenopausal women, most simple (thin-walled) ovarian cysts less than 5 cm in maximum diameter resolve in 2 to 3 menstrual cycles and do not require further intervention.³ Larger cysts (5–7 cm in diameter) should be followed with ultrasonography yearly. Cysts larger than 7 cm require advanced imaging or surgical intervention, and the patient should be referred to a gynecologist.³

In postmenopausal women, serum markers are combined with ultrasonography results to determine the risk of malignancy. Markers studied include cancer antigen 125 (CA-125), human epididymis protein 4, lactate dehydrogenase, alpha fetoprotein, and beta human chorionic gonadotropin (beta hCG).⁷

CA-125, the most studied marker, is elevated in more than 90% of advanced-stage ovarian cancers, but in only 50% of patients wth early-stage cancer.^1,8 However, CA-125 may be elevated in a variety of other settings, including benign gynecologic disorders (pelvic infection, fibroids, endometriosis, adenomyosis) and nongynecologic disorders (liver disease, pancreatitis, and diverticulitis). Thus, it is unreliable for distinguishing benign from malignant ovarian masses in premenopausal women.^1,3

Current guidelines recommend routine measurement of CA-125 in the initial evaluation of all postmenopausal women with an ovarian mass.^7,8

Using a cutoff of 30 IU/mL, CA-125 has a sensitivity of 81% and a specificity of 75% for ovarian malignancy. However, serial measurements may be more useful for assessing ovarian cancer risk, especially in the setting of rapidly rising values.^1,3

The Risk for Malignancy Index (RMI), which categorizes a cyst’s risk for malignancy, can be calculated based on the patient’s menopausal status, ultrasonographic characteristics (1 point each for multilocular cyst, solid area, metastasis, ascites, and bilateral lesions), and serum CA-125 level. The RMI has a sensitivity of 78% and a specificity of 87% for predicting ovarian cancer.8

Postmenopausal women with an asymptomatic small cyst (< 5 cm), a normal CA-125 level, and an RMI < 200 can be followed conservatively, with repeat ultrasonography in 4 to 6 months. At that time, if the cyst has not grown and the CA-125 level is normal, expectant management can continue, with reassessment in 4 to 6 months. If imaging remains unchanged and the CA-125 is persistently normal, the patient may be discharged from follow-up.⁸

If at any time during the evaluation the calculated RMI is greater than 200, there is an increased risk for malignancy, and the patient should be referred to a gynecologic oncologist for advanced imaging.

An algorithm from the Royal College of Obstetricians and Gynaecologists for managing ovarian cysts in postmenopausal women is available at www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/gtg_34.pdf.⁸

The American College of Radiology (ACR) has created a “Choosing Wisely” guideline to clarify when repeat imaging for ovarian cysts is indicated, to reduce both patient anxiety and healthcare costs.⁹ These guidelines highlight the distress women may experience from repeat testing due to concerns about cancer.

The guidelines also note that testing is often done during varying times of the menstrual cycle, thereby detecting new cysts, as opposed to monitoring previously detected cysts. Repeat ultrasonography may lead to surgical interventions that are not evidence-based, such as cystectomy or oophorectomy, in patients without radiologic features of malignancy or associated pelvic pain. And while ultrasonography is less expensive than other imaging tests, unnecessary imaging can mean additional costs to the patient, such as copayments, and possibly large payments for patients without insurance.

The American College of Obstetricians and Gynecologists (ACOG) and the ACR guidelines recommend against unnecessary repeat imaging for ovarian cysts.^7,10 The ACOG Practice Bulletin on the Evaluation and Management of Adnexal Masses states, “Simple cysts up to 10 cm in diameter on transvaginal ultrasonography performed by experienced ultrasonographers are likely benign and may be safely monitored using repeat imaging without surgical intervention, even in postmenopausal patients.”⁷

The ideal frequency for repeat testing is yet to be determined. In postmenopausal women with a simple cyst smaller than 5 cm, ACOG guidelines recommend an interval of 4 to 6 months for initial repeat imaging. ACR guidelines recommend no follow-up imaging for simple cysts smaller than 5 cm detected by high-quality ultrasonography in asymptomatic women of reproductive age or for simple cysts smaller than 1 cm in postmenopausal women.¹⁰

THE CLINICAL BOTTOM LINE

Simple ovarian cysts can develop as part of the normal menstrual cycle, and although they are more common in premenopausal women, they have been detected in 1 out of 5 postmenopausal women.⁹ Simple ovarian cysts are typically not cancerous in women of any age. Therefore, most simple ovarian cysts in asymp­tomatic women either require no follow-up imaging or can be safely monitored with limited repeat ultrasonography for a defined length of time.

Our 54-year-old postmenopausal patient has a simple cyst smaller than 5 cm. Based on current guidelines, the CA-125 level should be measured, with subsequent calculation of the RMI. Assuming a normal CA-125 and RMI, she should be reassured that the risk of progression to malignancy is extremely low. Repeating ultrasonography 4 to 6 months after the initial imaging is warranted. At that time, if no change in cyst size or composition is detected, ultrasonography can be repeated at 1 year after initial detection. After that, assuming no changes of the cyst on repeat imaging, the patient does not require additional follow-up.

A 54-year-old postmenopausal woman presents with a 3-day history of left lower quadrant pain. Abdominal and pelvic computed tomography confirm the diagnosis of acute diverticulitis, and a left ovarian cyst is incidentally noted. Her abdominal discomfort resolves with antibiotics.

Transvaginal ultrasonography confirms the presence of a 4.5-cm simple left ovarian cyst. The radiologist recommends follow-up ultrasonography in 3 months “if clinically indicated.” The patient feels well and is anxious about having additional testing. What do you recommend?

HOW USEFUL IS ULTRASONOGRAPHY FOR OVARIAN CYSTS?

Ovarian cysts are common and may affect up to 20% of women at some time during their life.¹ In a prospective study of almost 40,000 women enrolled in an ovarian cancer screening program, the prevalence of ovarian cysts was 15.3% in premenopausal women and 8.2% in postmenopausal women.²

Pelvic ultrasonography is the most effective way to evaluate incidentally noted cysts, and the transvaginal approach is preferred.³ The International Ovarian Tumor Analysis group has outlined morphologic features, referred to as “simple rules,” for predicting if a cyst is malignant or benign.⁴ In a prospective validation study, these simple rules were applied in 76% of cases, with a sensitivity of 95% and a specificity of 91%.⁴ However, it should be noted that these rules apply to examinations done by experienced gynecologic ultrasonographers, as accuracy of ultrasonography is both machine- and operator-dependent.

WHAT IS THE MALIGNANCY POTENTIAL OF A SIMPLE OVARIAN CYST?

A simple ovarian cyst is defined as an anechoic round or oval lesion, different from a unilocular cyst, which may contain septations, solid wall irregularities, or internal echoes.⁵ Overall, simple ovarian cysts have a very low likelihood of malignancy. In the large, multi-site Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, simple cysts were observed in 14% of postmenopausal women,6 but no cyst was associated with the development of ovarian cancer over 4 years of follow-up.

HOW OFTEN SHOULD IMAGING BE REPEATED?

In premenopausal women, most simple (thin-walled) ovarian cysts less than 5 cm in maximum diameter resolve in 2 to 3 menstrual cycles and do not require further intervention.³ Larger cysts (5–7 cm in diameter) should be followed with ultrasonography yearly. Cysts larger than 7 cm require advanced imaging or surgical intervention, and the patient should be referred to a gynecologist.³

In postmenopausal women, serum markers are combined with ultrasonography results to determine the risk of malignancy. Markers studied include cancer antigen 125 (CA-125), human epididymis protein 4, lactate dehydrogenase, alpha fetoprotein, and beta human chorionic gonadotropin (beta hCG).⁷

CA-125, the most studied marker, is elevated in more than 90% of advanced-stage ovarian cancers, but in only 50% of patients wth early-stage cancer.^1,8 However, CA-125 may be elevated in a variety of other settings, including benign gynecologic disorders (pelvic infection, fibroids, endometriosis, adenomyosis) and nongynecologic disorders (liver disease, pancreatitis, and diverticulitis). Thus, it is unreliable for distinguishing benign from malignant ovarian masses in premenopausal women.^1,3

Current guidelines recommend routine measurement of CA-125 in the initial evaluation of all postmenopausal women with an ovarian mass.^7,8

Using a cutoff of 30 IU/mL, CA-125 has a sensitivity of 81% and a specificity of 75% for ovarian malignancy. However, serial measurements may be more useful for assessing ovarian cancer risk, especially in the setting of rapidly rising values.^1,3

The Risk for Malignancy Index (RMI), which categorizes a cyst’s risk for malignancy, can be calculated based on the patient’s menopausal status, ultrasonographic characteristics (1 point each for multilocular cyst, solid area, metastasis, ascites, and bilateral lesions), and serum CA-125 level. The RMI has a sensitivity of 78% and a specificity of 87% for predicting ovarian cancer.8

Postmenopausal women with an asymptomatic small cyst (< 5 cm), a normal CA-125 level, and an RMI < 200 can be followed conservatively, with repeat ultrasonography in 4 to 6 months. At that time, if the cyst has not grown and the CA-125 level is normal, expectant management can continue, with reassessment in 4 to 6 months. If imaging remains unchanged and the CA-125 is persistently normal, the patient may be discharged from follow-up.⁸

If at any time during the evaluation the calculated RMI is greater than 200, there is an increased risk for malignancy, and the patient should be referred to a gynecologic oncologist for advanced imaging.

An algorithm from the Royal College of Obstetricians and Gynaecologists for managing ovarian cysts in postmenopausal women is available at www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/gtg_34.pdf.⁸

The American College of Radiology (ACR) has created a “Choosing Wisely” guideline to clarify when repeat imaging for ovarian cysts is indicated, to reduce both patient anxiety and healthcare costs.⁹ These guidelines highlight the distress women may experience from repeat testing due to concerns about cancer.

The guidelines also note that testing is often done during varying times of the menstrual cycle, thereby detecting new cysts, as opposed to monitoring previously detected cysts. Repeat ultrasonography may lead to surgical interventions that are not evidence-based, such as cystectomy or oophorectomy, in patients without radiologic features of malignancy or associated pelvic pain. And while ultrasonography is less expensive than other imaging tests, unnecessary imaging can mean additional costs to the patient, such as copayments, and possibly large payments for patients without insurance.

The American College of Obstetricians and Gynecologists (ACOG) and the ACR guidelines recommend against unnecessary repeat imaging for ovarian cysts.^7,10 The ACOG Practice Bulletin on the Evaluation and Management of Adnexal Masses states, “Simple cysts up to 10 cm in diameter on transvaginal ultrasonography performed by experienced ultrasonographers are likely benign and may be safely monitored using repeat imaging without surgical intervention, even in postmenopausal patients.”⁷

The ideal frequency for repeat testing is yet to be determined. In postmenopausal women with a simple cyst smaller than 5 cm, ACOG guidelines recommend an interval of 4 to 6 months for initial repeat imaging. ACR guidelines recommend no follow-up imaging for simple cysts smaller than 5 cm detected by high-quality ultrasonography in asymptomatic women of reproductive age or for simple cysts smaller than 1 cm in postmenopausal women.¹⁰

THE CLINICAL BOTTOM LINE

Simple ovarian cysts can develop as part of the normal menstrual cycle, and although they are more common in premenopausal women, they have been detected in 1 out of 5 postmenopausal women.⁹ Simple ovarian cysts are typically not cancerous in women of any age. Therefore, most simple ovarian cysts in asymp­tomatic women either require no follow-up imaging or can be safely monitored with limited repeat ultrasonography for a defined length of time.

Our 54-year-old postmenopausal patient has a simple cyst smaller than 5 cm. Based on current guidelines, the CA-125 level should be measured, with subsequent calculation of the RMI. Assuming a normal CA-125 and RMI, she should be reassured that the risk of progression to malignancy is extremely low. Repeating ultrasonography 4 to 6 months after the initial imaging is warranted. At that time, if no change in cyst size or composition is detected, ultrasonography can be repeated at 1 year after initial detection. After that, assuming no changes of the cyst on repeat imaging, the patient does not require additional follow-up.

A 54-year-old postmenopausal woman presents with a 3-day history of left lower quadrant pain. Abdominal and pelvic computed tomography confirm the diagnosis of acute diverticulitis, and a left ovarian cyst is incidentally noted. Her abdominal discomfort resolves with antibiotics.

Transvaginal ultrasonography confirms the presence of a 4.5-cm simple left ovarian cyst. The radiologist recommends follow-up ultrasonography in 3 months “if clinically indicated.” The patient feels well and is anxious about having additional testing. What do you recommend?

HOW USEFUL IS ULTRASONOGRAPHY FOR OVARIAN CYSTS?

Ovarian cysts are common and may affect up to 20% of women at some time during their life.¹ In a prospective study of almost 40,000 women enrolled in an ovarian cancer screening program, the prevalence of ovarian cysts was 15.3% in premenopausal women and 8.2% in postmenopausal women.²

Pelvic ultrasonography is the most effective way to evaluate incidentally noted cysts, and the transvaginal approach is preferred.³ The International Ovarian Tumor Analysis group has outlined morphologic features, referred to as “simple rules,” for predicting if a cyst is malignant or benign.⁴ In a prospective validation study, these simple rules were applied in 76% of cases, with a sensitivity of 95% and a specificity of 91%.⁴ However, it should be noted that these rules apply to examinations done by experienced gynecologic ultrasonographers, as accuracy of ultrasonography is both machine- and operator-dependent.

WHAT IS THE MALIGNANCY POTENTIAL OF A SIMPLE OVARIAN CYST?

A simple ovarian cyst is defined as an anechoic round or oval lesion, different from a unilocular cyst, which may contain septations, solid wall irregularities, or internal echoes.⁵ Overall, simple ovarian cysts have a very low likelihood of malignancy. In the large, multi-site Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, simple cysts were observed in 14% of postmenopausal women,6 but no cyst was associated with the development of ovarian cancer over 4 years of follow-up.

HOW OFTEN SHOULD IMAGING BE REPEATED?

In premenopausal women, most simple (thin-walled) ovarian cysts less than 5 cm in maximum diameter resolve in 2 to 3 menstrual cycles and do not require further intervention.³ Larger cysts (5–7 cm in diameter) should be followed with ultrasonography yearly. Cysts larger than 7 cm require advanced imaging or surgical intervention, and the patient should be referred to a gynecologist.³

In postmenopausal women, serum markers are combined with ultrasonography results to determine the risk of malignancy. Markers studied include cancer antigen 125 (CA-125), human epididymis protein 4, lactate dehydrogenase, alpha fetoprotein, and beta human chorionic gonadotropin (beta hCG).⁷

CA-125, the most studied marker, is elevated in more than 90% of advanced-stage ovarian cancers, but in only 50% of patients wth early-stage cancer.^1,8 However, CA-125 may be elevated in a variety of other settings, including benign gynecologic disorders (pelvic infection, fibroids, endometriosis, adenomyosis) and nongynecologic disorders (liver disease, pancreatitis, and diverticulitis). Thus, it is unreliable for distinguishing benign from malignant ovarian masses in premenopausal women.^1,3

Current guidelines recommend routine measurement of CA-125 in the initial evaluation of all postmenopausal women with an ovarian mass.^7,8

Using a cutoff of 30 IU/mL, CA-125 has a sensitivity of 81% and a specificity of 75% for ovarian malignancy. However, serial measurements may be more useful for assessing ovarian cancer risk, especially in the setting of rapidly rising values.^1,3

The Risk for Malignancy Index (RMI), which categorizes a cyst’s risk for malignancy, can be calculated based on the patient’s menopausal status, ultrasonographic characteristics (1 point each for multilocular cyst, solid area, metastasis, ascites, and bilateral lesions), and serum CA-125 level. The RMI has a sensitivity of 78% and a specificity of 87% for predicting ovarian cancer.8

Postmenopausal women with an asymptomatic small cyst (< 5 cm), a normal CA-125 level, and an RMI < 200 can be followed conservatively, with repeat ultrasonography in 4 to 6 months. At that time, if the cyst has not grown and the CA-125 level is normal, expectant management can continue, with reassessment in 4 to 6 months. If imaging remains unchanged and the CA-125 is persistently normal, the patient may be discharged from follow-up.⁸

If at any time during the evaluation the calculated RMI is greater than 200, there is an increased risk for malignancy, and the patient should be referred to a gynecologic oncologist for advanced imaging.

An algorithm from the Royal College of Obstetricians and Gynaecologists for managing ovarian cysts in postmenopausal women is available at www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/gtg_34.pdf.⁸

The American College of Radiology (ACR) has created a “Choosing Wisely” guideline to clarify when repeat imaging for ovarian cysts is indicated, to reduce both patient anxiety and healthcare costs.⁹ These guidelines highlight the distress women may experience from repeat testing due to concerns about cancer.

The guidelines also note that testing is often done during varying times of the menstrual cycle, thereby detecting new cysts, as opposed to monitoring previously detected cysts. Repeat ultrasonography may lead to surgical interventions that are not evidence-based, such as cystectomy or oophorectomy, in patients without radiologic features of malignancy or associated pelvic pain. And while ultrasonography is less expensive than other imaging tests, unnecessary imaging can mean additional costs to the patient, such as copayments, and possibly large payments for patients without insurance.

The American College of Obstetricians and Gynecologists (ACOG) and the ACR guidelines recommend against unnecessary repeat imaging for ovarian cysts.^7,10 The ACOG Practice Bulletin on the Evaluation and Management of Adnexal Masses states, “Simple cysts up to 10 cm in diameter on transvaginal ultrasonography performed by experienced ultrasonographers are likely benign and may be safely monitored using repeat imaging without surgical intervention, even in postmenopausal patients.”⁷

The ideal frequency for repeat testing is yet to be determined. In postmenopausal women with a simple cyst smaller than 5 cm, ACOG guidelines recommend an interval of 4 to 6 months for initial repeat imaging. ACR guidelines recommend no follow-up imaging for simple cysts smaller than 5 cm detected by high-quality ultrasonography in asymptomatic women of reproductive age or for simple cysts smaller than 1 cm in postmenopausal women.¹⁰

THE CLINICAL BOTTOM LINE

Simple ovarian cysts can develop as part of the normal menstrual cycle, and although they are more common in premenopausal women, they have been detected in 1 out of 5 postmenopausal women.⁹ Simple ovarian cysts are typically not cancerous in women of any age. Therefore, most simple ovarian cysts in asymp­tomatic women either require no follow-up imaging or can be safely monitored with limited repeat ultrasonography for a defined length of time.

Our 54-year-old postmenopausal patient has a simple cyst smaller than 5 cm. Based on current guidelines, the CA-125 level should be measured, with subsequent calculation of the RMI. Assuming a normal CA-125 and RMI, she should be reassured that the risk of progression to malignancy is extremely low. Repeating ultrasonography 4 to 6 months after the initial imaging is warranted. At that time, if no change in cyst size or composition is detected, ultrasonography can be repeated at 1 year after initial detection. After that, assuming no changes of the cyst on repeat imaging, the patient does not require additional follow-up.

In 2017, the American College of Cardiology (ACC), American Heart Association (AHA), and 9 other professional associations published a new guideline on high blood pressure in adults.¹ Their document addresses a range of topics relevant to preventing, diagnosing, and managing hypertension. It incorporates evidence from randomized controlled trials, including the Systolic Blood Pressure Intervention Trial (SPRINT),² systematic reviews, and expert opinion.

The new guidelines contain many noteworthy changes, some of which are generating intense debate and discussion. Here, we provide our opinions to help practicing clinicians broaden their perspective and make informed decisions about management.

ACC AND AHA ARE NOW RESPONSIBLE FOR HYPERTENSION GUIDELINES

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), organized by the National Heart, Lung, and Blood Institute, began issuing hypertension guidelines in 1977. Based on observational and clinical trial data, succeeding JNC reports recommended ever-lower blood pressure goals, with emphasis shifting to treatment of systolic hypertension.

The last official JNC report—JNC 7—was published in 2003.³ In 2013, the Institute transferred the responsibility for cardiovascular prevention guidelines to the ACC and AHA.⁴

A report from the panel members appointed to JNC 8 was published independently in 2014.⁵ It focused on a few key questions and used evidence limited to randomized controlled trials. In this report, the panel relaxed the goals for many subgroups, leading to criticism from many professional societies and from some members of the panel writing group.⁶

WHAT'S NEW IN THE 2017 GUIDELINES?

The new ACC/AHA guidelines contain a number of changes from previous documents that have been the topic of debate.

New definition and classification of hypertension

Strong recommendation, based on moderate-quality evidence­.

Our opinion. While this new classification is intended to promote closer monitoring and earlier intervention to lower cardiovascular event rates, creating a new level of disease may lead to more pharmacologic treatment for those with lower risk, without emphasis on lifestyle modifications.

Emphasis on measurement technique and out-of-office measurements

Strong recommendation, based on expert opinion, for accurate measurement of blood pressure in the office, high-quality evidence from systematic review for out-of-office measurement.

Appropriate management of hypertension entails accurate blood pressure measurement. While office-based measurement remains the most commonly used method, this “snapshot” may not reflect a patient’s true baseline blood pressure.

Out-of-office measurements. Based on the results of a systematic review commissioned by the guideline committee, out-of-office measurements are now recommended to confirm the diagnosis of hypertension and to assess response to therapy.

Ambulatory blood pressure monitoring should be strongly considered as the preferred method for out-of-office monitoring; home blood pressure monitoring can be done if ambulatory monitoring is not feasible. Ambulatory monitoring provides additional information on nighttime blood pressure, including the dipping status (normal defined as a nighttime blood pressure decrease of 10% to 20%). Ambulatory monitoring predicts long-term cardiovascular outcomes independent of office blood pressure, and elevated nighttime pressure and non-dipping have been shown to be independently associated with increased cardiovascular mortality rates.^8,9 Unfortunately, despite evidence supporting its use, ambulatory blood pressure monitoring is not widely available for a variety of reasons, including high cost (roughly $2,000–$4,000) and minimal reimbursement.

Out-of-office measurements can also detect white coat hypertension and masked hypertension. White coat hypertension is defined as blood pressure that is elevated in the office but normal in an out-of-office setting, and masked hypertension is blood pressure that is normal in the office and elevated in an out-of-office setting. Currently, pharmacologic therapy is not recommended to treat white coat hypertension, and treatment for masked hypertension should be the same as for sustained hypertension.

While the guidelines do not comment specifically on manual office measurement vs automated office measurements using devices that take multiple measurements with the patient alone in the room to reduce the white coat effect, they acknowledge “increasing evidence” favoring the use of automated office measurement.

Proper technique for measuring blood pressure is appropriately emphasized; correct patient positioning, allowing a period of rest, and using the appropriate cuff size are all important. Unfortunately, many busy clinical practices may not follow correct technique when measuring blood pressure in the office, leading to misdiagnosis and unnecessary pharmacologic therapy that may result in adverse events.

Of note, the SPRINT trial, which informed many of the new guideline recommendations, followed a strict protocol of blood pressure measurement with an automated device, checking sitting blood pressure 3 times at 1-minute intervals, with the patient alone in the room and without an observer present at many of the sites.¹⁰

Most guidelines^11,12 agree on an average of at least 135/85 mm Hg as the threshold for diagnosing hypertension by home monitoring, or an average daytime pressure of at least 135/85 mm Hg by ambulatory monitoring, corresponding with office-based blood pressure of 140/90 mm Hg.­ However, the new guidelines recommend a lower threshold of 130/80 mm Hg for both home monitoring and average daytime ambulatory monitoring, corresponding with an office blood pressure of 130/80 mm Hg. They do not specify whether the office-based measurement is manual or automated.

Our opinion. Since office-based measurement will likely remain the principal method for managing hypertension due to constraints with ambulatory or home monitoring, the use of automated devices for office measurement should be strongly considered. Studies have shown that, compared with routine office measurements, automated measurements more closely approximate those obtained by ambulatory and home blood pressure monitoring.¹³

Risk-based approach to hypertension management

The algorithm for hypertension management now incorporates objective assessment of cardiovascular risk. Specifically, it calls for estimation of the 10-year risk of atherosclerotic cardiovascular disease, defined as coronary heart disease death, nonfatal myocardial infarction, or fatal or nonfatal stroke.

The information required to estimate risk includes age, sex, race, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, use of blood pressure-lowering medication, diabetes status, and smoking status. The guideline recommends an easy-to-use online risk calculator (http://tools.acc.org/ASCVD-Risk-Estimator).

A 10-year risk of 10% or more is designated as the cutoff between high risk and low risk. However, this is not based on trial evidence, and the risk calculator has not been verified in prospective trials to show that its use reduces cardiovascular events. The SPRINT trial,² which was a study of blood pressure-lowering in high-risk patients, used a 10-year risk of 15% or more based on the Framingham risk score to delineate high risk.

Additionally, the 10-year risk calculator is valid only in patients ages 40 through 79, and some studies indicate that it may overestimate risk in older adults.^14,15 This overestimation may lead to patients being started on pharmacologic therapy when it may not truly be indicated. The risk calculator controversy has been discussed in a previous issue of this journal.¹⁶

Blood pressure goals

Strong recommendation for known cardiovascular disease or atherosclerotic cardiovascular disease risk 10% or greater, weak recommendation for risk less than 10%, based on moderate-quality evidence for systolic blood pressure, expert opinion for diastolic.

The guidelines recommend a blood pressure goal of less than 130/80 mm Hg for all patients, including the elderly and patients with chronic kidney disease or diabetes.

The SPRINT trial,² which showed better cardiovascular outcomes in the intensive treatment group (aiming for systolic pressure < 120 mm Hg) compared with a standard treatment group (aiming for systolic pressure < 140 mm Hg), excluded participants with diabetes and severe chronic kidney disease (estimated glomerular filtration rate < 20 mL/min/m² and proteinuria > 1 g/day), and those who were in nursing homes or had dementia.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial showed that intensive blood pressure control did not have cardiovascular benefits compared with standard therapy.¹⁷ However, many now believe that the study may have been underpowered due to its design, and a meta-analysis of the results from SPRINT and ACCORD suggested that findings from both trials were consistent, favoring intensive blood pressure control in a high-risk population.¹⁸

While the totality of evidence favors a lower achieved blood pressure for many patients, this lower goal may be difficult to achieve in many, particularly those with vascular stiffness, which is common in the elderly. These patients also tend to have low diastolic pressure, and lowering diastolic pressure below 60 mm Hg in those with documented coronary artery disease could increase the risk of adverse cardiovascular outcomes.^19,20 The guidelines do not address the potential issues with lowering diastolic blood pressure.

Our opinion. While a “universal” blood pressure goal may simplify decision-making, we believe it is important to individualize goals, taking into account patient characteristics, lifestyle factors, medication side effects, patient preferences, cost issues, and adherence to therapy.

The goal blood pressure should also consider the method of measurement. Systolic blood pressure readings have been reported to be 5 to 10 mm Hg lower with automated office measurement than with routine office measurement.²¹

It is also not clear that the magnitude of absolute benefit from pursuing more intensive blood pressure control with antihypertensive therapy in patients with high cardiovascular risk (as in SPRINT) would translate to similar benefits in a lower-risk population. Thus, we believe that in patients with lower cardiovascular risk, a goal blood pressure of less than 140/90 mm Hg (if routine office measurement is done) and less than 135/85 mm Hg (if automated office measurement is done) would be reasonable.

We also believe that it is reasonable to relax these goals in the very elderly (age ≥ 80), especially those who are frail and at risk of falls, with low diastolic pressures. In these patients, we recommend individualizing blood pressure goals that can be achieved without significant side effects from antihypertensive therapy.

Nonpharmacologic therapy

Strong recommendation, based on high-quality evidence from randomized controlled trials

Nonpharmacologic therapy and lifestyle modification are appropriately emphasized in the new guidelines. Most of the lifestyle changes that are recommended are in concordance with prior JNC 7 recommendations.³

Recognizing the roles of sodium and potassium in the pathogenesis of hypertension, the guidelines emphasize a diet that is higher in potassium, the DASH (Dietary Approaches to Stop Hypertension) diet, and a low-sodium diet. The recommended optimal goal of sodium intake of less than 1,500 mg/day may be difficult to achieve with a Western diet, and there is debate about the potential adverse effects of a very-low sodium diet.²² The general recommendation for sodium intake of less than 2,300 mg/day is supported in the literature, and it is unclear if further reduction has additional beneficial effects on blood pressure.²³

The guidelines recommend a 3- to 6-month reassessment of patients who are prescribed risk-factor modification, but are unclear about initiation of pharmacologic therapy or other steps if these low-risk patients have not responded to lifestyle modifications alone at the time of reassessment.

Pharmacologic therapy

Strong recommendation, based on high-quality evidence from randomized controlled trials for systolic blood pressure, expert opinion for diastolic blood pressure for those with atherosclerotic cardiovascular disease risk 10% or greater, and limited data for those with risk less than 10%.

Pharmacologic therapy is recommended in patients with stage 1 hypertension and pre-existing cardiovascular disease or 10-year risk of atherosclerotic cardiovascular disease of 10% or more, and in those with stage 2 hypertension even if their 10-year risk is less than 10%.

In the absence of compelling indications, the primary drugs recommended for initial therapy are:

• Thiazide or thiazide-type diuretics (preferably chlorthalidone)
• Angiotensin-converting enzyme (ACE) inhibitors
• Angiotensin II receptor blockers (ARBs)
• Calcium channel blockers (CCBs).

In black adults, thiazide diuretics or CCBs are recommended for initial therapy. Beta-blockers are not recommended as first-line agents in the absence of a compelling indication, although meta-analyses that suggested beta-blockers are less effective than other classes of agents included trials that used beta-blockers in doses now considered suboptimal. ACE inhibitors or ARBs are recommended as initial therapy in proteinuric patients with chronic kidney disease or diabetes. Combining an ACE inhibitor and an ARB or renin inhibitor is potentially harmful and is not recommended. The guidelines provide a helpful table describing important characteristics and available dosage forms of the commonly used antihypertensive agents.

These recommendations are concordant with the JNC 8 panel recommendations,⁵ and differ from JNC 7, which recommended thiazide-type diuretics as first-line therapy.³ The European guidelines recommend that all major classes of antihypertensive agents, including beta-blockers, are suitable for initiation of therapy.²⁴ The UK National Institute for Clinical Excellence guidelines adopt an age-based approach to deciding initial therapy—with ACE inhibitors or ARBs favored in those below the age of 55 and CCBs in those who are 55 and older.²⁵

Starting with a single antihypertensive agent is recommended for stage 1 hypertension with increased cardiovascular risk, and starting with 2 agents (either separately or in fixed-dose combination) is recommended for stage 2 hypertension. The guidelines emphasize a team-based approach to improve hypertension care, using adjunctive interventions such as telehealth strategies and leveraging electronic medical records to guide quality improvement initiatives.

Our opinion. We agree with Bakris and Sorrentino^₂₆ that general patient profiles should be considered to decide on efficient pharmacologic management in clinical practice—thiazide diuretics would be best in those who are volume-expanded; ACE inhibitors, ARBs, or CCBs in those who are obese or have metabolic syndrome; and beta-blockers or nondihydropyridine CCBs in those who are hyperadrenergic. More patients will likely be classified as having resistant hypertension based on the blood pressure goal of less than 130/80 mm Hg, which may require greater use of mineralocorticoid receptor antagonists such as spironolactone.

STRENGTHS AND LIMITATIONS

The new guidelines stress correct technique of blood pressure measurement, out-of-office and self-monitoring of blood pressure, and lifestyle modifications. In addition, they comprehensively review topics relevant to hypertension management of practical use for healthcare providers, including resistant hypertension, secondary hypertension, hypertensive crises, and special populations. The guidelines also incorporate multiple lines of evidence rather than just randomized controlled trials (which may not be available for every scenario).

There will be ongoing debate and discussion about the new definition and classification of hypertension, and the “conversion” of previously healthy adults to a new disease category. The blood pressure goals will also be debated: Should the goal for a young patient be applied to an elderly patient? The pathophysiology of the disease process should be considered rather than a one-size-fits-all approach. For example, older patients with stiff arteries and low diastolic blood pressure will have more difficulty achieving a lower systolic pressure, are more likely to experience medication side effects, and may have adherence issues due to polypharmacy.

A clinical trial, with strict adherence to protocols and rigorous follow-up procedures, is different from real-world clinical practice. Busy clinical practices with time and space constraints may forgo the steps needed for accurate blood pressure measurement in the office and may not reinforce lifestyle modifications, instead opting for more pharmacologic therapy to achieve a blood pressure goal that may become mandated by healthcare payment models without consideration for clinical judgment and individual patient characteristics.

The ACC/AHA guidelines have not been universally endorsed. The American College of Physicians and the American Academy of Family Physicians released their own guidelines for older adults earlier in 2017, echoing the recommendations from the panel appointed to JNC 8.²⁷ Contrasting recommendations can unfortunately lead to confusion among healthcare providers and patients and can undermine confidence and trust in the healthcare system.

In the background of ongoing debate, where battle lines have been drawn by key stakeholders with regard to their contrasting positions, it is even more important for the practicing clinician who is in the front lines of hypertension management to be knowledgeable about the pros and cons of different recommendations as they apply to individual patients, and to be able to clearly communicate this with patients when deciding on a treatment plan.

FINAL THOUGHTS

• Accurate measurement of blood pressure in the office is imperative—position the patient properly, use an appropriately sized  cuff, and allow for a period of rest. Consider using automated office measurement to minimize potential white coat effect.
• Out-of-office blood pressure monitoring is recommended to confirm the diagnosis of hypertension and for monitoring response to therapy. Ambulatory monitoring is preferred, but home blood pressure monitoring can be done if ambulatory monitoring is unavailable or unfeasible.
• Nonpharmacologic therapy should be emphasized for everyone, regardless of blood pressure level.
• Guidelines should be used as a framework for management. Individualize decisions about blood pressure goals and pharmacologic therapy based on patient characteristics and clinical judgment.

In 2017, the American College of Cardiology (ACC), American Heart Association (AHA), and 9 other professional associations published a new guideline on high blood pressure in adults.¹ Their document addresses a range of topics relevant to preventing, diagnosing, and managing hypertension. It incorporates evidence from randomized controlled trials, including the Systolic Blood Pressure Intervention Trial (SPRINT),² systematic reviews, and expert opinion.

The new guidelines contain many noteworthy changes, some of which are generating intense debate and discussion. Here, we provide our opinions to help practicing clinicians broaden their perspective and make informed decisions about management.

ACC AND AHA ARE NOW RESPONSIBLE FOR HYPERTENSION GUIDELINES

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), organized by the National Heart, Lung, and Blood Institute, began issuing hypertension guidelines in 1977. Based on observational and clinical trial data, succeeding JNC reports recommended ever-lower blood pressure goals, with emphasis shifting to treatment of systolic hypertension.

The last official JNC report—JNC 7—was published in 2003.³ In 2013, the Institute transferred the responsibility for cardiovascular prevention guidelines to the ACC and AHA.⁴

A report from the panel members appointed to JNC 8 was published independently in 2014.⁵ It focused on a few key questions and used evidence limited to randomized controlled trials. In this report, the panel relaxed the goals for many subgroups, leading to criticism from many professional societies and from some members of the panel writing group.⁶

WHAT'S NEW IN THE 2017 GUIDELINES?

The new ACC/AHA guidelines contain a number of changes from previous documents that have been the topic of debate.

New definition and classification of hypertension

Strong recommendation, based on moderate-quality evidence­.

Our opinion. While this new classification is intended to promote closer monitoring and earlier intervention to lower cardiovascular event rates, creating a new level of disease may lead to more pharmacologic treatment for those with lower risk, without emphasis on lifestyle modifications.

Emphasis on measurement technique and out-of-office measurements

Strong recommendation, based on expert opinion, for accurate measurement of blood pressure in the office, high-quality evidence from systematic review for out-of-office measurement.

Appropriate management of hypertension entails accurate blood pressure measurement. While office-based measurement remains the most commonly used method, this “snapshot” may not reflect a patient’s true baseline blood pressure.

Out-of-office measurements. Based on the results of a systematic review commissioned by the guideline committee, out-of-office measurements are now recommended to confirm the diagnosis of hypertension and to assess response to therapy.

Ambulatory blood pressure monitoring should be strongly considered as the preferred method for out-of-office monitoring; home blood pressure monitoring can be done if ambulatory monitoring is not feasible. Ambulatory monitoring provides additional information on nighttime blood pressure, including the dipping status (normal defined as a nighttime blood pressure decrease of 10% to 20%). Ambulatory monitoring predicts long-term cardiovascular outcomes independent of office blood pressure, and elevated nighttime pressure and non-dipping have been shown to be independently associated with increased cardiovascular mortality rates.^8,9 Unfortunately, despite evidence supporting its use, ambulatory blood pressure monitoring is not widely available for a variety of reasons, including high cost (roughly $2,000–$4,000) and minimal reimbursement.

Out-of-office measurements can also detect white coat hypertension and masked hypertension. White coat hypertension is defined as blood pressure that is elevated in the office but normal in an out-of-office setting, and masked hypertension is blood pressure that is normal in the office and elevated in an out-of-office setting. Currently, pharmacologic therapy is not recommended to treat white coat hypertension, and treatment for masked hypertension should be the same as for sustained hypertension.

While the guidelines do not comment specifically on manual office measurement vs automated office measurements using devices that take multiple measurements with the patient alone in the room to reduce the white coat effect, they acknowledge “increasing evidence” favoring the use of automated office measurement.

Proper technique for measuring blood pressure is appropriately emphasized; correct patient positioning, allowing a period of rest, and using the appropriate cuff size are all important. Unfortunately, many busy clinical practices may not follow correct technique when measuring blood pressure in the office, leading to misdiagnosis and unnecessary pharmacologic therapy that may result in adverse events.

Of note, the SPRINT trial, which informed many of the new guideline recommendations, followed a strict protocol of blood pressure measurement with an automated device, checking sitting blood pressure 3 times at 1-minute intervals, with the patient alone in the room and without an observer present at many of the sites.¹⁰

Most guidelines^11,12 agree on an average of at least 135/85 mm Hg as the threshold for diagnosing hypertension by home monitoring, or an average daytime pressure of at least 135/85 mm Hg by ambulatory monitoring, corresponding with office-based blood pressure of 140/90 mm Hg.­ However, the new guidelines recommend a lower threshold of 130/80 mm Hg for both home monitoring and average daytime ambulatory monitoring, corresponding with an office blood pressure of 130/80 mm Hg. They do not specify whether the office-based measurement is manual or automated.

Our opinion. Since office-based measurement will likely remain the principal method for managing hypertension due to constraints with ambulatory or home monitoring, the use of automated devices for office measurement should be strongly considered. Studies have shown that, compared with routine office measurements, automated measurements more closely approximate those obtained by ambulatory and home blood pressure monitoring.¹³

Risk-based approach to hypertension management

The algorithm for hypertension management now incorporates objective assessment of cardiovascular risk. Specifically, it calls for estimation of the 10-year risk of atherosclerotic cardiovascular disease, defined as coronary heart disease death, nonfatal myocardial infarction, or fatal or nonfatal stroke.

The information required to estimate risk includes age, sex, race, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, use of blood pressure-lowering medication, diabetes status, and smoking status. The guideline recommends an easy-to-use online risk calculator (http://tools.acc.org/ASCVD-Risk-Estimator).

A 10-year risk of 10% or more is designated as the cutoff between high risk and low risk. However, this is not based on trial evidence, and the risk calculator has not been verified in prospective trials to show that its use reduces cardiovascular events. The SPRINT trial,² which was a study of blood pressure-lowering in high-risk patients, used a 10-year risk of 15% or more based on the Framingham risk score to delineate high risk.

Additionally, the 10-year risk calculator is valid only in patients ages 40 through 79, and some studies indicate that it may overestimate risk in older adults.^14,15 This overestimation may lead to patients being started on pharmacologic therapy when it may not truly be indicated. The risk calculator controversy has been discussed in a previous issue of this journal.¹⁶

Blood pressure goals

Strong recommendation for known cardiovascular disease or atherosclerotic cardiovascular disease risk 10% or greater, weak recommendation for risk less than 10%, based on moderate-quality evidence for systolic blood pressure, expert opinion for diastolic.

The guidelines recommend a blood pressure goal of less than 130/80 mm Hg for all patients, including the elderly and patients with chronic kidney disease or diabetes.

The SPRINT trial,² which showed better cardiovascular outcomes in the intensive treatment group (aiming for systolic pressure < 120 mm Hg) compared with a standard treatment group (aiming for systolic pressure < 140 mm Hg), excluded participants with diabetes and severe chronic kidney disease (estimated glomerular filtration rate < 20 mL/min/m² and proteinuria > 1 g/day), and those who were in nursing homes or had dementia.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial showed that intensive blood pressure control did not have cardiovascular benefits compared with standard therapy.¹⁷ However, many now believe that the study may have been underpowered due to its design, and a meta-analysis of the results from SPRINT and ACCORD suggested that findings from both trials were consistent, favoring intensive blood pressure control in a high-risk population.¹⁸

While the totality of evidence favors a lower achieved blood pressure for many patients, this lower goal may be difficult to achieve in many, particularly those with vascular stiffness, which is common in the elderly. These patients also tend to have low diastolic pressure, and lowering diastolic pressure below 60 mm Hg in those with documented coronary artery disease could increase the risk of adverse cardiovascular outcomes.^19,20 The guidelines do not address the potential issues with lowering diastolic blood pressure.

Our opinion. While a “universal” blood pressure goal may simplify decision-making, we believe it is important to individualize goals, taking into account patient characteristics, lifestyle factors, medication side effects, patient preferences, cost issues, and adherence to therapy.

The goal blood pressure should also consider the method of measurement. Systolic blood pressure readings have been reported to be 5 to 10 mm Hg lower with automated office measurement than with routine office measurement.²¹

It is also not clear that the magnitude of absolute benefit from pursuing more intensive blood pressure control with antihypertensive therapy in patients with high cardiovascular risk (as in SPRINT) would translate to similar benefits in a lower-risk population. Thus, we believe that in patients with lower cardiovascular risk, a goal blood pressure of less than 140/90 mm Hg (if routine office measurement is done) and less than 135/85 mm Hg (if automated office measurement is done) would be reasonable.

We also believe that it is reasonable to relax these goals in the very elderly (age ≥ 80), especially those who are frail and at risk of falls, with low diastolic pressures. In these patients, we recommend individualizing blood pressure goals that can be achieved without significant side effects from antihypertensive therapy.

Nonpharmacologic therapy

Strong recommendation, based on high-quality evidence from randomized controlled trials

Nonpharmacologic therapy and lifestyle modification are appropriately emphasized in the new guidelines. Most of the lifestyle changes that are recommended are in concordance with prior JNC 7 recommendations.³

Recognizing the roles of sodium and potassium in the pathogenesis of hypertension, the guidelines emphasize a diet that is higher in potassium, the DASH (Dietary Approaches to Stop Hypertension) diet, and a low-sodium diet. The recommended optimal goal of sodium intake of less than 1,500 mg/day may be difficult to achieve with a Western diet, and there is debate about the potential adverse effects of a very-low sodium diet.²² The general recommendation for sodium intake of less than 2,300 mg/day is supported in the literature, and it is unclear if further reduction has additional beneficial effects on blood pressure.²³

The guidelines recommend a 3- to 6-month reassessment of patients who are prescribed risk-factor modification, but are unclear about initiation of pharmacologic therapy or other steps if these low-risk patients have not responded to lifestyle modifications alone at the time of reassessment.

Pharmacologic therapy

Strong recommendation, based on high-quality evidence from randomized controlled trials for systolic blood pressure, expert opinion for diastolic blood pressure for those with atherosclerotic cardiovascular disease risk 10% or greater, and limited data for those with risk less than 10%.

Pharmacologic therapy is recommended in patients with stage 1 hypertension and pre-existing cardiovascular disease or 10-year risk of atherosclerotic cardiovascular disease of 10% or more, and in those with stage 2 hypertension even if their 10-year risk is less than 10%.

In the absence of compelling indications, the primary drugs recommended for initial therapy are:

• Thiazide or thiazide-type diuretics (preferably chlorthalidone)
• Angiotensin-converting enzyme (ACE) inhibitors
• Angiotensin II receptor blockers (ARBs)
• Calcium channel blockers (CCBs).

In black adults, thiazide diuretics or CCBs are recommended for initial therapy. Beta-blockers are not recommended as first-line agents in the absence of a compelling indication, although meta-analyses that suggested beta-blockers are less effective than other classes of agents included trials that used beta-blockers in doses now considered suboptimal. ACE inhibitors or ARBs are recommended as initial therapy in proteinuric patients with chronic kidney disease or diabetes. Combining an ACE inhibitor and an ARB or renin inhibitor is potentially harmful and is not recommended. The guidelines provide a helpful table describing important characteristics and available dosage forms of the commonly used antihypertensive agents.

These recommendations are concordant with the JNC 8 panel recommendations,⁵ and differ from JNC 7, which recommended thiazide-type diuretics as first-line therapy.³ The European guidelines recommend that all major classes of antihypertensive agents, including beta-blockers, are suitable for initiation of therapy.²⁴ The UK National Institute for Clinical Excellence guidelines adopt an age-based approach to deciding initial therapy—with ACE inhibitors or ARBs favored in those below the age of 55 and CCBs in those who are 55 and older.²⁵

Starting with a single antihypertensive agent is recommended for stage 1 hypertension with increased cardiovascular risk, and starting with 2 agents (either separately or in fixed-dose combination) is recommended for stage 2 hypertension. The guidelines emphasize a team-based approach to improve hypertension care, using adjunctive interventions such as telehealth strategies and leveraging electronic medical records to guide quality improvement initiatives.

Our opinion. We agree with Bakris and Sorrentino^₂₆ that general patient profiles should be considered to decide on efficient pharmacologic management in clinical practice—thiazide diuretics would be best in those who are volume-expanded; ACE inhibitors, ARBs, or CCBs in those who are obese or have metabolic syndrome; and beta-blockers or nondihydropyridine CCBs in those who are hyperadrenergic. More patients will likely be classified as having resistant hypertension based on the blood pressure goal of less than 130/80 mm Hg, which may require greater use of mineralocorticoid receptor antagonists such as spironolactone.

STRENGTHS AND LIMITATIONS

The new guidelines stress correct technique of blood pressure measurement, out-of-office and self-monitoring of blood pressure, and lifestyle modifications. In addition, they comprehensively review topics relevant to hypertension management of practical use for healthcare providers, including resistant hypertension, secondary hypertension, hypertensive crises, and special populations. The guidelines also incorporate multiple lines of evidence rather than just randomized controlled trials (which may not be available for every scenario).

There will be ongoing debate and discussion about the new definition and classification of hypertension, and the “conversion” of previously healthy adults to a new disease category. The blood pressure goals will also be debated: Should the goal for a young patient be applied to an elderly patient? The pathophysiology of the disease process should be considered rather than a one-size-fits-all approach. For example, older patients with stiff arteries and low diastolic blood pressure will have more difficulty achieving a lower systolic pressure, are more likely to experience medication side effects, and may have adherence issues due to polypharmacy.

A clinical trial, with strict adherence to protocols and rigorous follow-up procedures, is different from real-world clinical practice. Busy clinical practices with time and space constraints may forgo the steps needed for accurate blood pressure measurement in the office and may not reinforce lifestyle modifications, instead opting for more pharmacologic therapy to achieve a blood pressure goal that may become mandated by healthcare payment models without consideration for clinical judgment and individual patient characteristics.

The ACC/AHA guidelines have not been universally endorsed. The American College of Physicians and the American Academy of Family Physicians released their own guidelines for older adults earlier in 2017, echoing the recommendations from the panel appointed to JNC 8.²⁷ Contrasting recommendations can unfortunately lead to confusion among healthcare providers and patients and can undermine confidence and trust in the healthcare system.

In the background of ongoing debate, where battle lines have been drawn by key stakeholders with regard to their contrasting positions, it is even more important for the practicing clinician who is in the front lines of hypertension management to be knowledgeable about the pros and cons of different recommendations as they apply to individual patients, and to be able to clearly communicate this with patients when deciding on a treatment plan.

FINAL THOUGHTS

• Accurate measurement of blood pressure in the office is imperative—position the patient properly, use an appropriately sized  cuff, and allow for a period of rest. Consider using automated office measurement to minimize potential white coat effect.
• Out-of-office blood pressure monitoring is recommended to confirm the diagnosis of hypertension and for monitoring response to therapy. Ambulatory monitoring is preferred, but home blood pressure monitoring can be done if ambulatory monitoring is unavailable or unfeasible.
• Nonpharmacologic therapy should be emphasized for everyone, regardless of blood pressure level.
• Guidelines should be used as a framework for management. Individualize decisions about blood pressure goals and pharmacologic therapy based on patient characteristics and clinical judgment.

In 2017, the American College of Cardiology (ACC), American Heart Association (AHA), and 9 other professional associations published a new guideline on high blood pressure in adults.¹ Their document addresses a range of topics relevant to preventing, diagnosing, and managing hypertension. It incorporates evidence from randomized controlled trials, including the Systolic Blood Pressure Intervention Trial (SPRINT),² systematic reviews, and expert opinion.

The new guidelines contain many noteworthy changes, some of which are generating intense debate and discussion. Here, we provide our opinions to help practicing clinicians broaden their perspective and make informed decisions about management.

ACC AND AHA ARE NOW RESPONSIBLE FOR HYPERTENSION GUIDELINES

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), organized by the National Heart, Lung, and Blood Institute, began issuing hypertension guidelines in 1977. Based on observational and clinical trial data, succeeding JNC reports recommended ever-lower blood pressure goals, with emphasis shifting to treatment of systolic hypertension.

The last official JNC report—JNC 7—was published in 2003.³ In 2013, the Institute transferred the responsibility for cardiovascular prevention guidelines to the ACC and AHA.⁴

A report from the panel members appointed to JNC 8 was published independently in 2014.⁵ It focused on a few key questions and used evidence limited to randomized controlled trials. In this report, the panel relaxed the goals for many subgroups, leading to criticism from many professional societies and from some members of the panel writing group.⁶

WHAT'S NEW IN THE 2017 GUIDELINES?

The new ACC/AHA guidelines contain a number of changes from previous documents that have been the topic of debate.

New definition and classification of hypertension

Strong recommendation, based on moderate-quality evidence­.

Our opinion. While this new classification is intended to promote closer monitoring and earlier intervention to lower cardiovascular event rates, creating a new level of disease may lead to more pharmacologic treatment for those with lower risk, without emphasis on lifestyle modifications.

Emphasis on measurement technique and out-of-office measurements

Strong recommendation, based on expert opinion, for accurate measurement of blood pressure in the office, high-quality evidence from systematic review for out-of-office measurement.

Appropriate management of hypertension entails accurate blood pressure measurement. While office-based measurement remains the most commonly used method, this “snapshot” may not reflect a patient’s true baseline blood pressure.

Out-of-office measurements. Based on the results of a systematic review commissioned by the guideline committee, out-of-office measurements are now recommended to confirm the diagnosis of hypertension and to assess response to therapy.

Ambulatory blood pressure monitoring should be strongly considered as the preferred method for out-of-office monitoring; home blood pressure monitoring can be done if ambulatory monitoring is not feasible. Ambulatory monitoring provides additional information on nighttime blood pressure, including the dipping status (normal defined as a nighttime blood pressure decrease of 10% to 20%). Ambulatory monitoring predicts long-term cardiovascular outcomes independent of office blood pressure, and elevated nighttime pressure and non-dipping have been shown to be independently associated with increased cardiovascular mortality rates.^8,9 Unfortunately, despite evidence supporting its use, ambulatory blood pressure monitoring is not widely available for a variety of reasons, including high cost (roughly $2,000–$4,000) and minimal reimbursement.

Out-of-office measurements can also detect white coat hypertension and masked hypertension. White coat hypertension is defined as blood pressure that is elevated in the office but normal in an out-of-office setting, and masked hypertension is blood pressure that is normal in the office and elevated in an out-of-office setting. Currently, pharmacologic therapy is not recommended to treat white coat hypertension, and treatment for masked hypertension should be the same as for sustained hypertension.

While the guidelines do not comment specifically on manual office measurement vs automated office measurements using devices that take multiple measurements with the patient alone in the room to reduce the white coat effect, they acknowledge “increasing evidence” favoring the use of automated office measurement.

Proper technique for measuring blood pressure is appropriately emphasized; correct patient positioning, allowing a period of rest, and using the appropriate cuff size are all important. Unfortunately, many busy clinical practices may not follow correct technique when measuring blood pressure in the office, leading to misdiagnosis and unnecessary pharmacologic therapy that may result in adverse events.

Of note, the SPRINT trial, which informed many of the new guideline recommendations, followed a strict protocol of blood pressure measurement with an automated device, checking sitting blood pressure 3 times at 1-minute intervals, with the patient alone in the room and without an observer present at many of the sites.¹⁰

Most guidelines^11,12 agree on an average of at least 135/85 mm Hg as the threshold for diagnosing hypertension by home monitoring, or an average daytime pressure of at least 135/85 mm Hg by ambulatory monitoring, corresponding with office-based blood pressure of 140/90 mm Hg.­ However, the new guidelines recommend a lower threshold of 130/80 mm Hg for both home monitoring and average daytime ambulatory monitoring, corresponding with an office blood pressure of 130/80 mm Hg. They do not specify whether the office-based measurement is manual or automated.

Our opinion. Since office-based measurement will likely remain the principal method for managing hypertension due to constraints with ambulatory or home monitoring, the use of automated devices for office measurement should be strongly considered. Studies have shown that, compared with routine office measurements, automated measurements more closely approximate those obtained by ambulatory and home blood pressure monitoring.¹³

Risk-based approach to hypertension management

The algorithm for hypertension management now incorporates objective assessment of cardiovascular risk. Specifically, it calls for estimation of the 10-year risk of atherosclerotic cardiovascular disease, defined as coronary heart disease death, nonfatal myocardial infarction, or fatal or nonfatal stroke.

The information required to estimate risk includes age, sex, race, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, use of blood pressure-lowering medication, diabetes status, and smoking status. The guideline recommends an easy-to-use online risk calculator (http://tools.acc.org/ASCVD-Risk-Estimator).

A 10-year risk of 10% or more is designated as the cutoff between high risk and low risk. However, this is not based on trial evidence, and the risk calculator has not been verified in prospective trials to show that its use reduces cardiovascular events. The SPRINT trial,² which was a study of blood pressure-lowering in high-risk patients, used a 10-year risk of 15% or more based on the Framingham risk score to delineate high risk.

Additionally, the 10-year risk calculator is valid only in patients ages 40 through 79, and some studies indicate that it may overestimate risk in older adults.^14,15 This overestimation may lead to patients being started on pharmacologic therapy when it may not truly be indicated. The risk calculator controversy has been discussed in a previous issue of this journal.¹⁶

Blood pressure goals

Strong recommendation for known cardiovascular disease or atherosclerotic cardiovascular disease risk 10% or greater, weak recommendation for risk less than 10%, based on moderate-quality evidence for systolic blood pressure, expert opinion for diastolic.

The guidelines recommend a blood pressure goal of less than 130/80 mm Hg for all patients, including the elderly and patients with chronic kidney disease or diabetes.

The SPRINT trial,² which showed better cardiovascular outcomes in the intensive treatment group (aiming for systolic pressure < 120 mm Hg) compared with a standard treatment group (aiming for systolic pressure < 140 mm Hg), excluded participants with diabetes and severe chronic kidney disease (estimated glomerular filtration rate < 20 mL/min/m² and proteinuria > 1 g/day), and those who were in nursing homes or had dementia.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure trial showed that intensive blood pressure control did not have cardiovascular benefits compared with standard therapy.¹⁷ However, many now believe that the study may have been underpowered due to its design, and a meta-analysis of the results from SPRINT and ACCORD suggested that findings from both trials were consistent, favoring intensive blood pressure control in a high-risk population.¹⁸

While the totality of evidence favors a lower achieved blood pressure for many patients, this lower goal may be difficult to achieve in many, particularly those with vascular stiffness, which is common in the elderly. These patients also tend to have low diastolic pressure, and lowering diastolic pressure below 60 mm Hg in those with documented coronary artery disease could increase the risk of adverse cardiovascular outcomes.^19,20 The guidelines do not address the potential issues with lowering diastolic blood pressure.

Our opinion. While a “universal” blood pressure goal may simplify decision-making, we believe it is important to individualize goals, taking into account patient characteristics, lifestyle factors, medication side effects, patient preferences, cost issues, and adherence to therapy.

The goal blood pressure should also consider the method of measurement. Systolic blood pressure readings have been reported to be 5 to 10 mm Hg lower with automated office measurement than with routine office measurement.²¹

It is also not clear that the magnitude of absolute benefit from pursuing more intensive blood pressure control with antihypertensive therapy in patients with high cardiovascular risk (as in SPRINT) would translate to similar benefits in a lower-risk population. Thus, we believe that in patients with lower cardiovascular risk, a goal blood pressure of less than 140/90 mm Hg (if routine office measurement is done) and less than 135/85 mm Hg (if automated office measurement is done) would be reasonable.

We also believe that it is reasonable to relax these goals in the very elderly (age ≥ 80), especially those who are frail and at risk of falls, with low diastolic pressures. In these patients, we recommend individualizing blood pressure goals that can be achieved without significant side effects from antihypertensive therapy.

Nonpharmacologic therapy

Strong recommendation, based on high-quality evidence from randomized controlled trials

Nonpharmacologic therapy and lifestyle modification are appropriately emphasized in the new guidelines. Most of the lifestyle changes that are recommended are in concordance with prior JNC 7 recommendations.³

Recognizing the roles of sodium and potassium in the pathogenesis of hypertension, the guidelines emphasize a diet that is higher in potassium, the DASH (Dietary Approaches to Stop Hypertension) diet, and a low-sodium diet. The recommended optimal goal of sodium intake of less than 1,500 mg/day may be difficult to achieve with a Western diet, and there is debate about the potential adverse effects of a very-low sodium diet.²² The general recommendation for sodium intake of less than 2,300 mg/day is supported in the literature, and it is unclear if further reduction has additional beneficial effects on blood pressure.²³

The guidelines recommend a 3- to 6-month reassessment of patients who are prescribed risk-factor modification, but are unclear about initiation of pharmacologic therapy or other steps if these low-risk patients have not responded to lifestyle modifications alone at the time of reassessment.

Pharmacologic therapy

Strong recommendation, based on high-quality evidence from randomized controlled trials for systolic blood pressure, expert opinion for diastolic blood pressure for those with atherosclerotic cardiovascular disease risk 10% or greater, and limited data for those with risk less than 10%.

Pharmacologic therapy is recommended in patients with stage 1 hypertension and pre-existing cardiovascular disease or 10-year risk of atherosclerotic cardiovascular disease of 10% or more, and in those with stage 2 hypertension even if their 10-year risk is less than 10%.

In the absence of compelling indications, the primary drugs recommended for initial therapy are:

• Thiazide or thiazide-type diuretics (preferably chlorthalidone)
• Angiotensin-converting enzyme (ACE) inhibitors
• Angiotensin II receptor blockers (ARBs)
• Calcium channel blockers (CCBs).

In black adults, thiazide diuretics or CCBs are recommended for initial therapy. Beta-blockers are not recommended as first-line agents in the absence of a compelling indication, although meta-analyses that suggested beta-blockers are less effective than other classes of agents included trials that used beta-blockers in doses now considered suboptimal. ACE inhibitors or ARBs are recommended as initial therapy in proteinuric patients with chronic kidney disease or diabetes. Combining an ACE inhibitor and an ARB or renin inhibitor is potentially harmful and is not recommended. The guidelines provide a helpful table describing important characteristics and available dosage forms of the commonly used antihypertensive agents.

These recommendations are concordant with the JNC 8 panel recommendations,⁵ and differ from JNC 7, which recommended thiazide-type diuretics as first-line therapy.³ The European guidelines recommend that all major classes of antihypertensive agents, including beta-blockers, are suitable for initiation of therapy.²⁴ The UK National Institute for Clinical Excellence guidelines adopt an age-based approach to deciding initial therapy—with ACE inhibitors or ARBs favored in those below the age of 55 and CCBs in those who are 55 and older.²⁵

Starting with a single antihypertensive agent is recommended for stage 1 hypertension with increased cardiovascular risk, and starting with 2 agents (either separately or in fixed-dose combination) is recommended for stage 2 hypertension. The guidelines emphasize a team-based approach to improve hypertension care, using adjunctive interventions such as telehealth strategies and leveraging electronic medical records to guide quality improvement initiatives.

Our opinion. We agree with Bakris and Sorrentino^₂₆ that general patient profiles should be considered to decide on efficient pharmacologic management in clinical practice—thiazide diuretics would be best in those who are volume-expanded; ACE inhibitors, ARBs, or CCBs in those who are obese or have metabolic syndrome; and beta-blockers or nondihydropyridine CCBs in those who are hyperadrenergic. More patients will likely be classified as having resistant hypertension based on the blood pressure goal of less than 130/80 mm Hg, which may require greater use of mineralocorticoid receptor antagonists such as spironolactone.

STRENGTHS AND LIMITATIONS

The new guidelines stress correct technique of blood pressure measurement, out-of-office and self-monitoring of blood pressure, and lifestyle modifications. In addition, they comprehensively review topics relevant to hypertension management of practical use for healthcare providers, including resistant hypertension, secondary hypertension, hypertensive crises, and special populations. The guidelines also incorporate multiple lines of evidence rather than just randomized controlled trials (which may not be available for every scenario).

There will be ongoing debate and discussion about the new definition and classification of hypertension, and the “conversion” of previously healthy adults to a new disease category. The blood pressure goals will also be debated: Should the goal for a young patient be applied to an elderly patient? The pathophysiology of the disease process should be considered rather than a one-size-fits-all approach. For example, older patients with stiff arteries and low diastolic blood pressure will have more difficulty achieving a lower systolic pressure, are more likely to experience medication side effects, and may have adherence issues due to polypharmacy.

A clinical trial, with strict adherence to protocols and rigorous follow-up procedures, is different from real-world clinical practice. Busy clinical practices with time and space constraints may forgo the steps needed for accurate blood pressure measurement in the office and may not reinforce lifestyle modifications, instead opting for more pharmacologic therapy to achieve a blood pressure goal that may become mandated by healthcare payment models without consideration for clinical judgment and individual patient characteristics.

The ACC/AHA guidelines have not been universally endorsed. The American College of Physicians and the American Academy of Family Physicians released their own guidelines for older adults earlier in 2017, echoing the recommendations from the panel appointed to JNC 8.²⁷ Contrasting recommendations can unfortunately lead to confusion among healthcare providers and patients and can undermine confidence and trust in the healthcare system.

In the background of ongoing debate, where battle lines have been drawn by key stakeholders with regard to their contrasting positions, it is even more important for the practicing clinician who is in the front lines of hypertension management to be knowledgeable about the pros and cons of different recommendations as they apply to individual patients, and to be able to clearly communicate this with patients when deciding on a treatment plan.

FINAL THOUGHTS

• Accurate measurement of blood pressure in the office is imperative—position the patient properly, use an appropriately sized  cuff, and allow for a period of rest. Consider using automated office measurement to minimize potential white coat effect.
• Out-of-office blood pressure monitoring is recommended to confirm the diagnosis of hypertension and for monitoring response to therapy. Ambulatory monitoring is preferred, but home blood pressure monitoring can be done if ambulatory monitoring is unavailable or unfeasible.
• Nonpharmacologic therapy should be emphasized for everyone, regardless of blood pressure level.
• Guidelines should be used as a framework for management. Individualize decisions about blood pressure goals and pharmacologic therapy based on patient characteristics and clinical judgment.

Bicuspid aortic valve is the most common congenital cardiac abnormality in humans and is a significant risk factor for premature aortic valve dysfunction due to accelerated leaflet deterioration and calcification from altered hemodynamics. From 20% to 50% of patients with bicuspid aortic valve need aortic valve replacement during their lifetime, mostly for aortic stenosis.^1,2

See related article

While 0.5% to 2% of the general population are born with a bicuspid aortic valve, more than 40% of patients (mainly younger patients) who undergo surgical or transcatheter intervention for aortic valve disease in some cohorts have this abnormality, suggesting that its true prevalence may be underreported.³

In the past decade, transcatheter aortic valve replacement (TAVR) has cemented its place as an option for patients with severe tricuspid aortic stenosis who cannot undergo surgery because their surgical risk is intermediate or high.⁴ However, most of the studies of balloon-expandable and self-expanding TAVR devices have excluded patients with bicuspid aortic valve.

BICUSPID AORTIC VALVE POSES CHALLENGES FOR TAVR

As TAVR is explored in younger and lower-risk populations, in which the prevalence of bicuspid aortic valve is presumably higher, the discussion of feasibility, safety, and efficacy of TAVR in patients with bicuspid aortic valve is both important and timely.

Bicuspid aortic valve is commonly categorized according to the Sievers classification,⁵ which describes 3 main morphologic types (designated types 0, 1, and 2) according to the number of raphes connecting the leaflets. Unique anatomic features of bicuspid aortic valve render the TAVR procedure challenging in these patients and merit consideration. These include, but are not limited to:

• Asymmetric calcification of the valve leaflets and calcified raphes. This results in asymmetric and incomplete expansion of the prosthesis, leading to incomplete sealing and paravalvular leak.
• A larger and more elliptically shaped aortic annulus, leading to challenges with proper sizing and apposition of the prosthesis
• Concomitant aortopathy, posing a higher risk of aortic rupture, dissection, paravalvular leak, and other complications during implantation.

Thus, compared with patients with tricuspid degenerative aortic stenosis, patients undergoing TAVR who have bicuspid aortic valve have a higher short-term risk of death and a higher risk of residual aortic regurgitation, and are more likely to need implantation of a second valve.

PARAVALVULAR LEAK

Paravalvular leak, arguably an independent marker of higher morbidity and mortality risk after TAVR, is more common in patients with bicuspid aortic valve undergoing TAVR than in those with tricuspid aortic valve. Earlier studies reported rates of moderate or severe paravalvular leak between 16% and 32%.^6,7

The newer-generation balloon-expandable Sapien 3 valve (Edwards Lifesciences, Irvine, CA) is associated with a lower incidence of moderate or severe paravalvular leak than earlier devices, mainly attributable to its outer skirt, which allows more complete sealing.⁸ There are also reports of successful treatment of bicuspid aortic valve stenosis using the Lotus device (Boston Scientific, Marlborough, MA).⁹ This device features adaptive sealing along with retrievability and repositioning ability, which may facilitate optimal positioning and prevent paravalvular leak.

Sizing of the prosthesis in patients with bicuspid aortic valve stenosis remains a challenge: some experts advocate the usual practice of measuring the perimeter and area at the level of the annulus, while others advocate measuring at the level of the commissures, 4 to 8 mm above the annulus. Balloon valvuloplasty may be a useful sizing tool, though it carries the hazards of severe aortic regurgitation and periprocedural stroke.

Angiography of the ascending aorta during balloon valvuloplasty can help verify whether an adequate seal is achievable and aid in selecting an appropriately sized prosthesis. Liu et al¹⁰ performed sequential balloon aortic valvuloplasty before TAVR with a self-expanding valve in 12 patients. Of these, 11 (91.7%) received a smaller device than they would have with multidetector computed tomography-guided annulus measurement.

Given that a larger valve may increase the risk of annular rupture, implantation of a smaller valve is always reasonable in bicuspid aortic valve as long as it achieves appropriate sealing with no paravalvular leak.

THE NEED FOR A PACEMAKER

After undergoing TAVR, more patients who have a bicuspid aortic valve need a permanent pacemaker than those who have a tricuspid aortic valve. This group appears to be more vulnerable to conduction abnormalities after TAVR, and rates of new pacemaker implantation as high as 25% have been reported with the newer-generation devices. Perlman et al⁸ observed that even when the Sapien 3 valve was implanted high in the left ventricular outflow tract, nearly 10% of patients needed a new pacemaker.

This is an important issue, as most patients with bicuspid aortic valve with severe aortic stenosis are relatively young and may endure deleterious effects from long-term pacing.

LONG-TERM OUTCOMES

The data on long-term outcomes of patients with bicuspid aortic valve who undergo TAVR are limited, and the available studies were small, with relatively short-term follow-up. However, Yoon et al compared TAVR outcomes between bicuspid and tricuspid aortic stenosis patients using propensity-score matching and demonstrated comparable all-cause mortality rates at 2 years (17.2% vs 19.4%, P = .28).⁶

Given the relatively long life expectancy of patients with bicuspid aortic valve undergoing TAVR, who tend to be younger than those with tricuspid aortic valve stenosis, longer-term data are needed to draw meaningful conclusions about the durability of transcatheter valves in this population. The bicuspid aortic valve is asymmetric, so that during TAVR the stent may not expand completely, and this in theory may result in more strain on the prosthesis and accelerate its structural deterioration.

In a recent meta-analysis, Reddy et al¹¹ analyzed 13 observational studies in 758 patients with severe bicuspid aortic valve stenosis undergoing TAVR with older and newer devices. The mean Society of Thoracic Surgeons Predicted Risk of Mortality score, which predicts the risk of death within 30 days, was 5.0%, but the actual rate was 3.7% (95% confidence interval [CI] 2.1%–5.6%). A high procedural success rate of 95% (95% CI 90.2%–98.5%] was also noted, but the rates of new permanent pacemaker implantation (17.9%, 95% CI 14.2%–22%) and severe perivalvular leak (12.2%, 95% CI 3.1%–24.8%) were somewhat elevated.¹¹

NOT FOR ALL, BUT AN EMERGING, VIABLE OPTION

As implanted prostheses and TAVR techniques undergo continuous improvement and as the experience of operators and institutions advances, procedural outcomes will likely improve.

The available data suggest that TAVR with the newer devices, when performed by experienced hands, is a viable option across most of the risk spectrum in patients with severe tricuspid aortic stenosis, including low-risk patients,¹² and selectively in patients with bicuspid aortic valve stenosis. However, for patients with bicuspid aortic valve with severe aortic stenosis and associated aortopathy, surgery remains the standard of care.

More study is needed to identify patients with bicuspid aortic valve who can be safely and effectively treated with TAVR.

Bicuspid aortic valve is the most common congenital cardiac abnormality in humans and is a significant risk factor for premature aortic valve dysfunction due to accelerated leaflet deterioration and calcification from altered hemodynamics. From 20% to 50% of patients with bicuspid aortic valve need aortic valve replacement during their lifetime, mostly for aortic stenosis.^1,2

See related article

While 0.5% to 2% of the general population are born with a bicuspid aortic valve, more than 40% of patients (mainly younger patients) who undergo surgical or transcatheter intervention for aortic valve disease in some cohorts have this abnormality, suggesting that its true prevalence may be underreported.³

In the past decade, transcatheter aortic valve replacement (TAVR) has cemented its place as an option for patients with severe tricuspid aortic stenosis who cannot undergo surgery because their surgical risk is intermediate or high.⁴ However, most of the studies of balloon-expandable and self-expanding TAVR devices have excluded patients with bicuspid aortic valve.

BICUSPID AORTIC VALVE POSES CHALLENGES FOR TAVR

As TAVR is explored in younger and lower-risk populations, in which the prevalence of bicuspid aortic valve is presumably higher, the discussion of feasibility, safety, and efficacy of TAVR in patients with bicuspid aortic valve is both important and timely.

Bicuspid aortic valve is commonly categorized according to the Sievers classification,⁵ which describes 3 main morphologic types (designated types 0, 1, and 2) according to the number of raphes connecting the leaflets. Unique anatomic features of bicuspid aortic valve render the TAVR procedure challenging in these patients and merit consideration. These include, but are not limited to:

• Asymmetric calcification of the valve leaflets and calcified raphes. This results in asymmetric and incomplete expansion of the prosthesis, leading to incomplete sealing and paravalvular leak.
• A larger and more elliptically shaped aortic annulus, leading to challenges with proper sizing and apposition of the prosthesis
• Concomitant aortopathy, posing a higher risk of aortic rupture, dissection, paravalvular leak, and other complications during implantation.

Thus, compared with patients with tricuspid degenerative aortic stenosis, patients undergoing TAVR who have bicuspid aortic valve have a higher short-term risk of death and a higher risk of residual aortic regurgitation, and are more likely to need implantation of a second valve.

PARAVALVULAR LEAK

Paravalvular leak, arguably an independent marker of higher morbidity and mortality risk after TAVR, is more common in patients with bicuspid aortic valve undergoing TAVR than in those with tricuspid aortic valve. Earlier studies reported rates of moderate or severe paravalvular leak between 16% and 32%.^6,7

The newer-generation balloon-expandable Sapien 3 valve (Edwards Lifesciences, Irvine, CA) is associated with a lower incidence of moderate or severe paravalvular leak than earlier devices, mainly attributable to its outer skirt, which allows more complete sealing.⁸ There are also reports of successful treatment of bicuspid aortic valve stenosis using the Lotus device (Boston Scientific, Marlborough, MA).⁹ This device features adaptive sealing along with retrievability and repositioning ability, which may facilitate optimal positioning and prevent paravalvular leak.

Sizing of the prosthesis in patients with bicuspid aortic valve stenosis remains a challenge: some experts advocate the usual practice of measuring the perimeter and area at the level of the annulus, while others advocate measuring at the level of the commissures, 4 to 8 mm above the annulus. Balloon valvuloplasty may be a useful sizing tool, though it carries the hazards of severe aortic regurgitation and periprocedural stroke.

Angiography of the ascending aorta during balloon valvuloplasty can help verify whether an adequate seal is achievable and aid in selecting an appropriately sized prosthesis. Liu et al¹⁰ performed sequential balloon aortic valvuloplasty before TAVR with a self-expanding valve in 12 patients. Of these, 11 (91.7%) received a smaller device than they would have with multidetector computed tomography-guided annulus measurement.

Given that a larger valve may increase the risk of annular rupture, implantation of a smaller valve is always reasonable in bicuspid aortic valve as long as it achieves appropriate sealing with no paravalvular leak.

THE NEED FOR A PACEMAKER

After undergoing TAVR, more patients who have a bicuspid aortic valve need a permanent pacemaker than those who have a tricuspid aortic valve. This group appears to be more vulnerable to conduction abnormalities after TAVR, and rates of new pacemaker implantation as high as 25% have been reported with the newer-generation devices. Perlman et al⁸ observed that even when the Sapien 3 valve was implanted high in the left ventricular outflow tract, nearly 10% of patients needed a new pacemaker.

This is an important issue, as most patients with bicuspid aortic valve with severe aortic stenosis are relatively young and may endure deleterious effects from long-term pacing.

LONG-TERM OUTCOMES

The data on long-term outcomes of patients with bicuspid aortic valve who undergo TAVR are limited, and the available studies were small, with relatively short-term follow-up. However, Yoon et al compared TAVR outcomes between bicuspid and tricuspid aortic stenosis patients using propensity-score matching and demonstrated comparable all-cause mortality rates at 2 years (17.2% vs 19.4%, P = .28).⁶

Given the relatively long life expectancy of patients with bicuspid aortic valve undergoing TAVR, who tend to be younger than those with tricuspid aortic valve stenosis, longer-term data are needed to draw meaningful conclusions about the durability of transcatheter valves in this population. The bicuspid aortic valve is asymmetric, so that during TAVR the stent may not expand completely, and this in theory may result in more strain on the prosthesis and accelerate its structural deterioration.

In a recent meta-analysis, Reddy et al¹¹ analyzed 13 observational studies in 758 patients with severe bicuspid aortic valve stenosis undergoing TAVR with older and newer devices. The mean Society of Thoracic Surgeons Predicted Risk of Mortality score, which predicts the risk of death within 30 days, was 5.0%, but the actual rate was 3.7% (95% confidence interval [CI] 2.1%–5.6%). A high procedural success rate of 95% (95% CI 90.2%–98.5%] was also noted, but the rates of new permanent pacemaker implantation (17.9%, 95% CI 14.2%–22%) and severe perivalvular leak (12.2%, 95% CI 3.1%–24.8%) were somewhat elevated.¹¹

NOT FOR ALL, BUT AN EMERGING, VIABLE OPTION

As implanted prostheses and TAVR techniques undergo continuous improvement and as the experience of operators and institutions advances, procedural outcomes will likely improve.

The available data suggest that TAVR with the newer devices, when performed by experienced hands, is a viable option across most of the risk spectrum in patients with severe tricuspid aortic stenosis, including low-risk patients,¹² and selectively in patients with bicuspid aortic valve stenosis. However, for patients with bicuspid aortic valve with severe aortic stenosis and associated aortopathy, surgery remains the standard of care.

More study is needed to identify patients with bicuspid aortic valve who can be safely and effectively treated with TAVR.

Bicuspid aortic valve is the most common congenital cardiac abnormality in humans and is a significant risk factor for premature aortic valve dysfunction due to accelerated leaflet deterioration and calcification from altered hemodynamics. From 20% to 50% of patients with bicuspid aortic valve need aortic valve replacement during their lifetime, mostly for aortic stenosis.^1,2

See related article

While 0.5% to 2% of the general population are born with a bicuspid aortic valve, more than 40% of patients (mainly younger patients) who undergo surgical or transcatheter intervention for aortic valve disease in some cohorts have this abnormality, suggesting that its true prevalence may be underreported.³

In the past decade, transcatheter aortic valve replacement (TAVR) has cemented its place as an option for patients with severe tricuspid aortic stenosis who cannot undergo surgery because their surgical risk is intermediate or high.⁴ However, most of the studies of balloon-expandable and self-expanding TAVR devices have excluded patients with bicuspid aortic valve.

BICUSPID AORTIC VALVE POSES CHALLENGES FOR TAVR

As TAVR is explored in younger and lower-risk populations, in which the prevalence of bicuspid aortic valve is presumably higher, the discussion of feasibility, safety, and efficacy of TAVR in patients with bicuspid aortic valve is both important and timely.

Bicuspid aortic valve is commonly categorized according to the Sievers classification,⁵ which describes 3 main morphologic types (designated types 0, 1, and 2) according to the number of raphes connecting the leaflets. Unique anatomic features of bicuspid aortic valve render the TAVR procedure challenging in these patients and merit consideration. These include, but are not limited to:

• Asymmetric calcification of the valve leaflets and calcified raphes. This results in asymmetric and incomplete expansion of the prosthesis, leading to incomplete sealing and paravalvular leak.
• A larger and more elliptically shaped aortic annulus, leading to challenges with proper sizing and apposition of the prosthesis
• Concomitant aortopathy, posing a higher risk of aortic rupture, dissection, paravalvular leak, and other complications during implantation.

Thus, compared with patients with tricuspid degenerative aortic stenosis, patients undergoing TAVR who have bicuspid aortic valve have a higher short-term risk of death and a higher risk of residual aortic regurgitation, and are more likely to need implantation of a second valve.

PARAVALVULAR LEAK

Paravalvular leak, arguably an independent marker of higher morbidity and mortality risk after TAVR, is more common in patients with bicuspid aortic valve undergoing TAVR than in those with tricuspid aortic valve. Earlier studies reported rates of moderate or severe paravalvular leak between 16% and 32%.^6,7

The newer-generation balloon-expandable Sapien 3 valve (Edwards Lifesciences, Irvine, CA) is associated with a lower incidence of moderate or severe paravalvular leak than earlier devices, mainly attributable to its outer skirt, which allows more complete sealing.⁸ There are also reports of successful treatment of bicuspid aortic valve stenosis using the Lotus device (Boston Scientific, Marlborough, MA).⁹ This device features adaptive sealing along with retrievability and repositioning ability, which may facilitate optimal positioning and prevent paravalvular leak.

Sizing of the prosthesis in patients with bicuspid aortic valve stenosis remains a challenge: some experts advocate the usual practice of measuring the perimeter and area at the level of the annulus, while others advocate measuring at the level of the commissures, 4 to 8 mm above the annulus. Balloon valvuloplasty may be a useful sizing tool, though it carries the hazards of severe aortic regurgitation and periprocedural stroke.

Angiography of the ascending aorta during balloon valvuloplasty can help verify whether an adequate seal is achievable and aid in selecting an appropriately sized prosthesis. Liu et al¹⁰ performed sequential balloon aortic valvuloplasty before TAVR with a self-expanding valve in 12 patients. Of these, 11 (91.7%) received a smaller device than they would have with multidetector computed tomography-guided annulus measurement.

Given that a larger valve may increase the risk of annular rupture, implantation of a smaller valve is always reasonable in bicuspid aortic valve as long as it achieves appropriate sealing with no paravalvular leak.

THE NEED FOR A PACEMAKER

After undergoing TAVR, more patients who have a bicuspid aortic valve need a permanent pacemaker than those who have a tricuspid aortic valve. This group appears to be more vulnerable to conduction abnormalities after TAVR, and rates of new pacemaker implantation as high as 25% have been reported with the newer-generation devices. Perlman et al⁸ observed that even when the Sapien 3 valve was implanted high in the left ventricular outflow tract, nearly 10% of patients needed a new pacemaker.

This is an important issue, as most patients with bicuspid aortic valve with severe aortic stenosis are relatively young and may endure deleterious effects from long-term pacing.

LONG-TERM OUTCOMES

The data on long-term outcomes of patients with bicuspid aortic valve who undergo TAVR are limited, and the available studies were small, with relatively short-term follow-up. However, Yoon et al compared TAVR outcomes between bicuspid and tricuspid aortic stenosis patients using propensity-score matching and demonstrated comparable all-cause mortality rates at 2 years (17.2% vs 19.4%, P = .28).⁶

Given the relatively long life expectancy of patients with bicuspid aortic valve undergoing TAVR, who tend to be younger than those with tricuspid aortic valve stenosis, longer-term data are needed to draw meaningful conclusions about the durability of transcatheter valves in this population. The bicuspid aortic valve is asymmetric, so that during TAVR the stent may not expand completely, and this in theory may result in more strain on the prosthesis and accelerate its structural deterioration.

In a recent meta-analysis, Reddy et al¹¹ analyzed 13 observational studies in 758 patients with severe bicuspid aortic valve stenosis undergoing TAVR with older and newer devices. The mean Society of Thoracic Surgeons Predicted Risk of Mortality score, which predicts the risk of death within 30 days, was 5.0%, but the actual rate was 3.7% (95% confidence interval [CI] 2.1%–5.6%). A high procedural success rate of 95% (95% CI 90.2%–98.5%] was also noted, but the rates of new permanent pacemaker implantation (17.9%, 95% CI 14.2%–22%) and severe perivalvular leak (12.2%, 95% CI 3.1%–24.8%) were somewhat elevated.¹¹

NOT FOR ALL, BUT AN EMERGING, VIABLE OPTION

As implanted prostheses and TAVR techniques undergo continuous improvement and as the experience of operators and institutions advances, procedural outcomes will likely improve.

The available data suggest that TAVR with the newer devices, when performed by experienced hands, is a viable option across most of the risk spectrum in patients with severe tricuspid aortic stenosis, including low-risk patients,¹² and selectively in patients with bicuspid aortic valve stenosis. However, for patients with bicuspid aortic valve with severe aortic stenosis and associated aortopathy, surgery remains the standard of care.

More study is needed to identify patients with bicuspid aortic valve who can be safely and effectively treated with TAVR.

To the Editor: We read with interest the article by Young et al on hypertrophic cardiomyop­athy (HCM)¹ and would like to raise a few important points.

HCM has a complex phenotypic expression and doesn’t necessarily involve left ventricular outflow obstruction. Midventricular obstruction is a unique subtype of HCM, with increased risk of left ventricular apical aneurysm (LVAA) formation. We reported that 25% of HCM patients with midventricular obstruction progress to LVAA compared with 0.3% of patients with other HCM subtypes.² Magnetic resonance imaging plays a pivotal role in assessing midventricular obstruction, owing to asymmetric geometry of the left ventricle and the shortcomings of echocardiography in assessing the apical aneurysm.²

Anticoagulation remains one of the cornerstones in treating midventricular obstruction with LVAA. We performed a systematic review and found a high prevalence of atrial arrhythmia, apical thrombus, and stroke, which necessitated anticoagulation in one-fifth of patients.²

Ventricular arrhythmias are prevalent in midventricular obstruction with LVAA, mainly from increased fibrosis formation at the apical rim.³ In our review, 25.7% of patients with midventricular obstruction with LVAA and an implantable cardioverter-defibrillator (ICD) experienced appropriate shocks.² Our finding was in line with those of Rowin et al,³ who showed appropriate ICD shocks in one-third of HCM patients with apical aneurysm. Apical aneurysm is currently considered an independent risk factor for sudden cardiac death in HCM, with an increased rate of sudden death of up to 5% every year.^3,4

It is imperative to distinguish midventricular obstruction with LVAA as a unique disease imposing a higher risk of thromboembolism, ventricular arrhythmia, and progression to end-stage heart failure.³ We suggest that those patients be evaluated early in the course of disease for anticoagulation, ICD implantation, and early surgical intervention.²

To the Editor: We read with interest the article by Young et al on hypertrophic cardiomyop­athy (HCM)¹ and would like to raise a few important points.

HCM has a complex phenotypic expression and doesn’t necessarily involve left ventricular outflow obstruction. Midventricular obstruction is a unique subtype of HCM, with increased risk of left ventricular apical aneurysm (LVAA) formation. We reported that 25% of HCM patients with midventricular obstruction progress to LVAA compared with 0.3% of patients with other HCM subtypes.² Magnetic resonance imaging plays a pivotal role in assessing midventricular obstruction, owing to asymmetric geometry of the left ventricle and the shortcomings of echocardiography in assessing the apical aneurysm.²

Anticoagulation remains one of the cornerstones in treating midventricular obstruction with LVAA. We performed a systematic review and found a high prevalence of atrial arrhythmia, apical thrombus, and stroke, which necessitated anticoagulation in one-fifth of patients.²

Ventricular arrhythmias are prevalent in midventricular obstruction with LVAA, mainly from increased fibrosis formation at the apical rim.³ In our review, 25.7% of patients with midventricular obstruction with LVAA and an implantable cardioverter-defibrillator (ICD) experienced appropriate shocks.² Our finding was in line with those of Rowin et al,³ who showed appropriate ICD shocks in one-third of HCM patients with apical aneurysm. Apical aneurysm is currently considered an independent risk factor for sudden cardiac death in HCM, with an increased rate of sudden death of up to 5% every year.^3,4

It is imperative to distinguish midventricular obstruction with LVAA as a unique disease imposing a higher risk of thromboembolism, ventricular arrhythmia, and progression to end-stage heart failure.³ We suggest that those patients be evaluated early in the course of disease for anticoagulation, ICD implantation, and early surgical intervention.²

To the Editor: We read with interest the article by Young et al on hypertrophic cardiomyop­athy (HCM)¹ and would like to raise a few important points.

HCM has a complex phenotypic expression and doesn’t necessarily involve left ventricular outflow obstruction. Midventricular obstruction is a unique subtype of HCM, with increased risk of left ventricular apical aneurysm (LVAA) formation. We reported that 25% of HCM patients with midventricular obstruction progress to LVAA compared with 0.3% of patients with other HCM subtypes.² Magnetic resonance imaging plays a pivotal role in assessing midventricular obstruction, owing to asymmetric geometry of the left ventricle and the shortcomings of echocardiography in assessing the apical aneurysm.²

Anticoagulation remains one of the cornerstones in treating midventricular obstruction with LVAA. We performed a systematic review and found a high prevalence of atrial arrhythmia, apical thrombus, and stroke, which necessitated anticoagulation in one-fifth of patients.²

Ventricular arrhythmias are prevalent in midventricular obstruction with LVAA, mainly from increased fibrosis formation at the apical rim.³ In our review, 25.7% of patients with midventricular obstruction with LVAA and an implantable cardioverter-defibrillator (ICD) experienced appropriate shocks.² Our finding was in line with those of Rowin et al,³ who showed appropriate ICD shocks in one-third of HCM patients with apical aneurysm. Apical aneurysm is currently considered an independent risk factor for sudden cardiac death in HCM, with an increased rate of sudden death of up to 5% every year.^3,4

It is imperative to distinguish midventricular obstruction with LVAA as a unique disease imposing a higher risk of thromboembolism, ventricular arrhythmia, and progression to end-stage heart failure.³ We suggest that those patients be evaluated early in the course of disease for anticoagulation, ICD implantation, and early surgical intervention.²

To the Editor: I read with interest the case of a 67-year-old woman with bilateral hand numbness, published in the March 2018 issue of the Journal, and I would like to suggest 2 important corrections to this article.¹

The authors present a case of hypocalcemia secondary to postsurgical hypoparathyroidism but describe it as due to primary hypoparathyroidism. The patient had undergone thyroidectomy 10 years earlier and since then had hypocalcemia, secondary to postsurgical hypoparathyroidism, that was treated with calcium and vitamin D, until she stopped taking these agents. Postsurgical hypothyroidism is the most common cause of acquired or secondary hypoparathyroidism and is not primary hypoparathyroidism. I strongly feel that this requires an update or correction to the article. This patient may have associated malabsorption, as the authors alluded to, as the cause of her “normal” serum parathyroid hormone level.

The patient also had hypomagnesemia, which the authors state could have been due to furosemide use and “uncontrolled” diabetes mellitus. Diabetes doesn’t need to be uncontrolled to cause hypomagnesemia. Hypomagnesemia is common in patients with type 2 diabetes mellitus, with a prevalence of 14% to 48% in patients with diabetes compared with 2.5% to 15% in the general population.² It is often multifactorial and may be secondary to one or more of the following factors: poor dietary intake, autonomic dysfunction, altered insulin resistance, glomerular hyperfiltration, osmotic diuresis (uncontrolled diabetes), recurrent metabolic acidosis, hypophosphatemia, hypokalemia, and therapy with drugs such as metformin and sulfonylureas.

Patients with type 2 diabetes and hypo­magnesemia often enter a vicious cycle in which hypomagnesemia worsens insulin resistance and insulin resistance, by reducing the activity of renal magnesium channel transient receptor potential melastatin (TRPM) type 6, perpetuates hypomagnesemia.³

To the Editor: I read with interest the case of a 67-year-old woman with bilateral hand numbness, published in the March 2018 issue of the Journal, and I would like to suggest 2 important corrections to this article.¹

The authors present a case of hypocalcemia secondary to postsurgical hypoparathyroidism but describe it as due to primary hypoparathyroidism. The patient had undergone thyroidectomy 10 years earlier and since then had hypocalcemia, secondary to postsurgical hypoparathyroidism, that was treated with calcium and vitamin D, until she stopped taking these agents. Postsurgical hypothyroidism is the most common cause of acquired or secondary hypoparathyroidism and is not primary hypoparathyroidism. I strongly feel that this requires an update or correction to the article. This patient may have associated malabsorption, as the authors alluded to, as the cause of her “normal” serum parathyroid hormone level.

The patient also had hypomagnesemia, which the authors state could have been due to furosemide use and “uncontrolled” diabetes mellitus. Diabetes doesn’t need to be uncontrolled to cause hypomagnesemia. Hypomagnesemia is common in patients with type 2 diabetes mellitus, with a prevalence of 14% to 48% in patients with diabetes compared with 2.5% to 15% in the general population.² It is often multifactorial and may be secondary to one or more of the following factors: poor dietary intake, autonomic dysfunction, altered insulin resistance, glomerular hyperfiltration, osmotic diuresis (uncontrolled diabetes), recurrent metabolic acidosis, hypophosphatemia, hypokalemia, and therapy with drugs such as metformin and sulfonylureas.

Patients with type 2 diabetes and hypo­magnesemia often enter a vicious cycle in which hypomagnesemia worsens insulin resistance and insulin resistance, by reducing the activity of renal magnesium channel transient receptor potential melastatin (TRPM) type 6, perpetuates hypomagnesemia.³

To the Editor: I read with interest the case of a 67-year-old woman with bilateral hand numbness, published in the March 2018 issue of the Journal, and I would like to suggest 2 important corrections to this article.¹

The authors present a case of hypocalcemia secondary to postsurgical hypoparathyroidism but describe it as due to primary hypoparathyroidism. The patient had undergone thyroidectomy 10 years earlier and since then had hypocalcemia, secondary to postsurgical hypoparathyroidism, that was treated with calcium and vitamin D, until she stopped taking these agents. Postsurgical hypothyroidism is the most common cause of acquired or secondary hypoparathyroidism and is not primary hypoparathyroidism. I strongly feel that this requires an update or correction to the article. This patient may have associated malabsorption, as the authors alluded to, as the cause of her “normal” serum parathyroid hormone level.

The patient also had hypomagnesemia, which the authors state could have been due to furosemide use and “uncontrolled” diabetes mellitus. Diabetes doesn’t need to be uncontrolled to cause hypomagnesemia. Hypomagnesemia is common in patients with type 2 diabetes mellitus, with a prevalence of 14% to 48% in patients with diabetes compared with 2.5% to 15% in the general population.² It is often multifactorial and may be secondary to one or more of the following factors: poor dietary intake, autonomic dysfunction, altered insulin resistance, glomerular hyperfiltration, osmotic diuresis (uncontrolled diabetes), recurrent metabolic acidosis, hypophosphatemia, hypokalemia, and therapy with drugs such as metformin and sulfonylureas.

Patients with type 2 diabetes and hypo­magnesemia often enter a vicious cycle in which hypomagnesemia worsens insulin resistance and insulin resistance, by reducing the activity of renal magnesium channel transient receptor potential melastatin (TRPM) type 6, perpetuates hypomagnesemia.³

In Reply: We thank Dr. Parmar and appreciate his important comments.

Regarding the difference between primary and secondary hypoparathyroidism, the definition varies among investigators. Some define primary hypoparathyroidism as a condition characterized by primary absence or deficiency of parathyroid hormone (PTH), which results in hypocalcemia and which can be congenital or acquired, including postsurgical hypoparathyroidism.^1–4 In principle, this is similar to the classification of disorders affecting other endocrine glands as primary and secondary. For example, primary hypothyroidism refers to a state of low thyroid hormones resulting from impairment or loss of function of the thyroid gland itself, such as in Hashimoto thyroiditis, radioactive iodine therapy, or thyroidectomy, among others.⁵ We adopted this definition in our article. In contrast, secondary hypoparathyroidism is characterized by low PTH secretion in response to certain conditions that cause hypercalcemia. Non-PTH-mediated hypercalcemia is a more common term used to describe this state of secondary hypoparathyroidism.

Other investigators restrict the term “primary hypoparathyroidism” to nonacquired (congenital or hereditary) etiologies, while applying the term “secondary hypoparathyroidism” to acquired etiologies.⁶

Concerning the association between diabetes mellitus and hypomagnesemia, we agree that diabetes does not need to be uncontrolled to cause hypomagnesemia. However, the patient described in our article presented with severe hypomagnesemia (serum level 0.6 mg/dL), which is not commonly associated with diabetes. Most cases of hypomagnesemia in patients with type 2 diabetes mellitus are mild and asymptomatic, whereas severe manifestations including seizures, cardiac arrhythmias, and acute tetany are rarely encountered in clinical practice.⁷ Furthermore, numerous studies have shown a negative correlation between serum magnesium level and glycemic control.^7–11 A recent study reported that plasma triglyceride and glucose levels are the main determinants of the plasma magnesium concentration in patients with type 2 diabetes.¹²

Our patient’s diabetes was uncontrolled, as evidenced by her hemoglobin A_1c level of 9.7% and her random serum glucose level of 224 mg/dL. Therefore, it is more likely that “uncontrolled diabetes mellitus” (in addition to diuretic use) was the cause of her symptomatic severe hypomagnesemia rather than controlled diabetes mellitus.

In Reply: We thank Dr. Parmar and appreciate his important comments.

Regarding the difference between primary and secondary hypoparathyroidism, the definition varies among investigators. Some define primary hypoparathyroidism as a condition characterized by primary absence or deficiency of parathyroid hormone (PTH), which results in hypocalcemia and which can be congenital or acquired, including postsurgical hypoparathyroidism.^1–4 In principle, this is similar to the classification of disorders affecting other endocrine glands as primary and secondary. For example, primary hypothyroidism refers to a state of low thyroid hormones resulting from impairment or loss of function of the thyroid gland itself, such as in Hashimoto thyroiditis, radioactive iodine therapy, or thyroidectomy, among others.⁵ We adopted this definition in our article. In contrast, secondary hypoparathyroidism is characterized by low PTH secretion in response to certain conditions that cause hypercalcemia. Non-PTH-mediated hypercalcemia is a more common term used to describe this state of secondary hypoparathyroidism.

Other investigators restrict the term “primary hypoparathyroidism” to nonacquired (congenital or hereditary) etiologies, while applying the term “secondary hypoparathyroidism” to acquired etiologies.⁶

Concerning the association between diabetes mellitus and hypomagnesemia, we agree that diabetes does not need to be uncontrolled to cause hypomagnesemia. However, the patient described in our article presented with severe hypomagnesemia (serum level 0.6 mg/dL), which is not commonly associated with diabetes. Most cases of hypomagnesemia in patients with type 2 diabetes mellitus are mild and asymptomatic, whereas severe manifestations including seizures, cardiac arrhythmias, and acute tetany are rarely encountered in clinical practice.⁷ Furthermore, numerous studies have shown a negative correlation between serum magnesium level and glycemic control.^7–11 A recent study reported that plasma triglyceride and glucose levels are the main determinants of the plasma magnesium concentration in patients with type 2 diabetes.¹²

Our patient’s diabetes was uncontrolled, as evidenced by her hemoglobin A_1c level of 9.7% and her random serum glucose level of 224 mg/dL. Therefore, it is more likely that “uncontrolled diabetes mellitus” (in addition to diuretic use) was the cause of her symptomatic severe hypomagnesemia rather than controlled diabetes mellitus.

In Reply: We thank Dr. Parmar and appreciate his important comments.

Regarding the difference between primary and secondary hypoparathyroidism, the definition varies among investigators. Some define primary hypoparathyroidism as a condition characterized by primary absence or deficiency of parathyroid hormone (PTH), which results in hypocalcemia and which can be congenital or acquired, including postsurgical hypoparathyroidism.^1–4 In principle, this is similar to the classification of disorders affecting other endocrine glands as primary and secondary. For example, primary hypothyroidism refers to a state of low thyroid hormones resulting from impairment or loss of function of the thyroid gland itself, such as in Hashimoto thyroiditis, radioactive iodine therapy, or thyroidectomy, among others.⁵ We adopted this definition in our article. In contrast, secondary hypoparathyroidism is characterized by low PTH secretion in response to certain conditions that cause hypercalcemia. Non-PTH-mediated hypercalcemia is a more common term used to describe this state of secondary hypoparathyroidism.

Other investigators restrict the term “primary hypoparathyroidism” to nonacquired (congenital or hereditary) etiologies, while applying the term “secondary hypoparathyroidism” to acquired etiologies.⁶

Concerning the association between diabetes mellitus and hypomagnesemia, we agree that diabetes does not need to be uncontrolled to cause hypomagnesemia. However, the patient described in our article presented with severe hypomagnesemia (serum level 0.6 mg/dL), which is not commonly associated with diabetes. Most cases of hypomagnesemia in patients with type 2 diabetes mellitus are mild and asymptomatic, whereas severe manifestations including seizures, cardiac arrhythmias, and acute tetany are rarely encountered in clinical practice.⁷ Furthermore, numerous studies have shown a negative correlation between serum magnesium level and glycemic control.^7–11 A recent study reported that plasma triglyceride and glucose levels are the main determinants of the plasma magnesium concentration in patients with type 2 diabetes.¹²

Our patient’s diabetes was uncontrolled, as evidenced by her hemoglobin A_1c level of 9.7% and her random serum glucose level of 224 mg/dL. Therefore, it is more likely that “uncontrolled diabetes mellitus” (in addition to diuretic use) was the cause of her symptomatic severe hypomagnesemia rather than controlled diabetes mellitus.

In the article by Agganis B, Lee D, Sepe T (Liver enzymes: No trivial elevations, even if asymptomatic. Cleve Clin J Med 2018; 85(8):612–617, doi:10.3949/ccjm.85a.17103), an error occurred on page 613, in the second paragraph in the section about alcohol intake. The words ALT and AST were reversed. The paragraph should read as follows:

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

We thank Avinash Alexander, MD, Texas Tech University Health Sciences Center, for calling this to our attention. The correction has been made online.

In the article by Agganis B, Lee D, Sepe T (Liver enzymes: No trivial elevations, even if asymptomatic. Cleve Clin J Med 2018; 85(8):612–617, doi:10.3949/ccjm.85a.17103), an error occurred on page 613, in the second paragraph in the section about alcohol intake. The words ALT and AST were reversed. The paragraph should read as follows:

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

We thank Avinash Alexander, MD, Texas Tech University Health Sciences Center, for calling this to our attention. The correction has been made online.

In the article by Agganis B, Lee D, Sepe T (Liver enzymes: No trivial elevations, even if asymptomatic. Cleve Clin J Med 2018; 85(8):612–617, doi:10.3949/ccjm.85a.17103), an error occurred on page 613, in the second paragraph in the section about alcohol intake. The words ALT and AST were reversed. The paragraph should read as follows:

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

We thank Avinash Alexander, MD, Texas Tech University Health Sciences Center, for calling this to our attention. The correction has been made online.