Survey results paint a stark picture of discrimination among racial minorities in the cardiology workforce but also a strong sense of belonging.

Hiraman/Getty Images

Among respondents to the 2015 American College of Cardiology (ACC) Professional Life Survey, which is the most recent survey, over half (52.3%) of underrepresented racial and ethnic minorities (URMs) and 45.5% of Asian or Pacific Islanders reported experiencing discrimination compared with 36.4% of Whites (both P < .01).

Nevertheless, 91.2% of URMs reported being satisfied with their career, as did 90% of Asians or Pacific Islanders and 89.1% of Whites.

Satisfaction with financial compensation also did not differ between groups, and most cardiologists believed their opportunities for advancement were similar to those of their peers.

One possible explanation is that the respondents may simply be people who’ve had better experiences, lead author Kevin L. Thomas, MD, Duke Clinical Research Institute, Durham, N.C., and colleagues told this news organization. A second hypothesis looks more to sheer determination, or grit.

“Perhaps along the sometimes circuitous pathway to being a cardiologist – which is a lot of training, a lot of standardized testing, a lot of applications – that maybe you sub-select a group of individuals who are simply more resilient based on their life experiences and things that they’ve overcome to get where they are,” he said.

Interestingly, rates of burnout were lower among URMs (22.4%) and Asians/Pacific Islanders (20.1%) than Whites (30.3%; P = .02 and P < .01, respectively). The finding is unexpected but in line with a recent report of more than 4,400 U.S. physicians finding lower odds of burnout among Asian, Hispanic/Latinx, and Black physicians.

The new study, published October 18 in the Journal of the American College of Cardiology, however, affirms that women of all racial and ethnic groups face significant headwinds in the White, male-dominated cardiology workforce.

Just 13.9% of White men reported experiencing discrimination, compared with 44.6% of URM men and 36.2% of Asians/Pacific Islander men. In comparison, 69.2% of White women reported discrimination, as did 62.7% of URM women and 57% of Asian/Pacific Islander women (both P <.01).

“When you look specifically at White men versus White women, there is a large discrepancy there, and it just shows us, I think, for a lot of different groups, we still have a long way to go in terms of trying to achieve equity and to try to be inclusive in the workplace,” Dr. Thomas said.

Men were more likely to experience race- and religion-based discrimination in the workplace, whereas nearly all women reported sex discrimination, with parenting an important second. Approximately 85% of cardiologists reported being satisfied with their family lives, although unpublished data suggest URMs were less likely to be married and to have fewer children, Dr. Thomas said.

During job negotiations, URM cardiologists were less likely to prioritize salary, benefits, and work hours for their first job (13.6%, 10.9% 19.3%) than White cardiologists (20.6%, 23.3%, 31.3%; P < .02 for all).

In subsequent negotiations, URMs placed more emphasis on salary, benefits, and work hours than Whites, whereas both URMs and Asians/Pacific Islanders placed a greater importance on travel benefits, diversity, mentoring, workspace, time to promotion, academic rank, and roles with community, institutional, or national recognition, which the authors say, “might indicate a greater need to overcome systemic barriers.”

Three-fourths of all cardiologist respondents had a mentor during training, which can take many shapes, Dr. Thomas noted. “Within my own section as an electrophysiologist, which is a very subspecialized category, we have four Black electrophysiologists, and I think it was because many of us mentored each other as we came along, and it inspired us.”

URMs are more likely to experience the so-called “minority tax” of being tapped for added responsibilities in the name of inclusivity efforts, he said, and called on individuals from the dominant culture to mentor or sponsor cardiologists from other racial groups and to carve out leadership pathways for women and minorities so they “can use their gifts to benefit the profession at large,” leading clinical trials or steering committees and serving in high-profile roles.

Although the events of 2020 sharpened attention on the issue of diversity in America, Dr. Thomas and colleagues say that more work needs to be done defining the problem and that professional organizations and health systems also should systematically collect sex, racial, and ethnic identifies of members using classifications similar to the 2020 U.S. Census.

The study was based on 2,245 respondents to the 2015 Professional Life Survey, which was not specifically designed to assess racial/ethnic diversity topics and had a response rate of 21%, which limited representatives of each group.

In all, 197 were from URMs (80 Blacks, 113 Hispanics, 4 Native Americans), 564 were Asians/Pacific Islanders, 1,447 were Whites, and 37 listed multiracial/other. More than half (58%) were men, and most were adult cardiologists (83% to 85%), followed by pediatric cardiology (6% to 10%) and cardiovascular surgery (1% to 2%).

“Further research is needed to understand these findings and their significance, because ongoing efforts within ACC and other organizations to increase diversity will fail unless this is successfully addressed,” the authors conclude.

To that end, Dr. Thomas said they are looking to develop a new survey that taps other groups like the Association of Black Cardiologists and members of the LGBTQ community.

“I’m really excited about the opportunity to develop a survey that specifically has the objective of trying to understand the experiences of systematically disadvantaged, historically marginalized groups to see if we can see the same information, but maybe through a clear lens, and then be able to develop strategies to mitigate some of the challenges that we see” he said. “So we can increase the numbers and also have a workforce that is reflective of the populations that we take care of and the nation as a whole.”

The study was funded by the American College of Cardiology. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Survey results paint a stark picture of discrimination among racial minorities in the cardiology workforce but also a strong sense of belonging.

Hiraman/Getty Images

Among respondents to the 2015 American College of Cardiology (ACC) Professional Life Survey, which is the most recent survey, over half (52.3%) of underrepresented racial and ethnic minorities (URMs) and 45.5% of Asian or Pacific Islanders reported experiencing discrimination compared with 36.4% of Whites (both P < .01).

Nevertheless, 91.2% of URMs reported being satisfied with their career, as did 90% of Asians or Pacific Islanders and 89.1% of Whites.

Satisfaction with financial compensation also did not differ between groups, and most cardiologists believed their opportunities for advancement were similar to those of their peers.

One possible explanation is that the respondents may simply be people who’ve had better experiences, lead author Kevin L. Thomas, MD, Duke Clinical Research Institute, Durham, N.C., and colleagues told this news organization. A second hypothesis looks more to sheer determination, or grit.

“Perhaps along the sometimes circuitous pathway to being a cardiologist – which is a lot of training, a lot of standardized testing, a lot of applications – that maybe you sub-select a group of individuals who are simply more resilient based on their life experiences and things that they’ve overcome to get where they are,” he said.

Interestingly, rates of burnout were lower among URMs (22.4%) and Asians/Pacific Islanders (20.1%) than Whites (30.3%; P = .02 and P < .01, respectively). The finding is unexpected but in line with a recent report of more than 4,400 U.S. physicians finding lower odds of burnout among Asian, Hispanic/Latinx, and Black physicians.

The new study, published October 18 in the Journal of the American College of Cardiology, however, affirms that women of all racial and ethnic groups face significant headwinds in the White, male-dominated cardiology workforce.

Just 13.9% of White men reported experiencing discrimination, compared with 44.6% of URM men and 36.2% of Asians/Pacific Islander men. In comparison, 69.2% of White women reported discrimination, as did 62.7% of URM women and 57% of Asian/Pacific Islander women (both P <.01).

“When you look specifically at White men versus White women, there is a large discrepancy there, and it just shows us, I think, for a lot of different groups, we still have a long way to go in terms of trying to achieve equity and to try to be inclusive in the workplace,” Dr. Thomas said.

Men were more likely to experience race- and religion-based discrimination in the workplace, whereas nearly all women reported sex discrimination, with parenting an important second. Approximately 85% of cardiologists reported being satisfied with their family lives, although unpublished data suggest URMs were less likely to be married and to have fewer children, Dr. Thomas said.

During job negotiations, URM cardiologists were less likely to prioritize salary, benefits, and work hours for their first job (13.6%, 10.9% 19.3%) than White cardiologists (20.6%, 23.3%, 31.3%; P < .02 for all).

In subsequent negotiations, URMs placed more emphasis on salary, benefits, and work hours than Whites, whereas both URMs and Asians/Pacific Islanders placed a greater importance on travel benefits, diversity, mentoring, workspace, time to promotion, academic rank, and roles with community, institutional, or national recognition, which the authors say, “might indicate a greater need to overcome systemic barriers.”

Three-fourths of all cardiologist respondents had a mentor during training, which can take many shapes, Dr. Thomas noted. “Within my own section as an electrophysiologist, which is a very subspecialized category, we have four Black electrophysiologists, and I think it was because many of us mentored each other as we came along, and it inspired us.”

URMs are more likely to experience the so-called “minority tax” of being tapped for added responsibilities in the name of inclusivity efforts, he said, and called on individuals from the dominant culture to mentor or sponsor cardiologists from other racial groups and to carve out leadership pathways for women and minorities so they “can use their gifts to benefit the profession at large,” leading clinical trials or steering committees and serving in high-profile roles.

Although the events of 2020 sharpened attention on the issue of diversity in America, Dr. Thomas and colleagues say that more work needs to be done defining the problem and that professional organizations and health systems also should systematically collect sex, racial, and ethnic identifies of members using classifications similar to the 2020 U.S. Census.

The study was based on 2,245 respondents to the 2015 Professional Life Survey, which was not specifically designed to assess racial/ethnic diversity topics and had a response rate of 21%, which limited representatives of each group.

In all, 197 were from URMs (80 Blacks, 113 Hispanics, 4 Native Americans), 564 were Asians/Pacific Islanders, 1,447 were Whites, and 37 listed multiracial/other. More than half (58%) were men, and most were adult cardiologists (83% to 85%), followed by pediatric cardiology (6% to 10%) and cardiovascular surgery (1% to 2%).

“Further research is needed to understand these findings and their significance, because ongoing efforts within ACC and other organizations to increase diversity will fail unless this is successfully addressed,” the authors conclude.

To that end, Dr. Thomas said they are looking to develop a new survey that taps other groups like the Association of Black Cardiologists and members of the LGBTQ community.

“I’m really excited about the opportunity to develop a survey that specifically has the objective of trying to understand the experiences of systematically disadvantaged, historically marginalized groups to see if we can see the same information, but maybe through a clear lens, and then be able to develop strategies to mitigate some of the challenges that we see” he said. “So we can increase the numbers and also have a workforce that is reflective of the populations that we take care of and the nation as a whole.”

The study was funded by the American College of Cardiology. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Survey results paint a stark picture of discrimination among racial minorities in the cardiology workforce but also a strong sense of belonging.

Hiraman/Getty Images

Among respondents to the 2015 American College of Cardiology (ACC) Professional Life Survey, which is the most recent survey, over half (52.3%) of underrepresented racial and ethnic minorities (URMs) and 45.5% of Asian or Pacific Islanders reported experiencing discrimination compared with 36.4% of Whites (both P < .01).

Nevertheless, 91.2% of URMs reported being satisfied with their career, as did 90% of Asians or Pacific Islanders and 89.1% of Whites.

Satisfaction with financial compensation also did not differ between groups, and most cardiologists believed their opportunities for advancement were similar to those of their peers.

One possible explanation is that the respondents may simply be people who’ve had better experiences, lead author Kevin L. Thomas, MD, Duke Clinical Research Institute, Durham, N.C., and colleagues told this news organization. A second hypothesis looks more to sheer determination, or grit.

“Perhaps along the sometimes circuitous pathway to being a cardiologist – which is a lot of training, a lot of standardized testing, a lot of applications – that maybe you sub-select a group of individuals who are simply more resilient based on their life experiences and things that they’ve overcome to get where they are,” he said.

Interestingly, rates of burnout were lower among URMs (22.4%) and Asians/Pacific Islanders (20.1%) than Whites (30.3%; P = .02 and P < .01, respectively). The finding is unexpected but in line with a recent report of more than 4,400 U.S. physicians finding lower odds of burnout among Asian, Hispanic/Latinx, and Black physicians.

The new study, published October 18 in the Journal of the American College of Cardiology, however, affirms that women of all racial and ethnic groups face significant headwinds in the White, male-dominated cardiology workforce.

Just 13.9% of White men reported experiencing discrimination, compared with 44.6% of URM men and 36.2% of Asians/Pacific Islander men. In comparison, 69.2% of White women reported discrimination, as did 62.7% of URM women and 57% of Asian/Pacific Islander women (both P <.01).

“When you look specifically at White men versus White women, there is a large discrepancy there, and it just shows us, I think, for a lot of different groups, we still have a long way to go in terms of trying to achieve equity and to try to be inclusive in the workplace,” Dr. Thomas said.

Men were more likely to experience race- and religion-based discrimination in the workplace, whereas nearly all women reported sex discrimination, with parenting an important second. Approximately 85% of cardiologists reported being satisfied with their family lives, although unpublished data suggest URMs were less likely to be married and to have fewer children, Dr. Thomas said.

During job negotiations, URM cardiologists were less likely to prioritize salary, benefits, and work hours for their first job (13.6%, 10.9% 19.3%) than White cardiologists (20.6%, 23.3%, 31.3%; P < .02 for all).

In subsequent negotiations, URMs placed more emphasis on salary, benefits, and work hours than Whites, whereas both URMs and Asians/Pacific Islanders placed a greater importance on travel benefits, diversity, mentoring, workspace, time to promotion, academic rank, and roles with community, institutional, or national recognition, which the authors say, “might indicate a greater need to overcome systemic barriers.”

Three-fourths of all cardiologist respondents had a mentor during training, which can take many shapes, Dr. Thomas noted. “Within my own section as an electrophysiologist, which is a very subspecialized category, we have four Black electrophysiologists, and I think it was because many of us mentored each other as we came along, and it inspired us.”

URMs are more likely to experience the so-called “minority tax” of being tapped for added responsibilities in the name of inclusivity efforts, he said, and called on individuals from the dominant culture to mentor or sponsor cardiologists from other racial groups and to carve out leadership pathways for women and minorities so they “can use their gifts to benefit the profession at large,” leading clinical trials or steering committees and serving in high-profile roles.

Although the events of 2020 sharpened attention on the issue of diversity in America, Dr. Thomas and colleagues say that more work needs to be done defining the problem and that professional organizations and health systems also should systematically collect sex, racial, and ethnic identifies of members using classifications similar to the 2020 U.S. Census.

The study was based on 2,245 respondents to the 2015 Professional Life Survey, which was not specifically designed to assess racial/ethnic diversity topics and had a response rate of 21%, which limited representatives of each group.

In all, 197 were from URMs (80 Blacks, 113 Hispanics, 4 Native Americans), 564 were Asians/Pacific Islanders, 1,447 were Whites, and 37 listed multiracial/other. More than half (58%) were men, and most were adult cardiologists (83% to 85%), followed by pediatric cardiology (6% to 10%) and cardiovascular surgery (1% to 2%).

“Further research is needed to understand these findings and their significance, because ongoing efforts within ACC and other organizations to increase diversity will fail unless this is successfully addressed,” the authors conclude.

To that end, Dr. Thomas said they are looking to develop a new survey that taps other groups like the Association of Black Cardiologists and members of the LGBTQ community.

“I’m really excited about the opportunity to develop a survey that specifically has the objective of trying to understand the experiences of systematically disadvantaged, historically marginalized groups to see if we can see the same information, but maybe through a clear lens, and then be able to develop strategies to mitigate some of the challenges that we see” he said. “So we can increase the numbers and also have a workforce that is reflective of the populations that we take care of and the nation as a whole.”

The study was funded by the American College of Cardiology. The authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A large international team of experts has developed two comprehensive guidelines for diagnosing, evaluating, and managing hypoparathyroidism and hyperparathyroidism, which replace guidelines issued 5 and 7 years ago.

Aliya A. Khan, MD, presented an overview of the hypoparathyroidism guidelines and John P. Bilezikian, MD, presented key aspects of the hyperparathyroidism guidelines at the American Society of Bone and Mineral Research (ASBMR) 2021 Annual Meeting.

The guidelines will be published as 17 articles in two issues of the society’s Journal of Bone and Mineral Research in 2022 – one on hypoparathyroidism and the other on hyperparathyroidism.

The work represents an “unprecedented effort” by more than 100 experts from 16 countries (United States, Canada, Australia, Brazil, China, Denmark, France, Germany, India, Italy, Israel, Lebanon, Singapore, Spain, Sweden, and the United Kingdom), Dr. Bilezikian told this news organization in an interview.

More than 100 international and national endocrine and osteoporosis organizations, societies, and patient advocacy groups from more than 50 countries have expressed interest in endorsing the guidelines.
 

Management of hypoparathyroidism

The new guidelines on hypoparathyroidism replace the guidelines issued in 2016 that were developed at the First International Conference on the Management of Hypoparathyroidism, Dr. Khan, from McMaster University, Hamilton, Ont., said in an email.

There was a need for new hypoparathyroidism guidelines, she explained, because of the better understanding of associated complications, how to predict who will develop hypoparathyroidism postoperatively (and how to prevent this), how and when to investigate a genetic cause further, when to consider parathyroid hormone (PTH) replacement therapy (and the benefits of the various molecules available today as well as those being evaluated in clinical research), and how to diagnose and manage hypoparathyroidism during pregnancy and lactation.

The experts in hypoparathyroidism were divided into four task forces that covered epidemiology and financial burden, etiology and pathophysiology, genetics and diagnosis, and patient evaluation and management.

The guidelines, developed over the past 18 months, provide detailed evidence-based graded (strong to weak) as well as ungraded (current practice) recommendations.

Summarizing a few key takeaways, Dr. Khan noted the guidelines recommend that clinicians treating patients with hypoparathyroidism should:

• Diagnose hypoparathyroidism if serum calcium corrected for albumin is low in the presence of a low or inappropriately normal PTH confirmed on two occasions 2 weeks apart (which may be supported by other specified abnormalities).
• Determine the cause for the hypoparathyroidism (which includes postsurgery, genetic variant, autoimmune, radiation, or idiopathic causes).
• Evaluate target organ damage.
• Try to achieve treatment goals and minimize risks for long-term complications.
• Consider PTH replacement therapy if patients have inadequate control, with symptoms of hypocalcemia or hypercalcemia, high phosphate, kidney disease, or high urine calcium, or poor quality of life. 

The guideline strongly recommends using PTH measurements after total thyroidectomy to try to predict which patients will develop permanent postsurgical hypoparathyroidism.

It provides a clinical approach for establishing the genetic etiology of hypoparathyroidism.

A meta-analysis of 81 studies identified that the most common symptoms/complications of chronic hypoparathyroidism were, in descending order, cataract (24%), infection (18%), nephrolithiasis, renal insufficiency, seizures, depression, ischemic heart disease, and arrhythmias.

Based on the best available evidence, the guideline advises that “clinicians need to carefully determine why a patient has hypoparathyroidism and develop an individualized treatment plan with conventional therapy consisting of calcium, active vitamin D, hydrochlorothiazide, and plain vitamin D,” Dr. Khan continued.

“If a patient has poorly controlled hypoparathyroidism with many symptoms or is not doing well, then clinicians must consider PTH replacement therapy, since this will replace the missing hormone, lower the urine calcium losses, bring the serum calcium back up to the normal reference range, and lower phosphate (which appears to be associated with kidney calcification and may also contribute to basal ganglia calcification and calcium deposits in the eye),” she noted.

The guideline also discusses the optimal way to monitor and treat patients during pregnancy, delivery, and breastfeeding to optimize outcomes for mother and baby. The key points are closer patient monitoring with normalization of calcium, urine calcium, phosphate, and vitamin D.  
 

Management of primary hyperparathyroidism

There was a need to update the previous 2014 guidelines developed at the Fourth International Workshop on the Management of Primary Hyperparathyroidism because, among other things, recent studies have provided new evidence about the different clinical phenotypes of primary hyperparathyroidism and ways the disease affects the skeleton and kidneys, Dr. Bilezikian, from the College of Physicians and Surgeons, Columbia University, New York, explained.

The experts in hyperparathyroidism were divided into four task forces that covered epidemiology, pathophysiology and genetics; classical and nonclassical disease manifestations; surgical aspects; and patient evaluation and management.

As part of these topics, the experts reviewed biochemical, skeletal, and renal findings, nonclassical features (such as neurocognitive complaints), nutritional and pharmacologic approaches, and disease course with or without surgical or medical intervention.

They made recommendations for diagnosis of hypercalcemic and normocalcemic phenotypes, differential diagnosis, evaluation of the skeleton and the kidney, indications for surgery, role of parathyroid imaging, indications for pharmacologic intervention, and monitoring.

“Consider the way this disease has appeared to change in the last 50 years,” said Dr. Bilezikian. In the 1940s, 50s, and 60s, patients with hyperparathyroidism were really sick and had severe bone disease and kidney disease. Then in the 70s, 80s, and 90s, the disease was more often discovered because of a screening test; high serum calcium was a hallmark of finding asymptomatic hyperparathyroidism.

In recent years, hyperparathyroidism is often discovered incidentally, when examining the skeleton or kidneys, he continued.

Primary hyperparathyroidism can now be subdivided into three types: patients who have target organ (kidney, bone) involvement, patients who don’t have this, and patients who have normocalcemic primary hyperparathyroidism.

The guideline discusses new medications that have become available for hyperparathyroidism, as well as surgery (the only cure), including how preoperative imaging can identify the overactive parathyroid gland, and the guidelines go into detail about how to monitor a patient and why a clinician would or would not recommend surgery, Dr. Bilezikian explained.

In the end, treatment is tailored to the individual.

Last, the guideline identifies eight areas where more research is needed.

The guidelines were funded by unrestricted educational grants from Amolyt, Ascendis, Calcilytix, and Takeda. Dr. Khan has reported participating on advisory boards for Alexion, Amgen, Amolyt, and Takeda, being a consultant for Amgen, receiving grants from Alexion, Amgen, Takeda, and Ascendis, being an investigator for Alexion, Amgen, Takeda, Ascendis, and Chugai, and being a speaker for Alexion, Amgen, Takeda, and Ultragenyx. Dr. Bilezikian has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A large international team of experts has developed two comprehensive guidelines for diagnosing, evaluating, and managing hypoparathyroidism and hyperparathyroidism, which replace guidelines issued 5 and 7 years ago.

Aliya A. Khan, MD, presented an overview of the hypoparathyroidism guidelines and John P. Bilezikian, MD, presented key aspects of the hyperparathyroidism guidelines at the American Society of Bone and Mineral Research (ASBMR) 2021 Annual Meeting.

The guidelines will be published as 17 articles in two issues of the society’s Journal of Bone and Mineral Research in 2022 – one on hypoparathyroidism and the other on hyperparathyroidism.

The work represents an “unprecedented effort” by more than 100 experts from 16 countries (United States, Canada, Australia, Brazil, China, Denmark, France, Germany, India, Italy, Israel, Lebanon, Singapore, Spain, Sweden, and the United Kingdom), Dr. Bilezikian told this news organization in an interview.

More than 100 international and national endocrine and osteoporosis organizations, societies, and patient advocacy groups from more than 50 countries have expressed interest in endorsing the guidelines.
 

Management of hypoparathyroidism

The new guidelines on hypoparathyroidism replace the guidelines issued in 2016 that were developed at the First International Conference on the Management of Hypoparathyroidism, Dr. Khan, from McMaster University, Hamilton, Ont., said in an email.

There was a need for new hypoparathyroidism guidelines, she explained, because of the better understanding of associated complications, how to predict who will develop hypoparathyroidism postoperatively (and how to prevent this), how and when to investigate a genetic cause further, when to consider parathyroid hormone (PTH) replacement therapy (and the benefits of the various molecules available today as well as those being evaluated in clinical research), and how to diagnose and manage hypoparathyroidism during pregnancy and lactation.

The experts in hypoparathyroidism were divided into four task forces that covered epidemiology and financial burden, etiology and pathophysiology, genetics and diagnosis, and patient evaluation and management.

The guidelines, developed over the past 18 months, provide detailed evidence-based graded (strong to weak) as well as ungraded (current practice) recommendations.

Summarizing a few key takeaways, Dr. Khan noted the guidelines recommend that clinicians treating patients with hypoparathyroidism should:

• Diagnose hypoparathyroidism if serum calcium corrected for albumin is low in the presence of a low or inappropriately normal PTH confirmed on two occasions 2 weeks apart (which may be supported by other specified abnormalities).
• Determine the cause for the hypoparathyroidism (which includes postsurgery, genetic variant, autoimmune, radiation, or idiopathic causes).
• Evaluate target organ damage.
• Try to achieve treatment goals and minimize risks for long-term complications.
• Consider PTH replacement therapy if patients have inadequate control, with symptoms of hypocalcemia or hypercalcemia, high phosphate, kidney disease, or high urine calcium, or poor quality of life. 

The guideline strongly recommends using PTH measurements after total thyroidectomy to try to predict which patients will develop permanent postsurgical hypoparathyroidism.

It provides a clinical approach for establishing the genetic etiology of hypoparathyroidism.

A meta-analysis of 81 studies identified that the most common symptoms/complications of chronic hypoparathyroidism were, in descending order, cataract (24%), infection (18%), nephrolithiasis, renal insufficiency, seizures, depression, ischemic heart disease, and arrhythmias.

Based on the best available evidence, the guideline advises that “clinicians need to carefully determine why a patient has hypoparathyroidism and develop an individualized treatment plan with conventional therapy consisting of calcium, active vitamin D, hydrochlorothiazide, and plain vitamin D,” Dr. Khan continued.

“If a patient has poorly controlled hypoparathyroidism with many symptoms or is not doing well, then clinicians must consider PTH replacement therapy, since this will replace the missing hormone, lower the urine calcium losses, bring the serum calcium back up to the normal reference range, and lower phosphate (which appears to be associated with kidney calcification and may also contribute to basal ganglia calcification and calcium deposits in the eye),” she noted.

The guideline also discusses the optimal way to monitor and treat patients during pregnancy, delivery, and breastfeeding to optimize outcomes for mother and baby. The key points are closer patient monitoring with normalization of calcium, urine calcium, phosphate, and vitamin D.  
 

Management of primary hyperparathyroidism

There was a need to update the previous 2014 guidelines developed at the Fourth International Workshop on the Management of Primary Hyperparathyroidism because, among other things, recent studies have provided new evidence about the different clinical phenotypes of primary hyperparathyroidism and ways the disease affects the skeleton and kidneys, Dr. Bilezikian, from the College of Physicians and Surgeons, Columbia University, New York, explained.

The experts in hyperparathyroidism were divided into four task forces that covered epidemiology, pathophysiology and genetics; classical and nonclassical disease manifestations; surgical aspects; and patient evaluation and management.

As part of these topics, the experts reviewed biochemical, skeletal, and renal findings, nonclassical features (such as neurocognitive complaints), nutritional and pharmacologic approaches, and disease course with or without surgical or medical intervention.

They made recommendations for diagnosis of hypercalcemic and normocalcemic phenotypes, differential diagnosis, evaluation of the skeleton and the kidney, indications for surgery, role of parathyroid imaging, indications for pharmacologic intervention, and monitoring.

“Consider the way this disease has appeared to change in the last 50 years,” said Dr. Bilezikian. In the 1940s, 50s, and 60s, patients with hyperparathyroidism were really sick and had severe bone disease and kidney disease. Then in the 70s, 80s, and 90s, the disease was more often discovered because of a screening test; high serum calcium was a hallmark of finding asymptomatic hyperparathyroidism.

In recent years, hyperparathyroidism is often discovered incidentally, when examining the skeleton or kidneys, he continued.

Primary hyperparathyroidism can now be subdivided into three types: patients who have target organ (kidney, bone) involvement, patients who don’t have this, and patients who have normocalcemic primary hyperparathyroidism.

The guideline discusses new medications that have become available for hyperparathyroidism, as well as surgery (the only cure), including how preoperative imaging can identify the overactive parathyroid gland, and the guidelines go into detail about how to monitor a patient and why a clinician would or would not recommend surgery, Dr. Bilezikian explained.

In the end, treatment is tailored to the individual.

Last, the guideline identifies eight areas where more research is needed.

The guidelines were funded by unrestricted educational grants from Amolyt, Ascendis, Calcilytix, and Takeda. Dr. Khan has reported participating on advisory boards for Alexion, Amgen, Amolyt, and Takeda, being a consultant for Amgen, receiving grants from Alexion, Amgen, Takeda, and Ascendis, being an investigator for Alexion, Amgen, Takeda, Ascendis, and Chugai, and being a speaker for Alexion, Amgen, Takeda, and Ultragenyx. Dr. Bilezikian has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A large international team of experts has developed two comprehensive guidelines for diagnosing, evaluating, and managing hypoparathyroidism and hyperparathyroidism, which replace guidelines issued 5 and 7 years ago.

Aliya A. Khan, MD, presented an overview of the hypoparathyroidism guidelines and John P. Bilezikian, MD, presented key aspects of the hyperparathyroidism guidelines at the American Society of Bone and Mineral Research (ASBMR) 2021 Annual Meeting.

The guidelines will be published as 17 articles in two issues of the society’s Journal of Bone and Mineral Research in 2022 – one on hypoparathyroidism and the other on hyperparathyroidism.

The work represents an “unprecedented effort” by more than 100 experts from 16 countries (United States, Canada, Australia, Brazil, China, Denmark, France, Germany, India, Italy, Israel, Lebanon, Singapore, Spain, Sweden, and the United Kingdom), Dr. Bilezikian told this news organization in an interview.

More than 100 international and national endocrine and osteoporosis organizations, societies, and patient advocacy groups from more than 50 countries have expressed interest in endorsing the guidelines.
 

Management of hypoparathyroidism

The new guidelines on hypoparathyroidism replace the guidelines issued in 2016 that were developed at the First International Conference on the Management of Hypoparathyroidism, Dr. Khan, from McMaster University, Hamilton, Ont., said in an email.

There was a need for new hypoparathyroidism guidelines, she explained, because of the better understanding of associated complications, how to predict who will develop hypoparathyroidism postoperatively (and how to prevent this), how and when to investigate a genetic cause further, when to consider parathyroid hormone (PTH) replacement therapy (and the benefits of the various molecules available today as well as those being evaluated in clinical research), and how to diagnose and manage hypoparathyroidism during pregnancy and lactation.

The experts in hypoparathyroidism were divided into four task forces that covered epidemiology and financial burden, etiology and pathophysiology, genetics and diagnosis, and patient evaluation and management.

The guidelines, developed over the past 18 months, provide detailed evidence-based graded (strong to weak) as well as ungraded (current practice) recommendations.

Summarizing a few key takeaways, Dr. Khan noted the guidelines recommend that clinicians treating patients with hypoparathyroidism should:

• Diagnose hypoparathyroidism if serum calcium corrected for albumin is low in the presence of a low or inappropriately normal PTH confirmed on two occasions 2 weeks apart (which may be supported by other specified abnormalities).
• Determine the cause for the hypoparathyroidism (which includes postsurgery, genetic variant, autoimmune, radiation, or idiopathic causes).
• Evaluate target organ damage.
• Try to achieve treatment goals and minimize risks for long-term complications.
• Consider PTH replacement therapy if patients have inadequate control, with symptoms of hypocalcemia or hypercalcemia, high phosphate, kidney disease, or high urine calcium, or poor quality of life. 

The guideline strongly recommends using PTH measurements after total thyroidectomy to try to predict which patients will develop permanent postsurgical hypoparathyroidism.

It provides a clinical approach for establishing the genetic etiology of hypoparathyroidism.

A meta-analysis of 81 studies identified that the most common symptoms/complications of chronic hypoparathyroidism were, in descending order, cataract (24%), infection (18%), nephrolithiasis, renal insufficiency, seizures, depression, ischemic heart disease, and arrhythmias.

Based on the best available evidence, the guideline advises that “clinicians need to carefully determine why a patient has hypoparathyroidism and develop an individualized treatment plan with conventional therapy consisting of calcium, active vitamin D, hydrochlorothiazide, and plain vitamin D,” Dr. Khan continued.

“If a patient has poorly controlled hypoparathyroidism with many symptoms or is not doing well, then clinicians must consider PTH replacement therapy, since this will replace the missing hormone, lower the urine calcium losses, bring the serum calcium back up to the normal reference range, and lower phosphate (which appears to be associated with kidney calcification and may also contribute to basal ganglia calcification and calcium deposits in the eye),” she noted.

The guideline also discusses the optimal way to monitor and treat patients during pregnancy, delivery, and breastfeeding to optimize outcomes for mother and baby. The key points are closer patient monitoring with normalization of calcium, urine calcium, phosphate, and vitamin D.  
 

Management of primary hyperparathyroidism

There was a need to update the previous 2014 guidelines developed at the Fourth International Workshop on the Management of Primary Hyperparathyroidism because, among other things, recent studies have provided new evidence about the different clinical phenotypes of primary hyperparathyroidism and ways the disease affects the skeleton and kidneys, Dr. Bilezikian, from the College of Physicians and Surgeons, Columbia University, New York, explained.

The experts in hyperparathyroidism were divided into four task forces that covered epidemiology, pathophysiology and genetics; classical and nonclassical disease manifestations; surgical aspects; and patient evaluation and management.

As part of these topics, the experts reviewed biochemical, skeletal, and renal findings, nonclassical features (such as neurocognitive complaints), nutritional and pharmacologic approaches, and disease course with or without surgical or medical intervention.

They made recommendations for diagnosis of hypercalcemic and normocalcemic phenotypes, differential diagnosis, evaluation of the skeleton and the kidney, indications for surgery, role of parathyroid imaging, indications for pharmacologic intervention, and monitoring.

“Consider the way this disease has appeared to change in the last 50 years,” said Dr. Bilezikian. In the 1940s, 50s, and 60s, patients with hyperparathyroidism were really sick and had severe bone disease and kidney disease. Then in the 70s, 80s, and 90s, the disease was more often discovered because of a screening test; high serum calcium was a hallmark of finding asymptomatic hyperparathyroidism.

In recent years, hyperparathyroidism is often discovered incidentally, when examining the skeleton or kidneys, he continued.

Primary hyperparathyroidism can now be subdivided into three types: patients who have target organ (kidney, bone) involvement, patients who don’t have this, and patients who have normocalcemic primary hyperparathyroidism.

The guideline discusses new medications that have become available for hyperparathyroidism, as well as surgery (the only cure), including how preoperative imaging can identify the overactive parathyroid gland, and the guidelines go into detail about how to monitor a patient and why a clinician would or would not recommend surgery, Dr. Bilezikian explained.

In the end, treatment is tailored to the individual.

Last, the guideline identifies eight areas where more research is needed.

The guidelines were funded by unrestricted educational grants from Amolyt, Ascendis, Calcilytix, and Takeda. Dr. Khan has reported participating on advisory boards for Alexion, Amgen, Amolyt, and Takeda, being a consultant for Amgen, receiving grants from Alexion, Amgen, Takeda, and Ascendis, being an investigator for Alexion, Amgen, Takeda, Ascendis, and Chugai, and being a speaker for Alexion, Amgen, Takeda, and Ultragenyx. Dr. Bilezikian has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Targeted agents for the treatment of diffuse large B-cell lymphoma (DLBCL) should be used in the context of oncogenic addictions within the lymphoma cells, and a thorough molecular analysis should be conducted prior to using specific agents, a review of the relevant literature suggests.

“In addition ... single-agent regimens are most likely not efficient enough to substantially improve the outcome of patients with DLBCL,” Wendan Xu and colleagues at University Hospital Munster, Germany, concluded, based on their review.

Indeed, novel combinations that include B-cell receptor (BCR) signaling and phosphatidylinositol 3-kinase (PI3K) inhibitors are needed for DLBCL treatment, and treatment should also include conventional chemoimmunotherapeutic regimens as well as other targeted agents and novel immunologic approaches, they wrote. Such novel combinations could overcome mechanisms of resistance and increase cure rates in individuals with DLBCL, they contended.

The authors’ observations are based on a search of the available data, from which they summarized the “current understanding of BCR signaling with a special focus on the PI3K pathway and its role in the pathogenesis of DLBCL.”

The addition of the anti-CD20 antibody rituximab to the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) significantly improved outcomes for patients with DLBCL, but about a third of patients are not cured by the rituximab-CHOP (R-CHOP) regimen and subsequent therapies, they said, explaining their rationale for the review.

“A better understanding of the molecular pathogenesis is warranted to use novel targeted agents in an optimal manner,” they said.

The authors also addressed clinical implications of the findings, and mechanisms of resistance to PI3k inhibitors. For example, they noted that:

–Bruton’s tyrosine kinase (BTK) inhibitors may be beneficial when added to R-CHOP.

In the randomized phase 3 PHOENIX trial, ibrutinib plus R-CHOP versus R-CHOP alone in patients with non–germinal center B-cell (non-GCB) DLBCL showed a survival benefit in patients over 60 years of age, which suggests a possible role for “an intensified R-CHOP regimen that includes a BTK inhibitor” in these patients, they said. They added that confirmatory trials are under way, including the ESCALADE trial looking at the second-generation BTK inhibitor acalabrutinib combined with R-CHOP versus R-CHOP alone in patients with untreated DLBCL.

–Results have been mixed with PI3K inhibitors.

Various PI3K inhibitors have been evaluated for the treatment of patients with DLBCL.

Idelalisib, a first-in-class PI3K-specific inhibitor approved for treatment of relapsed/refractory (r/r) follicular lymphoma, small lymphocytic lymphoma, and chronic lymphocytic leukemia (CLL), showed only modest activity in preclinical DLBCL models, and no responses were detectable in a small trial of patients with r/r DLBCL, the authors said. “Severe toxic side effects and treatment-related deaths occurred in several clinical trials that tested idelalisib in combination with antibodies alone or with antibodies and chemotherapy, leading to the premature discontinuation of some of these studies,” they noted.

Other studies investigating idelalisib plus lenalidomide and rituximab or the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with r/r CLL or lymphoma were also halted because of “overwhelming, immune-mediated pulmonary and/or hepatic toxicities.”

Copanlisib, an intravenous pan-class I PI3K inhibitor with preferential inhibition of PI3Ka and PI3Kd, showed some promise as monotherapy in a phase 2 trial of patients with r/r DLBCL. The overall response rate was about 20%, and response was “numerically higher” in activated B-cell like (ABC) DLBCL, compared with GCB DLBCL (32% vs. 13%), confirming preclinical data that showed PI3Ka/d inhibition effectiveness mainly in ABC DLBCL.

“Compared with idelalisib, copanlisib appears to have a more favorable toxicity profile, with a lower incidence of severe complications,” they said, adding that a phase 2 trial of copanlisib plus R-CHOP as first-line therapy for patients with DLBCL is under way.

Further, monotherapy with buparlisib, a pan-class I PI3K inhibitor, was associated with a low response rate of 11.5% in a DLBCL subcohort in a phase 2 study, whereas parsaclisib, a next-generation inhibitor with specificity to the PI3Kd isoform, showed efficacy as a monotherapy in patients with r/r DLBCL in a phase 2 study (overall response rate, 25.5%), they said, adding that other PI3K inhibitors with additional inhibitory effects are under clinical development.

–Various molecular mechanisms of resistance to PI3K inhibitors have been described preclinically and clinically.

In an unbiased exploratory analysis of samples from patients treated with copanlisib, a 16-gene mutation signature that separated responders from nonresponders was identified, the authors said.

The finding suggests that genetic aberrations dictate response to PI3K inhibitors, they noted.

“This 16-gene signature included TNFAIP3, CREBBP, and PRDM1, which are known to be important in the molecular pathogenesis of DLBCL,” they wrote. A composite score was developed to reflect the numerical presence or absence of mutations in the gene set, they explained, adding that patients with a high composite score had a significantly higher overall response rate and longer progression-free survival than did patients with a lower score.

In addition, idelalisib treatment resulted in a feedback activation of PI3Ka in ABC DLBCL cells.

“This rebound of PI3K activity was overcome by subsequent PI3Ka inhibition in preclinical DLBCL models, further underscoring the necessity of inhibiting both PI3Ka and PI3Kd to achieve responses in ABC DLBCL,” they wrote, adding that “[i]n ABC DLBCL models treated with the PI3Ka/PI3Kd inhibitor AZD8835, activated CARD11 mutations were identified as a mechanism of resistance.”

Investigations looking at various treatment combinations to overcome resistance to PI3K inhibition and improve the efficacy of targeted approaches are under way, they said.

For example, copanlisib plus the BCL-2 inhibitor venetoclax showed “synergistic activity in BCR-dependent DLBCLs, with genetic bases for BCL-2 dysregulation in vitro and in vivo,” and combination treatment with umbralisib and the proteasome inhibitor carfilzomib showed synergistic cytotoxicity in B-cell lymphoma, they said, noting that the latter combination is currently being evaluated in patients with DLBCL.

This work was supported by a research grant from the Deutsche Krebshilfe. Dr. Xu reported having no financial disclosures.

[email protected]

Targeted agents for the treatment of diffuse large B-cell lymphoma (DLBCL) should be used in the context of oncogenic addictions within the lymphoma cells, and a thorough molecular analysis should be conducted prior to using specific agents, a review of the relevant literature suggests.

“In addition ... single-agent regimens are most likely not efficient enough to substantially improve the outcome of patients with DLBCL,” Wendan Xu and colleagues at University Hospital Munster, Germany, concluded, based on their review.

Indeed, novel combinations that include B-cell receptor (BCR) signaling and phosphatidylinositol 3-kinase (PI3K) inhibitors are needed for DLBCL treatment, and treatment should also include conventional chemoimmunotherapeutic regimens as well as other targeted agents and novel immunologic approaches, they wrote. Such novel combinations could overcome mechanisms of resistance and increase cure rates in individuals with DLBCL, they contended.

The authors’ observations are based on a search of the available data, from which they summarized the “current understanding of BCR signaling with a special focus on the PI3K pathway and its role in the pathogenesis of DLBCL.”

The addition of the anti-CD20 antibody rituximab to the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) significantly improved outcomes for patients with DLBCL, but about a third of patients are not cured by the rituximab-CHOP (R-CHOP) regimen and subsequent therapies, they said, explaining their rationale for the review.

“A better understanding of the molecular pathogenesis is warranted to use novel targeted agents in an optimal manner,” they said.

The authors also addressed clinical implications of the findings, and mechanisms of resistance to PI3k inhibitors. For example, they noted that:

–Bruton’s tyrosine kinase (BTK) inhibitors may be beneficial when added to R-CHOP.

In the randomized phase 3 PHOENIX trial, ibrutinib plus R-CHOP versus R-CHOP alone in patients with non–germinal center B-cell (non-GCB) DLBCL showed a survival benefit in patients over 60 years of age, which suggests a possible role for “an intensified R-CHOP regimen that includes a BTK inhibitor” in these patients, they said. They added that confirmatory trials are under way, including the ESCALADE trial looking at the second-generation BTK inhibitor acalabrutinib combined with R-CHOP versus R-CHOP alone in patients with untreated DLBCL.

–Results have been mixed with PI3K inhibitors.

Various PI3K inhibitors have been evaluated for the treatment of patients with DLBCL.

Idelalisib, a first-in-class PI3K-specific inhibitor approved for treatment of relapsed/refractory (r/r) follicular lymphoma, small lymphocytic lymphoma, and chronic lymphocytic leukemia (CLL), showed only modest activity in preclinical DLBCL models, and no responses were detectable in a small trial of patients with r/r DLBCL, the authors said. “Severe toxic side effects and treatment-related deaths occurred in several clinical trials that tested idelalisib in combination with antibodies alone or with antibodies and chemotherapy, leading to the premature discontinuation of some of these studies,” they noted.

Other studies investigating idelalisib plus lenalidomide and rituximab or the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with r/r CLL or lymphoma were also halted because of “overwhelming, immune-mediated pulmonary and/or hepatic toxicities.”

Copanlisib, an intravenous pan-class I PI3K inhibitor with preferential inhibition of PI3Ka and PI3Kd, showed some promise as monotherapy in a phase 2 trial of patients with r/r DLBCL. The overall response rate was about 20%, and response was “numerically higher” in activated B-cell like (ABC) DLBCL, compared with GCB DLBCL (32% vs. 13%), confirming preclinical data that showed PI3Ka/d inhibition effectiveness mainly in ABC DLBCL.

“Compared with idelalisib, copanlisib appears to have a more favorable toxicity profile, with a lower incidence of severe complications,” they said, adding that a phase 2 trial of copanlisib plus R-CHOP as first-line therapy for patients with DLBCL is under way.

Further, monotherapy with buparlisib, a pan-class I PI3K inhibitor, was associated with a low response rate of 11.5% in a DLBCL subcohort in a phase 2 study, whereas parsaclisib, a next-generation inhibitor with specificity to the PI3Kd isoform, showed efficacy as a monotherapy in patients with r/r DLBCL in a phase 2 study (overall response rate, 25.5%), they said, adding that other PI3K inhibitors with additional inhibitory effects are under clinical development.

–Various molecular mechanisms of resistance to PI3K inhibitors have been described preclinically and clinically.

In an unbiased exploratory analysis of samples from patients treated with copanlisib, a 16-gene mutation signature that separated responders from nonresponders was identified, the authors said.

The finding suggests that genetic aberrations dictate response to PI3K inhibitors, they noted.

“This 16-gene signature included TNFAIP3, CREBBP, and PRDM1, which are known to be important in the molecular pathogenesis of DLBCL,” they wrote. A composite score was developed to reflect the numerical presence or absence of mutations in the gene set, they explained, adding that patients with a high composite score had a significantly higher overall response rate and longer progression-free survival than did patients with a lower score.

In addition, idelalisib treatment resulted in a feedback activation of PI3Ka in ABC DLBCL cells.

“This rebound of PI3K activity was overcome by subsequent PI3Ka inhibition in preclinical DLBCL models, further underscoring the necessity of inhibiting both PI3Ka and PI3Kd to achieve responses in ABC DLBCL,” they wrote, adding that “[i]n ABC DLBCL models treated with the PI3Ka/PI3Kd inhibitor AZD8835, activated CARD11 mutations were identified as a mechanism of resistance.”

Investigations looking at various treatment combinations to overcome resistance to PI3K inhibition and improve the efficacy of targeted approaches are under way, they said.

For example, copanlisib plus the BCL-2 inhibitor venetoclax showed “synergistic activity in BCR-dependent DLBCLs, with genetic bases for BCL-2 dysregulation in vitro and in vivo,” and combination treatment with umbralisib and the proteasome inhibitor carfilzomib showed synergistic cytotoxicity in B-cell lymphoma, they said, noting that the latter combination is currently being evaluated in patients with DLBCL.

This work was supported by a research grant from the Deutsche Krebshilfe. Dr. Xu reported having no financial disclosures.

[email protected]

Targeted agents for the treatment of diffuse large B-cell lymphoma (DLBCL) should be used in the context of oncogenic addictions within the lymphoma cells, and a thorough molecular analysis should be conducted prior to using specific agents, a review of the relevant literature suggests.

“In addition ... single-agent regimens are most likely not efficient enough to substantially improve the outcome of patients with DLBCL,” Wendan Xu and colleagues at University Hospital Munster, Germany, concluded, based on their review.

Indeed, novel combinations that include B-cell receptor (BCR) signaling and phosphatidylinositol 3-kinase (PI3K) inhibitors are needed for DLBCL treatment, and treatment should also include conventional chemoimmunotherapeutic regimens as well as other targeted agents and novel immunologic approaches, they wrote. Such novel combinations could overcome mechanisms of resistance and increase cure rates in individuals with DLBCL, they contended.

The authors’ observations are based on a search of the available data, from which they summarized the “current understanding of BCR signaling with a special focus on the PI3K pathway and its role in the pathogenesis of DLBCL.”

The addition of the anti-CD20 antibody rituximab to the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) significantly improved outcomes for patients with DLBCL, but about a third of patients are not cured by the rituximab-CHOP (R-CHOP) regimen and subsequent therapies, they said, explaining their rationale for the review.

“A better understanding of the molecular pathogenesis is warranted to use novel targeted agents in an optimal manner,” they said.

The authors also addressed clinical implications of the findings, and mechanisms of resistance to PI3k inhibitors. For example, they noted that:

–Bruton’s tyrosine kinase (BTK) inhibitors may be beneficial when added to R-CHOP.

In the randomized phase 3 PHOENIX trial, ibrutinib plus R-CHOP versus R-CHOP alone in patients with non–germinal center B-cell (non-GCB) DLBCL showed a survival benefit in patients over 60 years of age, which suggests a possible role for “an intensified R-CHOP regimen that includes a BTK inhibitor” in these patients, they said. They added that confirmatory trials are under way, including the ESCALADE trial looking at the second-generation BTK inhibitor acalabrutinib combined with R-CHOP versus R-CHOP alone in patients with untreated DLBCL.

–Results have been mixed with PI3K inhibitors.

Various PI3K inhibitors have been evaluated for the treatment of patients with DLBCL.

Idelalisib, a first-in-class PI3K-specific inhibitor approved for treatment of relapsed/refractory (r/r) follicular lymphoma, small lymphocytic lymphoma, and chronic lymphocytic leukemia (CLL), showed only modest activity in preclinical DLBCL models, and no responses were detectable in a small trial of patients with r/r DLBCL, the authors said. “Severe toxic side effects and treatment-related deaths occurred in several clinical trials that tested idelalisib in combination with antibodies alone or with antibodies and chemotherapy, leading to the premature discontinuation of some of these studies,” they noted.

Other studies investigating idelalisib plus lenalidomide and rituximab or the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with r/r CLL or lymphoma were also halted because of “overwhelming, immune-mediated pulmonary and/or hepatic toxicities.”

Copanlisib, an intravenous pan-class I PI3K inhibitor with preferential inhibition of PI3Ka and PI3Kd, showed some promise as monotherapy in a phase 2 trial of patients with r/r DLBCL. The overall response rate was about 20%, and response was “numerically higher” in activated B-cell like (ABC) DLBCL, compared with GCB DLBCL (32% vs. 13%), confirming preclinical data that showed PI3Ka/d inhibition effectiveness mainly in ABC DLBCL.

“Compared with idelalisib, copanlisib appears to have a more favorable toxicity profile, with a lower incidence of severe complications,” they said, adding that a phase 2 trial of copanlisib plus R-CHOP as first-line therapy for patients with DLBCL is under way.

Further, monotherapy with buparlisib, a pan-class I PI3K inhibitor, was associated with a low response rate of 11.5% in a DLBCL subcohort in a phase 2 study, whereas parsaclisib, a next-generation inhibitor with specificity to the PI3Kd isoform, showed efficacy as a monotherapy in patients with r/r DLBCL in a phase 2 study (overall response rate, 25.5%), they said, adding that other PI3K inhibitors with additional inhibitory effects are under clinical development.

–Various molecular mechanisms of resistance to PI3K inhibitors have been described preclinically and clinically.

In an unbiased exploratory analysis of samples from patients treated with copanlisib, a 16-gene mutation signature that separated responders from nonresponders was identified, the authors said.

The finding suggests that genetic aberrations dictate response to PI3K inhibitors, they noted.

“This 16-gene signature included TNFAIP3, CREBBP, and PRDM1, which are known to be important in the molecular pathogenesis of DLBCL,” they wrote. A composite score was developed to reflect the numerical presence or absence of mutations in the gene set, they explained, adding that patients with a high composite score had a significantly higher overall response rate and longer progression-free survival than did patients with a lower score.

In addition, idelalisib treatment resulted in a feedback activation of PI3Ka in ABC DLBCL cells.

“This rebound of PI3K activity was overcome by subsequent PI3Ka inhibition in preclinical DLBCL models, further underscoring the necessity of inhibiting both PI3Ka and PI3Kd to achieve responses in ABC DLBCL,” they wrote, adding that “[i]n ABC DLBCL models treated with the PI3Ka/PI3Kd inhibitor AZD8835, activated CARD11 mutations were identified as a mechanism of resistance.”

Investigations looking at various treatment combinations to overcome resistance to PI3K inhibition and improve the efficacy of targeted approaches are under way, they said.

For example, copanlisib plus the BCL-2 inhibitor venetoclax showed “synergistic activity in BCR-dependent DLBCLs, with genetic bases for BCL-2 dysregulation in vitro and in vivo,” and combination treatment with umbralisib and the proteasome inhibitor carfilzomib showed synergistic cytotoxicity in B-cell lymphoma, they said, noting that the latter combination is currently being evaluated in patients with DLBCL.

This work was supported by a research grant from the Deutsche Krebshilfe. Dr. Xu reported having no financial disclosures.

[email protected]

A 35-year-old woman presented to our clinic with a purple-red cyst on her right cheek that had been present for about 4 years but had worsened over the prior 2 weeks (FIGURE 1). She said she was experiencing excruciating pain and that the cyst had purulent drainage. She denied any history of diabetes, dental problems, recent trauma, or an inciting event.

On physical examination, there was no cervical lymphadenopathy, and her vital signs were normal. An incision and drainage procedure was performed. About 2 mL of purulent fluid was extracted and sent for aerobic and anaerobic cultures.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Direct Gram stain showed gram-positive cocci, so the patient was started on a 7-day course of cephalexin 500 mg tid. Five days later, the anaerobic culture grew Actinomyces neuii, revealing the diagnosis as cervicofacial actinomycosis; the patient stopped taking cephalexin. The patient was then switched to a 3-month course of amoxicillin 875 mg bid.

Actinomyces are natural inhabitants of the human oropharynx and gastrointestinal and genitourinary tracts.^1-4 They are filamentous, gram-positive rods with characteristic sulfur granules (although these are not always present).^1-4 It is believed that actinomycosis is endogenously acquired from deep tissue either through dental trauma, penetrating wounds, or compound fractures.^2,4

The most common presentations of actinomycosis include cervicofacial (sometimes referred to as “lumpy jaw syndrome”), followed by abdominopelvic and thoracic/pulmonary, manifestations.^2-4 Primary cutaneous actinomycosis is rare.^5-9 Actinomycosis infection often manifests with indolent constitutional symptoms such as fatigue and anorexia.¹ Most cases occur in men ages 20 to 60 years, although cases in women are increasingly being reported.^2-4

Risk factors include poor dental hygiene or dental procedures, alcoholism, intrauterine device use, immunosuppression, appendicitis, and diverticulitis.^2-4 The exact cause of this patient’s actinomycosis was unknown, as she did not have any known risk factors.

Furunculosis and sporotrichosis are part of the differential

Actinomycosis is often called a “great mimicker” due to its ability to masquerade as infection, malignancy, or fungus.¹ The differential diagnosis for this patient’s presentation included bacterial soft-tissue infection (eg, furunculosis), infected epidermoid cyst, cutaneous tuberculosis, sporotrichosis, deep fungal infection, and nocardiosis.

Continue to: Furunculosis was initially suspected

Furunculosis was initially suspected, but the original wound culture demonstrated actinomycoses instead of traditional gram-positive bacteria.

A clinical diagnosis

The diagnosis of actinomycosis is usually made clinically, but definitive confirmation requires culture, which can be challenging with a slow-growing facultative or strict anaerobe that may take up to 14 days to appear.^2-4 A Gram stain can aid in the diagnosis, but overall, there is a high false-negative rate in identifying actinomycosis.^1,3,4

Treatment time can be lengthy, but prognosis is favorable

Unfortunately, there are no randomized controlled studies for treatment of actinomycosis. The majority of evidence for treatment comes from in vitro and clinical case studies.^2-4,10 In general, prognosis of actinomycosis is favorable with low mortality, but chronic infection without complete resolution of symptoms can occur.^1-4,7,8,10

First-line therapy for actinomycosis is a beta-lactam antibiotic, typically penicillin G or amoxicillin.^2-4,10 High doses of prolonged intravenous (IV) and oral antibiotic therapy (2 to 12 months) based on location and complexity are standard.^3,11 However, if there is minimal bone involvement and the patient shows rapid improvement, treatment could be shortened to a 4 to 6–week oral regimen.^1,11 Surgical intervention can also shorten the required length of antibiotic duration.^1,10

Cutaneous actinomycosis Tx. Amoxicillin/clavulanic acid has been shown to be an effective treatment for cutaneous actinomycosis, especially if polymicrobial infection is suspected.^5,6 Individualized regimens for cutaneous actinomycosis—based on severity, location, and treatment response—are acceptable with close monitoring.^1,2,11

Continue to: A lengthy recovery for our patient

A lengthy recovery for our patient

Seven weeks after the initial visit, the patient reported that she had taken only 20 days’ worth of the recommended 3-month course of amoxicillin. Fortunately, the lesion appeared to be healing well with no apparent fluid collection (FIGURE 2).

Actinomycosis is often called a “great mimicker” due to its ability to masquerade as infection, malignancy, or fungus.

The patient was then prescribed, and completed, a 3-month course of amoxicillin/clavulanic acid 875 mg/125 mg bid.

Nineteen months after initial treatment, the lesion reappeared as a painless cyst in a similar location (FIGURE 3). Plastic Surgery incised and drained the lesion and Infectious Diseases continued her on 3 months of amoxicillin/clavulanic acid 875 mg/125 mg bid, which she did complete.

Due to the continued presence of the lesion, a computed tomography scan of the face was ordered 2 years after the initial visit and demonstrated a superficial skin lesion with no mandibular involvement (FIGURE 4). She was then treated with 3 more months of amoxicillin/clavulanic acid 875 mg/125 mg bid, with the possibility of deep debridement if not improved. However, debridement was unnecessary as the cyst did not recur.

We believe that the course of this patient’s treatment was protracted because she never took oral antibiotics for more than 3 months at a time, and thus, her infection never completely resolved. In retrospect, we would have treated her more aggressively from the outset.

A 35-year-old woman presented to our clinic with a purple-red cyst on her right cheek that had been present for about 4 years but had worsened over the prior 2 weeks (FIGURE 1). She said she was experiencing excruciating pain and that the cyst had purulent drainage. She denied any history of diabetes, dental problems, recent trauma, or an inciting event.

On physical examination, there was no cervical lymphadenopathy, and her vital signs were normal. An incision and drainage procedure was performed. About 2 mL of purulent fluid was extracted and sent for aerobic and anaerobic cultures.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Direct Gram stain showed gram-positive cocci, so the patient was started on a 7-day course of cephalexin 500 mg tid. Five days later, the anaerobic culture grew Actinomyces neuii, revealing the diagnosis as cervicofacial actinomycosis; the patient stopped taking cephalexin. The patient was then switched to a 3-month course of amoxicillin 875 mg bid.

Actinomyces are natural inhabitants of the human oropharynx and gastrointestinal and genitourinary tracts.^1-4 They are filamentous, gram-positive rods with characteristic sulfur granules (although these are not always present).^1-4 It is believed that actinomycosis is endogenously acquired from deep tissue either through dental trauma, penetrating wounds, or compound fractures.^2,4

The most common presentations of actinomycosis include cervicofacial (sometimes referred to as “lumpy jaw syndrome”), followed by abdominopelvic and thoracic/pulmonary, manifestations.^2-4 Primary cutaneous actinomycosis is rare.^5-9 Actinomycosis infection often manifests with indolent constitutional symptoms such as fatigue and anorexia.¹ Most cases occur in men ages 20 to 60 years, although cases in women are increasingly being reported.^2-4

Risk factors include poor dental hygiene or dental procedures, alcoholism, intrauterine device use, immunosuppression, appendicitis, and diverticulitis.^2-4 The exact cause of this patient’s actinomycosis was unknown, as she did not have any known risk factors.

Furunculosis and sporotrichosis are part of the differential

Actinomycosis is often called a “great mimicker” due to its ability to masquerade as infection, malignancy, or fungus.¹ The differential diagnosis for this patient’s presentation included bacterial soft-tissue infection (eg, furunculosis), infected epidermoid cyst, cutaneous tuberculosis, sporotrichosis, deep fungal infection, and nocardiosis.

Continue to: Furunculosis was initially suspected

Furunculosis was initially suspected, but the original wound culture demonstrated actinomycoses instead of traditional gram-positive bacteria.

A clinical diagnosis

The diagnosis of actinomycosis is usually made clinically, but definitive confirmation requires culture, which can be challenging with a slow-growing facultative or strict anaerobe that may take up to 14 days to appear.^2-4 A Gram stain can aid in the diagnosis, but overall, there is a high false-negative rate in identifying actinomycosis.^1,3,4

Treatment time can be lengthy, but prognosis is favorable

Unfortunately, there are no randomized controlled studies for treatment of actinomycosis. The majority of evidence for treatment comes from in vitro and clinical case studies.^2-4,10 In general, prognosis of actinomycosis is favorable with low mortality, but chronic infection without complete resolution of symptoms can occur.^1-4,7,8,10

First-line therapy for actinomycosis is a beta-lactam antibiotic, typically penicillin G or amoxicillin.^2-4,10 High doses of prolonged intravenous (IV) and oral antibiotic therapy (2 to 12 months) based on location and complexity are standard.^3,11 However, if there is minimal bone involvement and the patient shows rapid improvement, treatment could be shortened to a 4 to 6–week oral regimen.^1,11 Surgical intervention can also shorten the required length of antibiotic duration.^1,10

Cutaneous actinomycosis Tx. Amoxicillin/clavulanic acid has been shown to be an effective treatment for cutaneous actinomycosis, especially if polymicrobial infection is suspected.^5,6 Individualized regimens for cutaneous actinomycosis—based on severity, location, and treatment response—are acceptable with close monitoring.^1,2,11

Continue to: A lengthy recovery for our patient

A lengthy recovery for our patient

Seven weeks after the initial visit, the patient reported that she had taken only 20 days’ worth of the recommended 3-month course of amoxicillin. Fortunately, the lesion appeared to be healing well with no apparent fluid collection (FIGURE 2).

Actinomycosis is often called a “great mimicker” due to its ability to masquerade as infection, malignancy, or fungus.

The patient was then prescribed, and completed, a 3-month course of amoxicillin/clavulanic acid 875 mg/125 mg bid.

Nineteen months after initial treatment, the lesion reappeared as a painless cyst in a similar location (FIGURE 3). Plastic Surgery incised and drained the lesion and Infectious Diseases continued her on 3 months of amoxicillin/clavulanic acid 875 mg/125 mg bid, which she did complete.

Due to the continued presence of the lesion, a computed tomography scan of the face was ordered 2 years after the initial visit and demonstrated a superficial skin lesion with no mandibular involvement (FIGURE 4). She was then treated with 3 more months of amoxicillin/clavulanic acid 875 mg/125 mg bid, with the possibility of deep debridement if not improved. However, debridement was unnecessary as the cyst did not recur.

We believe that the course of this patient’s treatment was protracted because she never took oral antibiotics for more than 3 months at a time, and thus, her infection never completely resolved. In retrospect, we would have treated her more aggressively from the outset.

A 35-year-old woman presented to our clinic with a purple-red cyst on her right cheek that had been present for about 4 years but had worsened over the prior 2 weeks (FIGURE 1). She said she was experiencing excruciating pain and that the cyst had purulent drainage. She denied any history of diabetes, dental problems, recent trauma, or an inciting event.

On physical examination, there was no cervical lymphadenopathy, and her vital signs were normal. An incision and drainage procedure was performed. About 2 mL of purulent fluid was extracted and sent for aerobic and anaerobic cultures.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Direct Gram stain showed gram-positive cocci, so the patient was started on a 7-day course of cephalexin 500 mg tid. Five days later, the anaerobic culture grew Actinomyces neuii, revealing the diagnosis as cervicofacial actinomycosis; the patient stopped taking cephalexin. The patient was then switched to a 3-month course of amoxicillin 875 mg bid.

Actinomyces are natural inhabitants of the human oropharynx and gastrointestinal and genitourinary tracts.^1-4 They are filamentous, gram-positive rods with characteristic sulfur granules (although these are not always present).^1-4 It is believed that actinomycosis is endogenously acquired from deep tissue either through dental trauma, penetrating wounds, or compound fractures.^2,4

The most common presentations of actinomycosis include cervicofacial (sometimes referred to as “lumpy jaw syndrome”), followed by abdominopelvic and thoracic/pulmonary, manifestations.^2-4 Primary cutaneous actinomycosis is rare.^5-9 Actinomycosis infection often manifests with indolent constitutional symptoms such as fatigue and anorexia.¹ Most cases occur in men ages 20 to 60 years, although cases in women are increasingly being reported.^2-4

Risk factors include poor dental hygiene or dental procedures, alcoholism, intrauterine device use, immunosuppression, appendicitis, and diverticulitis.^2-4 The exact cause of this patient’s actinomycosis was unknown, as she did not have any known risk factors.

Furunculosis and sporotrichosis are part of the differential

Actinomycosis is often called a “great mimicker” due to its ability to masquerade as infection, malignancy, or fungus.¹ The differential diagnosis for this patient’s presentation included bacterial soft-tissue infection (eg, furunculosis), infected epidermoid cyst, cutaneous tuberculosis, sporotrichosis, deep fungal infection, and nocardiosis.

Continue to: Furunculosis was initially suspected

Furunculosis was initially suspected, but the original wound culture demonstrated actinomycoses instead of traditional gram-positive bacteria.

A clinical diagnosis

The diagnosis of actinomycosis is usually made clinically, but definitive confirmation requires culture, which can be challenging with a slow-growing facultative or strict anaerobe that may take up to 14 days to appear.^2-4 A Gram stain can aid in the diagnosis, but overall, there is a high false-negative rate in identifying actinomycosis.^1,3,4

Treatment time can be lengthy, but prognosis is favorable

Unfortunately, there are no randomized controlled studies for treatment of actinomycosis. The majority of evidence for treatment comes from in vitro and clinical case studies.^2-4,10 In general, prognosis of actinomycosis is favorable with low mortality, but chronic infection without complete resolution of symptoms can occur.^1-4,7,8,10

First-line therapy for actinomycosis is a beta-lactam antibiotic, typically penicillin G or amoxicillin.^2-4,10 High doses of prolonged intravenous (IV) and oral antibiotic therapy (2 to 12 months) based on location and complexity are standard.^3,11 However, if there is minimal bone involvement and the patient shows rapid improvement, treatment could be shortened to a 4 to 6–week oral regimen.^1,11 Surgical intervention can also shorten the required length of antibiotic duration.^1,10

Cutaneous actinomycosis Tx. Amoxicillin/clavulanic acid has been shown to be an effective treatment for cutaneous actinomycosis, especially if polymicrobial infection is suspected.^5,6 Individualized regimens for cutaneous actinomycosis—based on severity, location, and treatment response—are acceptable with close monitoring.^1,2,11

Continue to: A lengthy recovery for our patient

A lengthy recovery for our patient

Seven weeks after the initial visit, the patient reported that she had taken only 20 days’ worth of the recommended 3-month course of amoxicillin. Fortunately, the lesion appeared to be healing well with no apparent fluid collection (FIGURE 2).

Actinomycosis is often called a “great mimicker” due to its ability to masquerade as infection, malignancy, or fungus.

The patient was then prescribed, and completed, a 3-month course of amoxicillin/clavulanic acid 875 mg/125 mg bid.

Nineteen months after initial treatment, the lesion reappeared as a painless cyst in a similar location (FIGURE 3). Plastic Surgery incised and drained the lesion and Infectious Diseases continued her on 3 months of amoxicillin/clavulanic acid 875 mg/125 mg bid, which she did complete.

Due to the continued presence of the lesion, a computed tomography scan of the face was ordered 2 years after the initial visit and demonstrated a superficial skin lesion with no mandibular involvement (FIGURE 4). She was then treated with 3 more months of amoxicillin/clavulanic acid 875 mg/125 mg bid, with the possibility of deep debridement if not improved. However, debridement was unnecessary as the cyst did not recur.

We believe that the course of this patient’s treatment was protracted because she never took oral antibiotics for more than 3 months at a time, and thus, her infection never completely resolved. In retrospect, we would have treated her more aggressively from the outset.

A 30-year-old man presented to the clinic with a complaint of small painful lumps in his armpit. He stated that he initially experienced some itching and discomfort, but after a while he noticed some red, tender, swollen areas. He also mentioned an odorous yellow fluid that would sometimes drain from the lumps. Since first noticing them 2 years earlier, he reported that the nodules had disappeared and reappeared on their own several times.

On physical exam, several small red subcutaneous nodules were present in the axilla and tender to palpation (FIGURE 1A). The patient also had comedonal acne on his back (FIGURE 1B). The patient’s body mass index was 31, and he was a nonsmoker.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The characteristic location and morphology of the lesions, along with the chronicity and odor, were critical in arriving at a diagnosis of hidradenitis suppurativa (HS).

HS is a chronic, inflammatory skin condition that normally manifests in areas of apocrine sweat glands, including the axilla, groin, and perianal, perineal, and inframammary locations.¹ It begins when an abnormal hair follicle gets occluded and ruptures, spilling keratin and bacteria into the dermis. An inflammatory response can ensue with surrounding neutrophils and lymphocytes, which leads to abscess formation and destruction of the pilosebaceous unit. Sinus tracts form between the lesions, and a cycle of scarring, fistulas, and contractures can occur.

In this case, the comedones from acne conglobata on the patient’s back indicated a more global follicular occlusion disorder. The characteristic triad is hidradenitis suppurativa, acne conglobata, and dissecting cellulitis of the scalp—of which the patient had 2.

Even when surgical excisions are performed, medical treatment is needed to prevent new lesions and recurrences.

Other potential causes of the pathology include abnormal secretion of apocrine glands, abnormal antimicrobial peptides, deficient numbers of sebaceous glands, and abnormal invaginations of the epidermis.² Increased levels of tumor necrosis factor alpha and other cytokines have been detected in HS lesions and are a potential target for therapy.

The prevalence of HS in the United States is approximately 0.1%.³ The condition typically begins between the ages of 18 and 39 years. The ratio of women to men affected by the condition is 3:1.² There is no evident racial or ethnic predilection. There is an association with diabetes and Crohn disease.³ Obesity and smoking are risk factors.¹

Continue to: The differential includes an array of common skin conditions

The differential diagnosis in this case included carbuncles, cysts, acne, and abscesses.

A furuncle or carbuncle can result from an infection of hair follicles that can manifest as individual (furuncle) or clusters of (carbuncle) red, painful boils. They form on parts of the skin where hair grows, including the face, neck, armpits, shoulders, and buttocks. They respond well to treatment with antibiotics and incision and drainage. They can be recurrent but usually don’t cluster together in apocrine-rich areas, as seen with HS.

Epidermal inclusion cysts are keratin-filled inclusion cysts with epithelial-lined cyst walls. The cysts are subcutaneous and occasionally more superficial. They can occur almost anywhere but are most often found on the back, scalp, neck, face, and chest. They are usually solitary; however, when there are multiple cysts, they are not linked by sinus tracts as found in HS.

Inflammatory acne lesions tend to form on the face, neck, back, chest, and shoulders, while HS lesions appear most often in apocrine-rich intertriginous areas.

Skin abscesses are local deep infections of the skin caused by bacterial pathogens. The most common agent is Staphylococcus aureus (frequently methicillin resistant). Injection drug use and immunosuppression are risk factors. Although bacteria do not cause HS lesions, bacteria can exacerbate HS through colonization.

Continue to: No lab test needed to diagnosis hidradenitis suppurativa

No lab test needed to diagnose hidradenitis suppurativa

Diagnosis of HS is largely clinical and based on a patient’s history and physical exam findings.² No specific laboratory test is needed.

Although the patient in this case did have comedonal acne on his back, the lesions that prompted his visit were in an apocrine-rich area, were recurrent, and broke open on their own to release foul-smelling contents—all typical characteristics of HS.

Treatment depends on the severity of the condition

There are 3 stages of HS: Hurley stage I involves abscess formation without tracts or scars. Hurley stage II involves recurrent abscesses with sinus tracts and scarring. Hurley stage III has diffuse involvement with multiple interconnected sinus tracts and abscesses across an entire area.² Our patient fits into Hurley stage III.

Evidence-based treatment of mild disease (Hurley stage I) includes topical clindamycin 1% solution/gel bid or doxycycline 100 mg bid for widespread disease (Hurley stage II or resistant stage I).² Chlorhexidine and benzoyl peroxide washes are also often recommended.³ If a patient does not respond to this treatment or the condition is moderate to severe, then clindamycin 300 po bid (with or without rifampin 600/d po) for 10 weeks should be considered.^4,5 In a randomized placebo-controlled trial that compared the efficacy of oral clindamycin vs clindamycin plus rifampin in patients with HS, both therapeutic options were statistically equivalent.⁵ One small, randomized controlled study of patients with mild-to-moderate HS showed that tetracycline 500 mg bid for 3 months resulted in fewer abscesses and nodules but was not superior to topical clindamycin.³

If the patient doesn’t show improvement (Hurley stage III), then adalimumab is an option, as follows: 160 mg subcutaneously at Week 0, 80 mg at Week 2, and then 40 mg weekly, if needed.⁴ Adalimumab is currently the only FDA-approved treatment for HS. Infliximab by IV infusion can be effective in improving pain, disease severity, and quality of life in patients with moderate-to-severe HS.³ This patient was also a candidate for treatment with systemic retinoids (isotretinoin or acitretin), which could have helped both the HS and the acne conglobata.

Continue to: Intralesional steroid injectiosn with triamcinolone

Intralesional steroid injections with triamcinolone 10 mg/mL can reduce local pain and inflammation rapidly. Pain management is also critical, as HS is painful. First-line therapy includes nonsteroidal anti-inflammatory drugs, acetaminophen, atypical anticonvulsants, and serotonin and norepinephrine reuptake inhibitors.² Opiate analgesics may be needed for breakthrough pain in patients with severe disease. Avoiding tight clothing, harsh products, and adhesive dressings, as well as using clear petroleum jelly, can prevent skin trauma and help with healing. Weight loss and smoking cessation are also associated with better outcomes.^6,7

If medical management fails …

If there is no improvement with medical management, it may be time to consider local procedures such as unroofing/deroofing, punch debridement, skin-tissue-sparing excision with electrosurgical peeling, and laser excision. Incision and drainage may be necessary for acutely inflamed, painful abscesses but should not be routinely performed because lesions can recur.³

Referral to a plastic surgeon is necessary when patients are considering wide excisions of largely affected areas. Even when surgical excisions are performed, medical treatment is needed to prevent new lesions and recurrences.

Our patient was treated initially with oral doxycycline 100 mg bid and intralesional triamcinolone (10 mg/mL) in the most tender lesions. He was also provided with a prescription for ibuprofen 800 mg tid to be taken with meals. The family physician encouraged the patient to lose weight. The patient derived some benefit from treatment but continued to experience new painful lesions.

Hidradenitis suppurativa is painful, and thus, pain management is critical.

The physician prescribed oral clindamycin 300 mg bid at a follow-up visit to replace the oral doxycycline. When this failed, the patient was sent for labs to determine if he would be a candidate for adalimumab. When the screening labs were normal, a prescription for adalimumab was provided: 160 mg subcutaneously at Week 0, 80 mg at Week 2, and then 40 mg weekly.⁴

A 30-year-old man presented to the clinic with a complaint of small painful lumps in his armpit. He stated that he initially experienced some itching and discomfort, but after a while he noticed some red, tender, swollen areas. He also mentioned an odorous yellow fluid that would sometimes drain from the lumps. Since first noticing them 2 years earlier, he reported that the nodules had disappeared and reappeared on their own several times.

On physical exam, several small red subcutaneous nodules were present in the axilla and tender to palpation (FIGURE 1A). The patient also had comedonal acne on his back (FIGURE 1B). The patient’s body mass index was 31, and he was a nonsmoker.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The characteristic location and morphology of the lesions, along with the chronicity and odor, were critical in arriving at a diagnosis of hidradenitis suppurativa (HS).

HS is a chronic, inflammatory skin condition that normally manifests in areas of apocrine sweat glands, including the axilla, groin, and perianal, perineal, and inframammary locations.¹ It begins when an abnormal hair follicle gets occluded and ruptures, spilling keratin and bacteria into the dermis. An inflammatory response can ensue with surrounding neutrophils and lymphocytes, which leads to abscess formation and destruction of the pilosebaceous unit. Sinus tracts form between the lesions, and a cycle of scarring, fistulas, and contractures can occur.

In this case, the comedones from acne conglobata on the patient’s back indicated a more global follicular occlusion disorder. The characteristic triad is hidradenitis suppurativa, acne conglobata, and dissecting cellulitis of the scalp—of which the patient had 2.

Even when surgical excisions are performed, medical treatment is needed to prevent new lesions and recurrences.

Other potential causes of the pathology include abnormal secretion of apocrine glands, abnormal antimicrobial peptides, deficient numbers of sebaceous glands, and abnormal invaginations of the epidermis.² Increased levels of tumor necrosis factor alpha and other cytokines have been detected in HS lesions and are a potential target for therapy.

The prevalence of HS in the United States is approximately 0.1%.³ The condition typically begins between the ages of 18 and 39 years. The ratio of women to men affected by the condition is 3:1.² There is no evident racial or ethnic predilection. There is an association with diabetes and Crohn disease.³ Obesity and smoking are risk factors.¹

Continue to: The differential includes an array of common skin conditions

The differential diagnosis in this case included carbuncles, cysts, acne, and abscesses.

A furuncle or carbuncle can result from an infection of hair follicles that can manifest as individual (furuncle) or clusters of (carbuncle) red, painful boils. They form on parts of the skin where hair grows, including the face, neck, armpits, shoulders, and buttocks. They respond well to treatment with antibiotics and incision and drainage. They can be recurrent but usually don’t cluster together in apocrine-rich areas, as seen with HS.

Epidermal inclusion cysts are keratin-filled inclusion cysts with epithelial-lined cyst walls. The cysts are subcutaneous and occasionally more superficial. They can occur almost anywhere but are most often found on the back, scalp, neck, face, and chest. They are usually solitary; however, when there are multiple cysts, they are not linked by sinus tracts as found in HS.

Inflammatory acne lesions tend to form on the face, neck, back, chest, and shoulders, while HS lesions appear most often in apocrine-rich intertriginous areas.

Skin abscesses are local deep infections of the skin caused by bacterial pathogens. The most common agent is Staphylococcus aureus (frequently methicillin resistant). Injection drug use and immunosuppression are risk factors. Although bacteria do not cause HS lesions, bacteria can exacerbate HS through colonization.

Continue to: No lab test needed to diagnosis hidradenitis suppurativa

No lab test needed to diagnose hidradenitis suppurativa

Diagnosis of HS is largely clinical and based on a patient’s history and physical exam findings.² No specific laboratory test is needed.

Although the patient in this case did have comedonal acne on his back, the lesions that prompted his visit were in an apocrine-rich area, were recurrent, and broke open on their own to release foul-smelling contents—all typical characteristics of HS.

Treatment depends on the severity of the condition

There are 3 stages of HS: Hurley stage I involves abscess formation without tracts or scars. Hurley stage II involves recurrent abscesses with sinus tracts and scarring. Hurley stage III has diffuse involvement with multiple interconnected sinus tracts and abscesses across an entire area.² Our patient fits into Hurley stage III.

Evidence-based treatment of mild disease (Hurley stage I) includes topical clindamycin 1% solution/gel bid or doxycycline 100 mg bid for widespread disease (Hurley stage II or resistant stage I).² Chlorhexidine and benzoyl peroxide washes are also often recommended.³ If a patient does not respond to this treatment or the condition is moderate to severe, then clindamycin 300 po bid (with or without rifampin 600/d po) for 10 weeks should be considered.^4,5 In a randomized placebo-controlled trial that compared the efficacy of oral clindamycin vs clindamycin plus rifampin in patients with HS, both therapeutic options were statistically equivalent.⁵ One small, randomized controlled study of patients with mild-to-moderate HS showed that tetracycline 500 mg bid for 3 months resulted in fewer abscesses and nodules but was not superior to topical clindamycin.³

If the patient doesn’t show improvement (Hurley stage III), then adalimumab is an option, as follows: 160 mg subcutaneously at Week 0, 80 mg at Week 2, and then 40 mg weekly, if needed.⁴ Adalimumab is currently the only FDA-approved treatment for HS. Infliximab by IV infusion can be effective in improving pain, disease severity, and quality of life in patients with moderate-to-severe HS.³ This patient was also a candidate for treatment with systemic retinoids (isotretinoin or acitretin), which could have helped both the HS and the acne conglobata.

Continue to: Intralesional steroid injectiosn with triamcinolone

Intralesional steroid injections with triamcinolone 10 mg/mL can reduce local pain and inflammation rapidly. Pain management is also critical, as HS is painful. First-line therapy includes nonsteroidal anti-inflammatory drugs, acetaminophen, atypical anticonvulsants, and serotonin and norepinephrine reuptake inhibitors.² Opiate analgesics may be needed for breakthrough pain in patients with severe disease. Avoiding tight clothing, harsh products, and adhesive dressings, as well as using clear petroleum jelly, can prevent skin trauma and help with healing. Weight loss and smoking cessation are also associated with better outcomes.^6,7

If medical management fails …

If there is no improvement with medical management, it may be time to consider local procedures such as unroofing/deroofing, punch debridement, skin-tissue-sparing excision with electrosurgical peeling, and laser excision. Incision and drainage may be necessary for acutely inflamed, painful abscesses but should not be routinely performed because lesions can recur.³

Referral to a plastic surgeon is necessary when patients are considering wide excisions of largely affected areas. Even when surgical excisions are performed, medical treatment is needed to prevent new lesions and recurrences.

Our patient was treated initially with oral doxycycline 100 mg bid and intralesional triamcinolone (10 mg/mL) in the most tender lesions. He was also provided with a prescription for ibuprofen 800 mg tid to be taken with meals. The family physician encouraged the patient to lose weight. The patient derived some benefit from treatment but continued to experience new painful lesions.

Hidradenitis suppurativa is painful, and thus, pain management is critical.

The physician prescribed oral clindamycin 300 mg bid at a follow-up visit to replace the oral doxycycline. When this failed, the patient was sent for labs to determine if he would be a candidate for adalimumab. When the screening labs were normal, a prescription for adalimumab was provided: 160 mg subcutaneously at Week 0, 80 mg at Week 2, and then 40 mg weekly.⁴

A 30-year-old man presented to the clinic with a complaint of small painful lumps in his armpit. He stated that he initially experienced some itching and discomfort, but after a while he noticed some red, tender, swollen areas. He also mentioned an odorous yellow fluid that would sometimes drain from the lumps. Since first noticing them 2 years earlier, he reported that the nodules had disappeared and reappeared on their own several times.

On physical exam, several small red subcutaneous nodules were present in the axilla and tender to palpation (FIGURE 1A). The patient also had comedonal acne on his back (FIGURE 1B). The patient’s body mass index was 31, and he was a nonsmoker.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The characteristic location and morphology of the lesions, along with the chronicity and odor, were critical in arriving at a diagnosis of hidradenitis suppurativa (HS).

HS is a chronic, inflammatory skin condition that normally manifests in areas of apocrine sweat glands, including the axilla, groin, and perianal, perineal, and inframammary locations.¹ It begins when an abnormal hair follicle gets occluded and ruptures, spilling keratin and bacteria into the dermis. An inflammatory response can ensue with surrounding neutrophils and lymphocytes, which leads to abscess formation and destruction of the pilosebaceous unit. Sinus tracts form between the lesions, and a cycle of scarring, fistulas, and contractures can occur.

In this case, the comedones from acne conglobata on the patient’s back indicated a more global follicular occlusion disorder. The characteristic triad is hidradenitis suppurativa, acne conglobata, and dissecting cellulitis of the scalp—of which the patient had 2.

Even when surgical excisions are performed, medical treatment is needed to prevent new lesions and recurrences.

Other potential causes of the pathology include abnormal secretion of apocrine glands, abnormal antimicrobial peptides, deficient numbers of sebaceous glands, and abnormal invaginations of the epidermis.² Increased levels of tumor necrosis factor alpha and other cytokines have been detected in HS lesions and are a potential target for therapy.

The prevalence of HS in the United States is approximately 0.1%.³ The condition typically begins between the ages of 18 and 39 years. The ratio of women to men affected by the condition is 3:1.² There is no evident racial or ethnic predilection. There is an association with diabetes and Crohn disease.³ Obesity and smoking are risk factors.¹

Continue to: The differential includes an array of common skin conditions

The differential diagnosis in this case included carbuncles, cysts, acne, and abscesses.

A furuncle or carbuncle can result from an infection of hair follicles that can manifest as individual (furuncle) or clusters of (carbuncle) red, painful boils. They form on parts of the skin where hair grows, including the face, neck, armpits, shoulders, and buttocks. They respond well to treatment with antibiotics and incision and drainage. They can be recurrent but usually don’t cluster together in apocrine-rich areas, as seen with HS.

Epidermal inclusion cysts are keratin-filled inclusion cysts with epithelial-lined cyst walls. The cysts are subcutaneous and occasionally more superficial. They can occur almost anywhere but are most often found on the back, scalp, neck, face, and chest. They are usually solitary; however, when there are multiple cysts, they are not linked by sinus tracts as found in HS.

Inflammatory acne lesions tend to form on the face, neck, back, chest, and shoulders, while HS lesions appear most often in apocrine-rich intertriginous areas.

Skin abscesses are local deep infections of the skin caused by bacterial pathogens. The most common agent is Staphylococcus aureus (frequently methicillin resistant). Injection drug use and immunosuppression are risk factors. Although bacteria do not cause HS lesions, bacteria can exacerbate HS through colonization.

Continue to: No lab test needed to diagnosis hidradenitis suppurativa

No lab test needed to diagnose hidradenitis suppurativa

Diagnosis of HS is largely clinical and based on a patient’s history and physical exam findings.² No specific laboratory test is needed.

Although the patient in this case did have comedonal acne on his back, the lesions that prompted his visit were in an apocrine-rich area, were recurrent, and broke open on their own to release foul-smelling contents—all typical characteristics of HS.

Treatment depends on the severity of the condition

There are 3 stages of HS: Hurley stage I involves abscess formation without tracts or scars. Hurley stage II involves recurrent abscesses with sinus tracts and scarring. Hurley stage III has diffuse involvement with multiple interconnected sinus tracts and abscesses across an entire area.² Our patient fits into Hurley stage III.

Evidence-based treatment of mild disease (Hurley stage I) includes topical clindamycin 1% solution/gel bid or doxycycline 100 mg bid for widespread disease (Hurley stage II or resistant stage I).² Chlorhexidine and benzoyl peroxide washes are also often recommended.³ If a patient does not respond to this treatment or the condition is moderate to severe, then clindamycin 300 po bid (with or without rifampin 600/d po) for 10 weeks should be considered.^4,5 In a randomized placebo-controlled trial that compared the efficacy of oral clindamycin vs clindamycin plus rifampin in patients with HS, both therapeutic options were statistically equivalent.⁵ One small, randomized controlled study of patients with mild-to-moderate HS showed that tetracycline 500 mg bid for 3 months resulted in fewer abscesses and nodules but was not superior to topical clindamycin.³

If the patient doesn’t show improvement (Hurley stage III), then adalimumab is an option, as follows: 160 mg subcutaneously at Week 0, 80 mg at Week 2, and then 40 mg weekly, if needed.⁴ Adalimumab is currently the only FDA-approved treatment for HS. Infliximab by IV infusion can be effective in improving pain, disease severity, and quality of life in patients with moderate-to-severe HS.³ This patient was also a candidate for treatment with systemic retinoids (isotretinoin or acitretin), which could have helped both the HS and the acne conglobata.

Continue to: Intralesional steroid injectiosn with triamcinolone

Intralesional steroid injections with triamcinolone 10 mg/mL can reduce local pain and inflammation rapidly. Pain management is also critical, as HS is painful. First-line therapy includes nonsteroidal anti-inflammatory drugs, acetaminophen, atypical anticonvulsants, and serotonin and norepinephrine reuptake inhibitors.² Opiate analgesics may be needed for breakthrough pain in patients with severe disease. Avoiding tight clothing, harsh products, and adhesive dressings, as well as using clear petroleum jelly, can prevent skin trauma and help with healing. Weight loss and smoking cessation are also associated with better outcomes.^6,7

If medical management fails …

If there is no improvement with medical management, it may be time to consider local procedures such as unroofing/deroofing, punch debridement, skin-tissue-sparing excision with electrosurgical peeling, and laser excision. Incision and drainage may be necessary for acutely inflamed, painful abscesses but should not be routinely performed because lesions can recur.³

Referral to a plastic surgeon is necessary when patients are considering wide excisions of largely affected areas. Even when surgical excisions are performed, medical treatment is needed to prevent new lesions and recurrences.

Our patient was treated initially with oral doxycycline 100 mg bid and intralesional triamcinolone (10 mg/mL) in the most tender lesions. He was also provided with a prescription for ibuprofen 800 mg tid to be taken with meals. The family physician encouraged the patient to lose weight. The patient derived some benefit from treatment but continued to experience new painful lesions.

Hidradenitis suppurativa is painful, and thus, pain management is critical.

The physician prescribed oral clindamycin 300 mg bid at a follow-up visit to replace the oral doxycycline. When this failed, the patient was sent for labs to determine if he would be a candidate for adalimumab. When the screening labs were normal, a prescription for adalimumab was provided: 160 mg subcutaneously at Week 0, 80 mg at Week 2, and then 40 mg weekly.⁴

THE CASE

A 75-year-old woman presented to the primary care clinic with right-side rib pain. The patient said the pain started 1 week earlier, after she ate fried chicken for dinner, and had since been exacerbated by rich meals, lying supine, and taking a deep inspiratory breath. She also said that prior to coming to the clinic that day, the pain had been radiating to her right shoulder.

The patient denied experiencing associated fevers, chills, shortness of breath, chest pain, nausea, vomiting, constipation, diarrhea, or changes in stool color. She had a history of hypertension, for which she was taking lisinopril 20 mg/d, and hypercholesterolemia, for which she was on simvastatin 10 mg/d. She was additionally using timolol ophthalmic solution for her glaucoma.

During the examination, the patient’s vital signs were stable, with a pulse of 80 beats/min, a respiratory rate of 16 breaths/min, and an oxygen saturation of 98% on room air. The patient had no abdominal tenderness upon palpation, and the physical exam revealed no abnormalities. An in-office electrocardiogram was performed, with normal results. Additionally, a comprehensive metabolic panel, lipase test, and d-dimer test were ordered. Lab results showed an isolated elevated d-dimer of 2.66 mcg/mL (normal range, < 0.54 mcg/mL), while all other labs were normal.

THE DIAGNOSIS

Based on the lab results, a stat computed tomography pulmonary angiogram (CTPA) was ordered and showed a right segmental and subsegmental pulmonary embolism (PE; FIGURE 1).

DISCUSSION

PE shares pathophysiologic mechanisms with deep vein thrombosis (DVT), and together these comprise venous thromboembolism (VTE). Risk factors for VTE include hypercoagulable disorders, use of estrogens, active malignancy, and immobilization.¹ Unprovoked VTE occurs in the absence of identifiable risk factors and carries a higher risk of recurrence.^2,3 While PE is classically thought to occur in the setting of a DVT, there is increasing literature describing de novo PE that can occur independent of a DVT.⁴

Common symptoms of PE include tachycardia, tachypnea, and pleuritic chest pain.⁵ Abdominal pain is a rare symptom described in some case reports.^6,7 Thus, a high clinical suspicion is needed for diagnosis of PE.

The Wells criteria is an established model for risk stratifying patients presenting with possible VTE (TABLE).⁸ For patients with low pretest probability, as in this case, a d-dimer is an effective diagnostic work-up, as a negative result will rule out PE. (If the d-dimer had been negative in this case, we would have considered other diagnoses, such as acute coronary syndrome, biliary colic, gastritis, pancreatitis, or musculoskeletal pain.) For high-risk patients, immediate anticoagulation and imaging should be performed, frequently with heparin and CTPA.⁹

Continue to: Length of treatment depends on gender and etiology

The cornerstone treatment for stable patients with VTE is therapeutic anticoagulation. The new oral anticoagulants, which directly inhibit factor Xa or thrombin, have become increasingly popular for management of VTE, in part because they don’t require INR testing and monitoring.²

The duration of anticoagulation, particularly in unprovoked PE, is debatable. As noted earlier, patients with an unprovoked PE are at higher risk of recurrence than those with a reversible cause, so the question becomes whether these patients should have indefinite anticoagulation.^2,3 Studies examining risk stratification of patients with a first, unprovoked VTE have found that men have the highest risk of recurrence, followed by women who were not taking estrogen during the index VTE, and lastly women who were taking estrogen therapy during the index VTE and subsequently discontinued it.^2,3,10

Thus, it is reasonable to give women the option to discontinue anticoagulation in the setting of a negative d-dimer follow-up.³ The 2016 CHEST guidelines recommend extended anticoagulation for a first-time, unprovoked VTE, but acknowledge this recommendation is strongest for men and that women with negative d-dimer assays may consider discontinuation.¹⁰

Our patient was directed to the emergency department for further monitoring following CT confirmation. She was discharged home after being deemed stable and prescribed apixaban 10 mg/d. A venous duplex ultrasound performed 12 days later for knee pain revealed no venous thrombosis. A CT of the abdomen performed 3 months later for other reasons revealed a normal gallbladder with no visible stones.

Apixaban was continued for 3 months and discontinued after discussion of risks and benefits of therapy cessation in the setting of a normal d-dimer and the 2016 CHEST guidelines for anticoagulation in VTE.¹⁰

Continue to: THE TAKEAWAY

THE TAKEAWAY

PE carries a significantly high mortality rate and can manifest with nonspecific and masquerading signs. A high index of suspicion is required to place PE on the differential diagnosis and carry out appropriate testing. Our patient presented with a history consistent with biliary colic but with pleuritic chest pain that warranted consideration of a PE.

CORRESPONDENCE
Alyssa Anderson, MD, 1 Continental Drive, Elizabethtown, PA 17022; [email protected]

THE CASE

A 75-year-old woman presented to the primary care clinic with right-side rib pain. The patient said the pain started 1 week earlier, after she ate fried chicken for dinner, and had since been exacerbated by rich meals, lying supine, and taking a deep inspiratory breath. She also said that prior to coming to the clinic that day, the pain had been radiating to her right shoulder.

The patient denied experiencing associated fevers, chills, shortness of breath, chest pain, nausea, vomiting, constipation, diarrhea, or changes in stool color. She had a history of hypertension, for which she was taking lisinopril 20 mg/d, and hypercholesterolemia, for which she was on simvastatin 10 mg/d. She was additionally using timolol ophthalmic solution for her glaucoma.

During the examination, the patient’s vital signs were stable, with a pulse of 80 beats/min, a respiratory rate of 16 breaths/min, and an oxygen saturation of 98% on room air. The patient had no abdominal tenderness upon palpation, and the physical exam revealed no abnormalities. An in-office electrocardiogram was performed, with normal results. Additionally, a comprehensive metabolic panel, lipase test, and d-dimer test were ordered. Lab results showed an isolated elevated d-dimer of 2.66 mcg/mL (normal range, < 0.54 mcg/mL), while all other labs were normal.

THE DIAGNOSIS

Based on the lab results, a stat computed tomography pulmonary angiogram (CTPA) was ordered and showed a right segmental and subsegmental pulmonary embolism (PE; FIGURE 1).

DISCUSSION

PE shares pathophysiologic mechanisms with deep vein thrombosis (DVT), and together these comprise venous thromboembolism (VTE). Risk factors for VTE include hypercoagulable disorders, use of estrogens, active malignancy, and immobilization.¹ Unprovoked VTE occurs in the absence of identifiable risk factors and carries a higher risk of recurrence.^2,3 While PE is classically thought to occur in the setting of a DVT, there is increasing literature describing de novo PE that can occur independent of a DVT.⁴

Common symptoms of PE include tachycardia, tachypnea, and pleuritic chest pain.⁵ Abdominal pain is a rare symptom described in some case reports.^6,7 Thus, a high clinical suspicion is needed for diagnosis of PE.

The Wells criteria is an established model for risk stratifying patients presenting with possible VTE (TABLE).⁸ For patients with low pretest probability, as in this case, a d-dimer is an effective diagnostic work-up, as a negative result will rule out PE. (If the d-dimer had been negative in this case, we would have considered other diagnoses, such as acute coronary syndrome, biliary colic, gastritis, pancreatitis, or musculoskeletal pain.) For high-risk patients, immediate anticoagulation and imaging should be performed, frequently with heparin and CTPA.⁹

Continue to: Length of treatment depends on gender and etiology

The cornerstone treatment for stable patients with VTE is therapeutic anticoagulation. The new oral anticoagulants, which directly inhibit factor Xa or thrombin, have become increasingly popular for management of VTE, in part because they don’t require INR testing and monitoring.²

The duration of anticoagulation, particularly in unprovoked PE, is debatable. As noted earlier, patients with an unprovoked PE are at higher risk of recurrence than those with a reversible cause, so the question becomes whether these patients should have indefinite anticoagulation.^2,3 Studies examining risk stratification of patients with a first, unprovoked VTE have found that men have the highest risk of recurrence, followed by women who were not taking estrogen during the index VTE, and lastly women who were taking estrogen therapy during the index VTE and subsequently discontinued it.^2,3,10

Thus, it is reasonable to give women the option to discontinue anticoagulation in the setting of a negative d-dimer follow-up.³ The 2016 CHEST guidelines recommend extended anticoagulation for a first-time, unprovoked VTE, but acknowledge this recommendation is strongest for men and that women with negative d-dimer assays may consider discontinuation.¹⁰

Our patient was directed to the emergency department for further monitoring following CT confirmation. She was discharged home after being deemed stable and prescribed apixaban 10 mg/d. A venous duplex ultrasound performed 12 days later for knee pain revealed no venous thrombosis. A CT of the abdomen performed 3 months later for other reasons revealed a normal gallbladder with no visible stones.

Apixaban was continued for 3 months and discontinued after discussion of risks and benefits of therapy cessation in the setting of a normal d-dimer and the 2016 CHEST guidelines for anticoagulation in VTE.¹⁰

Continue to: THE TAKEAWAY

THE TAKEAWAY

PE carries a significantly high mortality rate and can manifest with nonspecific and masquerading signs. A high index of suspicion is required to place PE on the differential diagnosis and carry out appropriate testing. Our patient presented with a history consistent with biliary colic but with pleuritic chest pain that warranted consideration of a PE.

CORRESPONDENCE
Alyssa Anderson, MD, 1 Continental Drive, Elizabethtown, PA 17022; [email protected]

THE CASE

A 75-year-old woman presented to the primary care clinic with right-side rib pain. The patient said the pain started 1 week earlier, after she ate fried chicken for dinner, and had since been exacerbated by rich meals, lying supine, and taking a deep inspiratory breath. She also said that prior to coming to the clinic that day, the pain had been radiating to her right shoulder.

The patient denied experiencing associated fevers, chills, shortness of breath, chest pain, nausea, vomiting, constipation, diarrhea, or changes in stool color. She had a history of hypertension, for which she was taking lisinopril 20 mg/d, and hypercholesterolemia, for which she was on simvastatin 10 mg/d. She was additionally using timolol ophthalmic solution for her glaucoma.

During the examination, the patient’s vital signs were stable, with a pulse of 80 beats/min, a respiratory rate of 16 breaths/min, and an oxygen saturation of 98% on room air. The patient had no abdominal tenderness upon palpation, and the physical exam revealed no abnormalities. An in-office electrocardiogram was performed, with normal results. Additionally, a comprehensive metabolic panel, lipase test, and d-dimer test were ordered. Lab results showed an isolated elevated d-dimer of 2.66 mcg/mL (normal range, < 0.54 mcg/mL), while all other labs were normal.

THE DIAGNOSIS

Based on the lab results, a stat computed tomography pulmonary angiogram (CTPA) was ordered and showed a right segmental and subsegmental pulmonary embolism (PE; FIGURE 1).

DISCUSSION

PE shares pathophysiologic mechanisms with deep vein thrombosis (DVT), and together these comprise venous thromboembolism (VTE). Risk factors for VTE include hypercoagulable disorders, use of estrogens, active malignancy, and immobilization.¹ Unprovoked VTE occurs in the absence of identifiable risk factors and carries a higher risk of recurrence.^2,3 While PE is classically thought to occur in the setting of a DVT, there is increasing literature describing de novo PE that can occur independent of a DVT.⁴

Common symptoms of PE include tachycardia, tachypnea, and pleuritic chest pain.⁵ Abdominal pain is a rare symptom described in some case reports.^6,7 Thus, a high clinical suspicion is needed for diagnosis of PE.

The Wells criteria is an established model for risk stratifying patients presenting with possible VTE (TABLE).⁸ For patients with low pretest probability, as in this case, a d-dimer is an effective diagnostic work-up, as a negative result will rule out PE. (If the d-dimer had been negative in this case, we would have considered other diagnoses, such as acute coronary syndrome, biliary colic, gastritis, pancreatitis, or musculoskeletal pain.) For high-risk patients, immediate anticoagulation and imaging should be performed, frequently with heparin and CTPA.⁹

Continue to: Length of treatment depends on gender and etiology

The cornerstone treatment for stable patients with VTE is therapeutic anticoagulation. The new oral anticoagulants, which directly inhibit factor Xa or thrombin, have become increasingly popular for management of VTE, in part because they don’t require INR testing and monitoring.²

The duration of anticoagulation, particularly in unprovoked PE, is debatable. As noted earlier, patients with an unprovoked PE are at higher risk of recurrence than those with a reversible cause, so the question becomes whether these patients should have indefinite anticoagulation.^2,3 Studies examining risk stratification of patients with a first, unprovoked VTE have found that men have the highest risk of recurrence, followed by women who were not taking estrogen during the index VTE, and lastly women who were taking estrogen therapy during the index VTE and subsequently discontinued it.^2,3,10

Thus, it is reasonable to give women the option to discontinue anticoagulation in the setting of a negative d-dimer follow-up.³ The 2016 CHEST guidelines recommend extended anticoagulation for a first-time, unprovoked VTE, but acknowledge this recommendation is strongest for men and that women with negative d-dimer assays may consider discontinuation.¹⁰

Our patient was directed to the emergency department for further monitoring following CT confirmation. She was discharged home after being deemed stable and prescribed apixaban 10 mg/d. A venous duplex ultrasound performed 12 days later for knee pain revealed no venous thrombosis. A CT of the abdomen performed 3 months later for other reasons revealed a normal gallbladder with no visible stones.

Apixaban was continued for 3 months and discontinued after discussion of risks and benefits of therapy cessation in the setting of a normal d-dimer and the 2016 CHEST guidelines for anticoagulation in VTE.¹⁰

Continue to: THE TAKEAWAY

THE TAKEAWAY

PE carries a significantly high mortality rate and can manifest with nonspecific and masquerading signs. A high index of suspicion is required to place PE on the differential diagnosis and carry out appropriate testing. Our patient presented with a history consistent with biliary colic but with pleuritic chest pain that warranted consideration of a PE.

CORRESPONDENCE
Alyssa Anderson, MD, 1 Continental Drive, Elizabethtown, PA 17022; [email protected]

ILLUSTRATIVE CASE

A 67-year-old man with a history of coronary artery stenting 7 years prior and nonvalvular AF that is well controlled with a beta-blocker comes in for a routine health maintenance visit. You note that the patient takes warfarin, metoprolol, and aspirin. The patient has not had any thrombotic or bleeding events in his lifetime. Does this patient need to take both warfarin and aspirin? Do the antithrombotic benefits of dual therapy outweigh the risk of bleeding?

Antiplatelet agents have long been recommended for secondary prevention of cardiovascular (CV) events in patients with IHD. The goal is to reduce the risk of coronary artery thrombosis.² Many patients with IHD also develop AF and are treated with OACs such as warfarin or direct oral anticoagulants (DOACs) to prevent thromboembolic events.

There has been a paucity of data to determine the risks and benefits of OAC monotherapy compared to OAC plus single antiplatelet therapy (SAPT). Given research that shows increased risks of bleeding and all-cause mortality when aspirin is used for primary prevention of CV disease,^3,4 it is prudent to examine if the harms of aspirin outweigh its benefits for the secondary prevention of acute coronary events in patients already taking antithrombotic agents.

STUDY SUMMARY

Reduced bleeding risk, with no difference in major adverse cardiovascular events

This study by Lee and colleagues¹ was a meta-analysis of 8855 patients with nonvalvular AF and stable coronary artery disease (CAD), from 6 trials comparing OAC monotherapy vs OAC plus SAPT. The meta-analysis involved 3 studies using patient registries, 2 cohort studies, and an open-label randomized trial that together spanned the period from 2002 to 2016. The longest study period was 9 years (1 study) and the shortest, 1 year (2 studies). Oral anticoagulation consisted of either vitamin K antagonist (VKA) therapy (the majority of the patients studied) or DOAC therapy (8.6% of the patients studied). SAPT was either aspirin or clopidogrel.

The primary outcome measure was major adverse CV events (MACE). Secondary outcome measures included major bleeding, stroke, all-cause mortality, and net adverse events. The definitions used by the studies for major bleeding were deemed “largely consistent” with the International Society on Thrombosis and Haemostasis major bleeding criteria, ie, fatal bleeding, symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular causing compartment syndrome), or a drop in hemoglobin (≥ 2 g/dL or requiring transfusion of ≥ 2 units of whole blood or red cells).⁵

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom single antiplatelet therapy should not be prescribed as a preventive medication.

There was no difference in MACE between the monotherapy and OAC plus SAPT groups (hazard ratio [HR] = 1.09; 95% CI, 0.92-1.29). Similarly, there were no differences in stroke and all-cause mortality between the groups. However, there was a significant association of higher risk of major bleeding (HR = 1.61; 95% CI, 1.38-1.87) and net adverse events (HR = 1.21; 95% CI, 1.02-1.43) in the OAC plus SAPT group compared with the OAC monotherapy group.

This study’s limitations included its low percentage of patients taking a DOAC. Also, due to variations in methods of reporting CHA₂DS₂-VASc and HAS-BLED scores among the studies (for risk of stroke in patients with nonrheumatic AF and for risk of bleeding in AF patients taking anticoagulants), this meta-analysis could not determine if different outcomes might be found in patients with different CHA₂DS₂-VASc and HAS-BLED scores.

Continue to: WHAT'S NEW

OAC monotherapy benefit for patients with nonvalvular AF

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom SAPT should not be prescribed as a preventive medication: patients with nonvalvular AF who are receiving OAC therapy. This study concurs with the results of the 2019 AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) trial in Japan, in which 2236 patients with stable IHD (coronary artery bypass grafting, stenting, or cardiac catheterization > 1 year earlier) were randomized to receive rivaroxaban either alone or with an antiplatelet agent. All-cause mortality and major bleeding were lower in the monotherapy group.⁶

This meta-analysis calls into question the baseline recommendation from the 2012 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline to prescribe aspirin indefinitely for patients with stable CAD unless there is a contraindication (oral anticoagulation is not listed as a contraindication).² The 2020 ACC Expert Consensus Decision Pathway⁷ published in February 2021 stated that for patients requiring long-term anticoagulation therapy who have completed 12 months of SAPT after percutaneous coronary intervention, anticoagulation therapy alone “could be used long-term”; however, the 2019 study by Lee was not listed among their references. Inclusion of the Lee study might have contributed to a stronger recommendation.

Also, the new guidelines include clinical situations in which dual therapy could still be continued: “… if perceived thrombotic risk is high (eg, prior myocardial infarction, complex lesions, presence of select traditional cardiovascular risk factors, or extensive [atherosclerotic cardiovascular disease]), and the patient is at low bleeding risk.” The guidelines state that in this situation, “… it is reasonable to continue SAPT beyond 12 months (in line with prior ACC/AHA recommendations).”⁷ However, the cited study compared dual therapy (dabigatran plus APT) to warfarin triple therapy. Single OAC therapy was not studied.⁸

CAVEATS

DOAC patient populationwas not well represented

The study had a low percentage of patients taking a DOAC. Also, because there were variations in how the studies reported CHA₂DS₂-VASc and HAS-BLED scores, this meta-analysis was unable to determine if different scores might have produced different outcomes. However, the studies involving registries had the advantage of looking at the data for this population over long periods of time and included a wide variety of patients, making the recommendation likely valid.

CHALLENGES TO IMPLEMENTATION

Primary care approach may not sync with specialist practice

We see no challenges to implementation except for potential differences between primary care physicians and specialists regarding the use of antiplatelet agents in this patient population.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 67-year-old man with a history of coronary artery stenting 7 years prior and nonvalvular AF that is well controlled with a beta-blocker comes in for a routine health maintenance visit. You note that the patient takes warfarin, metoprolol, and aspirin. The patient has not had any thrombotic or bleeding events in his lifetime. Does this patient need to take both warfarin and aspirin? Do the antithrombotic benefits of dual therapy outweigh the risk of bleeding?

Antiplatelet agents have long been recommended for secondary prevention of cardiovascular (CV) events in patients with IHD. The goal is to reduce the risk of coronary artery thrombosis.² Many patients with IHD also develop AF and are treated with OACs such as warfarin or direct oral anticoagulants (DOACs) to prevent thromboembolic events.

There has been a paucity of data to determine the risks and benefits of OAC monotherapy compared to OAC plus single antiplatelet therapy (SAPT). Given research that shows increased risks of bleeding and all-cause mortality when aspirin is used for primary prevention of CV disease,^3,4 it is prudent to examine if the harms of aspirin outweigh its benefits for the secondary prevention of acute coronary events in patients already taking antithrombotic agents.

STUDY SUMMARY

Reduced bleeding risk, with no difference in major adverse cardiovascular events

This study by Lee and colleagues¹ was a meta-analysis of 8855 patients with nonvalvular AF and stable coronary artery disease (CAD), from 6 trials comparing OAC monotherapy vs OAC plus SAPT. The meta-analysis involved 3 studies using patient registries, 2 cohort studies, and an open-label randomized trial that together spanned the period from 2002 to 2016. The longest study period was 9 years (1 study) and the shortest, 1 year (2 studies). Oral anticoagulation consisted of either vitamin K antagonist (VKA) therapy (the majority of the patients studied) or DOAC therapy (8.6% of the patients studied). SAPT was either aspirin or clopidogrel.

The primary outcome measure was major adverse CV events (MACE). Secondary outcome measures included major bleeding, stroke, all-cause mortality, and net adverse events. The definitions used by the studies for major bleeding were deemed “largely consistent” with the International Society on Thrombosis and Haemostasis major bleeding criteria, ie, fatal bleeding, symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular causing compartment syndrome), or a drop in hemoglobin (≥ 2 g/dL or requiring transfusion of ≥ 2 units of whole blood or red cells).⁵

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom single antiplatelet therapy should not be prescribed as a preventive medication.

There was no difference in MACE between the monotherapy and OAC plus SAPT groups (hazard ratio [HR] = 1.09; 95% CI, 0.92-1.29). Similarly, there were no differences in stroke and all-cause mortality between the groups. However, there was a significant association of higher risk of major bleeding (HR = 1.61; 95% CI, 1.38-1.87) and net adverse events (HR = 1.21; 95% CI, 1.02-1.43) in the OAC plus SAPT group compared with the OAC monotherapy group.

This study’s limitations included its low percentage of patients taking a DOAC. Also, due to variations in methods of reporting CHA₂DS₂-VASc and HAS-BLED scores among the studies (for risk of stroke in patients with nonrheumatic AF and for risk of bleeding in AF patients taking anticoagulants), this meta-analysis could not determine if different outcomes might be found in patients with different CHA₂DS₂-VASc and HAS-BLED scores.

Continue to: WHAT'S NEW

OAC monotherapy benefit for patients with nonvalvular AF

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom SAPT should not be prescribed as a preventive medication: patients with nonvalvular AF who are receiving OAC therapy. This study concurs with the results of the 2019 AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) trial in Japan, in which 2236 patients with stable IHD (coronary artery bypass grafting, stenting, or cardiac catheterization > 1 year earlier) were randomized to receive rivaroxaban either alone or with an antiplatelet agent. All-cause mortality and major bleeding were lower in the monotherapy group.⁶

This meta-analysis calls into question the baseline recommendation from the 2012 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline to prescribe aspirin indefinitely for patients with stable CAD unless there is a contraindication (oral anticoagulation is not listed as a contraindication).² The 2020 ACC Expert Consensus Decision Pathway⁷ published in February 2021 stated that for patients requiring long-term anticoagulation therapy who have completed 12 months of SAPT after percutaneous coronary intervention, anticoagulation therapy alone “could be used long-term”; however, the 2019 study by Lee was not listed among their references. Inclusion of the Lee study might have contributed to a stronger recommendation.

Also, the new guidelines include clinical situations in which dual therapy could still be continued: “… if perceived thrombotic risk is high (eg, prior myocardial infarction, complex lesions, presence of select traditional cardiovascular risk factors, or extensive [atherosclerotic cardiovascular disease]), and the patient is at low bleeding risk.” The guidelines state that in this situation, “… it is reasonable to continue SAPT beyond 12 months (in line with prior ACC/AHA recommendations).”⁷ However, the cited study compared dual therapy (dabigatran plus APT) to warfarin triple therapy. Single OAC therapy was not studied.⁸

CAVEATS

DOAC patient populationwas not well represented

The study had a low percentage of patients taking a DOAC. Also, because there were variations in how the studies reported CHA₂DS₂-VASc and HAS-BLED scores, this meta-analysis was unable to determine if different scores might have produced different outcomes. However, the studies involving registries had the advantage of looking at the data for this population over long periods of time and included a wide variety of patients, making the recommendation likely valid.

CHALLENGES TO IMPLEMENTATION

Primary care approach may not sync with specialist practice

We see no challenges to implementation except for potential differences between primary care physicians and specialists regarding the use of antiplatelet agents in this patient population.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 67-year-old man with a history of coronary artery stenting 7 years prior and nonvalvular AF that is well controlled with a beta-blocker comes in for a routine health maintenance visit. You note that the patient takes warfarin, metoprolol, and aspirin. The patient has not had any thrombotic or bleeding events in his lifetime. Does this patient need to take both warfarin and aspirin? Do the antithrombotic benefits of dual therapy outweigh the risk of bleeding?

Antiplatelet agents have long been recommended for secondary prevention of cardiovascular (CV) events in patients with IHD. The goal is to reduce the risk of coronary artery thrombosis.² Many patients with IHD also develop AF and are treated with OACs such as warfarin or direct oral anticoagulants (DOACs) to prevent thromboembolic events.

There has been a paucity of data to determine the risks and benefits of OAC monotherapy compared to OAC plus single antiplatelet therapy (SAPT). Given research that shows increased risks of bleeding and all-cause mortality when aspirin is used for primary prevention of CV disease,^3,4 it is prudent to examine if the harms of aspirin outweigh its benefits for the secondary prevention of acute coronary events in patients already taking antithrombotic agents.

STUDY SUMMARY

Reduced bleeding risk, with no difference in major adverse cardiovascular events

This study by Lee and colleagues¹ was a meta-analysis of 8855 patients with nonvalvular AF and stable coronary artery disease (CAD), from 6 trials comparing OAC monotherapy vs OAC plus SAPT. The meta-analysis involved 3 studies using patient registries, 2 cohort studies, and an open-label randomized trial that together spanned the period from 2002 to 2016. The longest study period was 9 years (1 study) and the shortest, 1 year (2 studies). Oral anticoagulation consisted of either vitamin K antagonist (VKA) therapy (the majority of the patients studied) or DOAC therapy (8.6% of the patients studied). SAPT was either aspirin or clopidogrel.

The primary outcome measure was major adverse CV events (MACE). Secondary outcome measures included major bleeding, stroke, all-cause mortality, and net adverse events. The definitions used by the studies for major bleeding were deemed “largely consistent” with the International Society on Thrombosis and Haemostasis major bleeding criteria, ie, fatal bleeding, symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular causing compartment syndrome), or a drop in hemoglobin (≥ 2 g/dL or requiring transfusion of ≥ 2 units of whole blood or red cells).⁵

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom single antiplatelet therapy should not be prescribed as a preventive medication.

There was no difference in MACE between the monotherapy and OAC plus SAPT groups (hazard ratio [HR] = 1.09; 95% CI, 0.92-1.29). Similarly, there were no differences in stroke and all-cause mortality between the groups. However, there was a significant association of higher risk of major bleeding (HR = 1.61; 95% CI, 1.38-1.87) and net adverse events (HR = 1.21; 95% CI, 1.02-1.43) in the OAC plus SAPT group compared with the OAC monotherapy group.

This study’s limitations included its low percentage of patients taking a DOAC. Also, due to variations in methods of reporting CHA₂DS₂-VASc and HAS-BLED scores among the studies (for risk of stroke in patients with nonrheumatic AF and for risk of bleeding in AF patients taking anticoagulants), this meta-analysis could not determine if different outcomes might be found in patients with different CHA₂DS₂-VASc and HAS-BLED scores.

Continue to: WHAT'S NEW

OAC monotherapy benefit for patients with nonvalvular AF

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom SAPT should not be prescribed as a preventive medication: patients with nonvalvular AF who are receiving OAC therapy. This study concurs with the results of the 2019 AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) trial in Japan, in which 2236 patients with stable IHD (coronary artery bypass grafting, stenting, or cardiac catheterization > 1 year earlier) were randomized to receive rivaroxaban either alone or with an antiplatelet agent. All-cause mortality and major bleeding were lower in the monotherapy group.⁶

This meta-analysis calls into question the baseline recommendation from the 2012 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline to prescribe aspirin indefinitely for patients with stable CAD unless there is a contraindication (oral anticoagulation is not listed as a contraindication).² The 2020 ACC Expert Consensus Decision Pathway⁷ published in February 2021 stated that for patients requiring long-term anticoagulation therapy who have completed 12 months of SAPT after percutaneous coronary intervention, anticoagulation therapy alone “could be used long-term”; however, the 2019 study by Lee was not listed among their references. Inclusion of the Lee study might have contributed to a stronger recommendation.

Also, the new guidelines include clinical situations in which dual therapy could still be continued: “… if perceived thrombotic risk is high (eg, prior myocardial infarction, complex lesions, presence of select traditional cardiovascular risk factors, or extensive [atherosclerotic cardiovascular disease]), and the patient is at low bleeding risk.” The guidelines state that in this situation, “… it is reasonable to continue SAPT beyond 12 months (in line with prior ACC/AHA recommendations).”⁷ However, the cited study compared dual therapy (dabigatran plus APT) to warfarin triple therapy. Single OAC therapy was not studied.⁸

CAVEATS

DOAC patient populationwas not well represented

The study had a low percentage of patients taking a DOAC. Also, because there were variations in how the studies reported CHA₂DS₂-VASc and HAS-BLED scores, this meta-analysis was unable to determine if different scores might have produced different outcomes. However, the studies involving registries had the advantage of looking at the data for this population over long periods of time and included a wide variety of patients, making the recommendation likely valid.

CHALLENGES TO IMPLEMENTATION

Primary care approach may not sync with specialist practice

We see no challenges to implementation except for potential differences between primary care physicians and specialists regarding the use of antiplatelet agents in this patient population.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Since their discovery in the early 1900s as the treatment for life-threatening deficiency syndromes, vitamins have been touted as panaceas for numerous ailments. While observational data have suggested potential correlations between vitamin status and every imaginable disease, randomized controlled trials (RCTs) have generally failed to find benefits from supplementation. Despite this lack of proven efficacy, more than half of older adults reported taking vitamins regularly.¹

While most clinicians consider vitamins to be, at worst, expensive placebos, the potential for harm and dangerous interactions exists. Unlike pharmaceuticals, vitamins are generally unregulated, and the true content of many dietary supplements is often difficult to elucidate. Understanding the physiologic role, foundational evidence, and specific indications for the various vitamins is key to providing the best recommendations to patients.

Vitamins are essential organic nutrients, required in small quantities for normal metabolism. Since they are not synthesized endogenously, they must be ingested via food intake. In the developed world, vitamin deficiency syndromes are rare, thanks to sufficiently balanced diets and availability of fortified foods. The focus of this article will be on vitamin supplementation in healthy patients with well-balanced diets. TABLE W1² (available at mdedge.com/familymedicine) lists the 13 recognized vitamins, their recommended dietary allowances, and any known toxicity risks. TABLE 2² outlines elements of the history to consider when evaluating for deficiency. A summary of the most clinically significant evidence for vitamin supplementation follows; a more comprehensive review can be found in TABLE 3.^3-96

B COMPLEX VITAMINS

Vitamin B1

Vitamers: Thiamine (thiamin)

Physiologic role: Critical in carbohydrate and amino-acid catabolism and energy metabolism

Dietary sources: Whole grains, meat, fish, fortified cereals, and breads

Thiamine serves as an essential cofactor in energy metabolism.² Thiamine deficiency is responsible for beriberi syndrome (rare in the developed world) and Wernicke-Korsakoff syndrome, the latter of which is a relatively common complication of chronic alcohol dependence. Although thiamine’s administration in these conditions can be curative, evidence is lacking to support its use preventively in patients with alcoholism.³ Thiamine has additionally been theorized to play a role in cardiac and cognitive function, but RCT data has not shown consistent patient-oriented benefits.^4,5

The takeaway: Given the lack of evidence, supplementation in the general population is not recommended.

Vitamin B2

Vitamers: Riboflavin

Physiologic role: Essential component of cellular function and growth, energy production, and metabolism of fats and drugs

Dietary sources: Eggs, organ meats, lean meats, milk, green vegetables, fortified cereals and grains

Riboflavin is essential to energy production, cellular growth, and metabolism.²

The takeaway: Its use as migraine prophylaxis has limited data,⁹⁷ but there is otherwise no evidence to support health benefits of riboflavin supplementation.

Vitamin B3

Vitamers: Nicotinic acid (niacin); nicotinamide (niacinamide); nicotinamide riboside

Physiologic role: Converted to nicotinamide adenine dinucleotide (NAD), which is widely required in most cellular metabolic redox processes. Crucial to the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Dietary sources: Poultry, beef, fish, nuts, legumes, grains. (Tryptophan can also be converted to NAD.)

Niacin is readily converted to NAD, an essential coenzyme for multiple catalytic processes in the body. While niacin at doses more than 100 times the recommended dietary allowance (RDA; 1-3 g/d) has been extensively studied for its role in dyslipidemias,² pharmacologic dosing is beyond the scope of this article.

The takeaway: There is no evidence supporting a clinical benefit from niacin supplementation.

Vitamin B5

Vitamers: Pantothenic acid; pantethine

Physiologic role: Required for synthesis of coenzyme A (CoA) and acyl carrier protein, both essential in fatty acid and other anabolic/catabolic processes

Dietary sources: Almost all plant/animal-based foods. Richest sources include beef, chicken, organ meats, whole grains, and some vegetables

Pantothenic acid is essential to multiple metabolic processes and readily available in sufficient amounts in most foods.² Although limited RCT data suggest pantethine may improve lipid measures,^12,98,99 pantothenic acid itself does not seem to share this effect.

The takeaway: There is no data that supplementation of any form of vitamin B5 has any patient-oriented clinical benefits.

Continue to: Vitamin B6

Vitamers: Pyridoxine; pyridoxamine; pyridoxal

Physiologic role: Widely involved coenzyme for cognitive development, neurotransmitter biosynthesis, homocysteine and glucose metabolism, immune function, and hemoglobin formation

Dietary sources: Fish, organ meats, potatoes/starchy vegetables, fruit (other than citrus), and fortified cereals

Pyridoxine is required for numerous enzymatic processes in the body, including biosynthesis of neurotransmitters and homeostasis of the amino acid homocysteine.² While overt deficiency is rare, marginal insufficiency may become clinically apparent and has been associated with malabsorption, malignancies, pregnancy, heart disease, alcoholism, and use of drugs such as isoniazid, hydralazine, and levodopa/carbidopa.² Vitamin B6 supplementation is known to decrease plasma homocysteine levels, a theorized intermediary for cardiovascular disease; however, studies have failed to consistently demonstrate patient-­oriented benefits.^100-102 While observational data has suggested a correlation between vitamin B6 status and cancer risk, RCTs have not supported benefit from supplementation.^14-16 Potential effects of vitamin B6 supplementation on cognitive function have also been studied without observed benefit.^17,18

The takeaway: Vitamin B6 is recommended as a potential treatment option for nausea in pregnancy.¹⁹ Otherwise, vitamin B6 is readily available in food, deficiency is rare, and no patient-oriented evidence supports supplementation in the general population.

Vitamin B7

Vitamers: Biotin

Physiologic role: Cofactor in the metabolism of fatty acids, glucose, and amino acids. Also plays key role in histone modifications, gene regulation, and cell signaling

Dietary sources: Widely available; most prevalent in organ meats, fish, meat, seeds, nuts, and vegetables (eg, sweet potatoes). Whole cooked eggs are a major source, but raw eggs contain avidin, which blocks absorption

Biotin serves a key role in metabolism, gene regulation, and cell signaling.² Biotin is known to interfere with laboratory assays— including cardiac enzymes, thyroid studies, and hormone studies—at normal supplementation doses, resulting in both false-positive and false-negative results.¹⁰³

The takeaway: No evidence supports the health benefits of biotin supplementation.

Vitamin B9

Vitamers: Folates; folic acid

Physiologic role: Functions as a coenzyme in the synthesis of DNA/RNA and metabolism of amino acids

Dietary sources: Highest content in spinach, liver, asparagus, and brussels sprouts. Generally found in green leafy vegetables, fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, grains, and fortified cereals.

Continue to: Vitamin B12

Vitamers: Cyanocobalamin; hydroxocobalamin; methylcobalamin; adenosylcobalamin

Physiologic role: Required for red blood cell formation, neurologic function, and DNA synthesis

Dietary sources: Only in animal products: fish, poultry, meat, eggs, and milk/dairy products. Not present in plant foods. Fortified cereals, nutritional yeast are sources for vegans/vegetarians.

Given their linked physiologic roles, vitamins B9 and B12 are frequently studied together. Folate and cobalamins play key roles in nucleic acid synthesis and amino acid metabolism, with their most clinically significant role in hematopoiesis. Vitamin B12 is also essential to normal neurologic function.²

The US Preventive Services Task Force (USPSTF) recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects (grade A).²¹ This is supported by high-quality RCT evidence demonstrating a protective effect of daily folate supplementation in preventing neural tube defects.²² Folate supplementation’s effect on other fetal birth defects has been investigated, but no benefit has been demonstrated. While observational studies have suggested an inverse relationship with folate status and fetal autism spectrum disorder,^23-25 the RCT data is mixed.²⁶

A potential role for folate in cancer prevention has been extensively investigated. An expert panel of the National Toxicology Program (NTP) concluded that folate supplementation does not reduce cancer risk in people with adequate baseline folate status based on high-quality meta-analysis data.^27,104 Conversely, long-term follow-up from RCTs demonstrated an increased risk of colorectal adenomas and cancers,^28,29 leading the NTP panel to conclude there is sufficient concern for adverse effects of folate on cancer growth to justify further research.¹⁰⁴

While observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation.

Given folate and vitamin B12’s ­homocysteine-reducing effects, it has been theorized that supplementation may protect from cardiovascular disease. However, despite extensive research, there remains no consistent patient-oriented outcomes data to support such a benefit.^31,32,105

The evidence is mixed but generally has found no benefit of folate or vitamin B12 supplementation on cognitive function.^18,33-35 Finally, RCT data has failed to demonstrate a reduction in fracture risk with supplementation.^36,106

The takeaway: High-quality RCT evidence demonstrates a protective effect of preconceptual daily folate supplementation in preventing neural tube defects.²² The USPSTF recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects.

Continue to: ANTIOXIDANTS

In addition to their individual roles, vitamins A, E, and C are antioxidants, functioning to protect cells from oxidative damage by free radical species.² Due to this shared role, these vitamins are commonly studied together. Antioxidants are hypothesized to protect from various diseases, including cancer, cardiovascular disease, dementia, autoimmune disorders, depression, cataracts, and age-related vision decline.^2,37,107-112

Though observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation and, in some cases, have found an increased risk of mortality. While several studies have found potential benefit of antioxidant use in reducing colon and breast cancer risk,^38,113-115 vitamins A and E have been associated with increased risk of lung and prostate cancer, respectively.^47,110 Cardiovascular disease and antioxidant vitamin supplementation has similar inconsistent data, ranging from slight benefit to harm.^2,116 After a large Cochrane review in 2012 found a significant increase in all-cause mortality associated with vitamin E and ­beta-carotene,¹¹⁷ the USPSTF made a specific recommendation against supplementation of these vitamins for the prevention of cardiovascular disease or cancer (grade D).¹¹⁸ Given its limited risk for harm, vitamin C was excluded from this recommendation.

Vitamin A

Vitamers: Retinol; retinal; retinyl esters; provitamin A carotenoids (beta-carotene, alpha-carotene, beta-cryptoxanthin)

Physiologic role: Essential for vision and corneal development. Also involved in general cell differentiation and immune function

Dietary sources: Liver, fish oil, dairy, and fortified cereals. Provitamin A sources: leafy green vegetables, orange/yellow vegetables, tomato products, fruits, and vegetable oils

Retinoids and their precursors, carotenoids, serve a critical function in vision, as well as regulating cell differentiation and proliferation throughout the body.² While evidence suggests mortality benefit of supplementation in populations at risk of deficiency,⁴⁵ wide-ranging studies have found either inconsistent benefit or outright harms in the developed world.

The takeaway: Given the USPSTF grade “D” recommendation and concern for potential harms, supplementation is not recommended in healthy patients without risk factors for deficiency.²

Vitamin E

Vitamers: Tocopherols (alpha-, beta-, ­gamma-, delta-); tocotrienol (alpha-, beta-, gamma-, delta-)

Physiologic role: Antioxidant; protects polyunsaturated fats from free radical oxidative damage. Involved in immune function, cell signaling, and regulation of gene expression

Dietary sources: Nuts, seeds, vegetable oil, green leafy vegetables, and fortified cereals

Vitamin E is the collective name of 8 compounds; alpha-tocopherol is the physiologically active form. Vitamin E is involved with cell proliferation as well as endothelial and platelet function.²

The takeaway: Vitamin E supplementation’s effects on cancer, cardiovascular disease, ophthalmologic disorders, and cognition have been investigated; data is either lacking to support a benefit or demonstrates harms as outlined above. Given this and the USPSTF grade “D” recommendation, supplementation is not recommended in healthy patients.²

Vitamin C

Vitamers: Ascorbic acid

Physiologic role: Required for synthesis of collagen, L-carnitine, and some neurotransmitters. Also involved in protein metabolism

Dietary sources: Primarily in fruits and vegetables: citrus, tomato, potatoes, red/green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, cantaloupe, and fortified cereals

Vitamin C supplementation at the onset of illness does not seem to have benefit.

Ascorbic acid is a required cofactor for biosynthesis of collagen, neurotransmitters, and protein metabolism.² In addition to the shared hypothesized benefits of antioxidants, vitamin C supplementation has undergone extensive research into its potential role in augmenting the immune system and preventing the common cold. Systematic reviews have found daily vitamin C supplementation of at least 200 mg did not affect the incidence of the common cold in healthy adults but may shorten duration and could be of benefit in those exposed to extreme physical exercise or cold.⁴⁸ Vitamin C supplementation at the onset of illness does not seem to have benefit.⁴⁸ Data is insufficient to draw conclusions about a potential effect on pneumonia incidence or severity.^119,120

The takeaway: Overall, data remain inconclusive as to potential benefits of vitamin C supplementation, although risks of potential harms are likely low.

Continue to: Vitamin D

Vitamers: Cholecalciferol (D3); ergocalciferol (D2)

Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function

Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure

Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.²

The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.

Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.^49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,^54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.⁵⁷

The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.⁵⁵

Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.^41,58-62

Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer^41,63-66,121 or cardiovascular disease risk.^41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.^{43,72-75,85-90,122}

The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.¹²³ RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.¹²⁴ The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.¹²³ Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.^52,53

Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,^51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).^125,126

Vitamin K

Vitamers: Phylloquinone (K1); menaquinones (K2)

Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism

Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods

Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.²

Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.

Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)⁹¹ and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.¹²⁷ Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.^128,129

Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,^92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.² The FDA considers the evidence insufficient at this time to support such a claim.² Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies⁹⁴ and supplementation was associated with improved disease measures,¹³⁰ but no patient-oriented outcomes have been demonstrated.¹³¹

The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-­oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.

Continue to: MULTIVITAMINS

Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.¹³² Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.¹³³

Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.

A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.⁴¹ Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.^134,135 This benefit appears to disappear at 5 years of follow-up.¹³⁶ RCT data have shown no benefit of multivitamin use on cognitive function,⁹⁵ and high-quality data suggest there is no effect on all-cause mortality.¹³⁷ Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.⁴¹

The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.^138-140 AAP does not recommend multivitamins for children with a well-balanced diet.¹⁴¹ Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.¹⁴²

The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.¹⁴³ Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.¹⁴⁴ Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.²

SUMMARY

Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.

CORRESPONDENCE
Joel Herness, MD, 4700 North Las Vegas Boulevard, Nellis AFB, NV 89191; [email protected]

Since their discovery in the early 1900s as the treatment for life-threatening deficiency syndromes, vitamins have been touted as panaceas for numerous ailments. While observational data have suggested potential correlations between vitamin status and every imaginable disease, randomized controlled trials (RCTs) have generally failed to find benefits from supplementation. Despite this lack of proven efficacy, more than half of older adults reported taking vitamins regularly.¹

While most clinicians consider vitamins to be, at worst, expensive placebos, the potential for harm and dangerous interactions exists. Unlike pharmaceuticals, vitamins are generally unregulated, and the true content of many dietary supplements is often difficult to elucidate. Understanding the physiologic role, foundational evidence, and specific indications for the various vitamins is key to providing the best recommendations to patients.

Vitamins are essential organic nutrients, required in small quantities for normal metabolism. Since they are not synthesized endogenously, they must be ingested via food intake. In the developed world, vitamin deficiency syndromes are rare, thanks to sufficiently balanced diets and availability of fortified foods. The focus of this article will be on vitamin supplementation in healthy patients with well-balanced diets. TABLE W1² (available at mdedge.com/familymedicine) lists the 13 recognized vitamins, their recommended dietary allowances, and any known toxicity risks. TABLE 2² outlines elements of the history to consider when evaluating for deficiency. A summary of the most clinically significant evidence for vitamin supplementation follows; a more comprehensive review can be found in TABLE 3.^3-96

B COMPLEX VITAMINS

Vitamin B1

Vitamers: Thiamine (thiamin)

Physiologic role: Critical in carbohydrate and amino-acid catabolism and energy metabolism

Dietary sources: Whole grains, meat, fish, fortified cereals, and breads

Thiamine serves as an essential cofactor in energy metabolism.² Thiamine deficiency is responsible for beriberi syndrome (rare in the developed world) and Wernicke-Korsakoff syndrome, the latter of which is a relatively common complication of chronic alcohol dependence. Although thiamine’s administration in these conditions can be curative, evidence is lacking to support its use preventively in patients with alcoholism.³ Thiamine has additionally been theorized to play a role in cardiac and cognitive function, but RCT data has not shown consistent patient-oriented benefits.^4,5

The takeaway: Given the lack of evidence, supplementation in the general population is not recommended.

Vitamin B2

Vitamers: Riboflavin

Physiologic role: Essential component of cellular function and growth, energy production, and metabolism of fats and drugs

Dietary sources: Eggs, organ meats, lean meats, milk, green vegetables, fortified cereals and grains

Riboflavin is essential to energy production, cellular growth, and metabolism.²

The takeaway: Its use as migraine prophylaxis has limited data,⁹⁷ but there is otherwise no evidence to support health benefits of riboflavin supplementation.

Vitamin B3

Vitamers: Nicotinic acid (niacin); nicotinamide (niacinamide); nicotinamide riboside

Physiologic role: Converted to nicotinamide adenine dinucleotide (NAD), which is widely required in most cellular metabolic redox processes. Crucial to the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Dietary sources: Poultry, beef, fish, nuts, legumes, grains. (Tryptophan can also be converted to NAD.)

Niacin is readily converted to NAD, an essential coenzyme for multiple catalytic processes in the body. While niacin at doses more than 100 times the recommended dietary allowance (RDA; 1-3 g/d) has been extensively studied for its role in dyslipidemias,² pharmacologic dosing is beyond the scope of this article.

The takeaway: There is no evidence supporting a clinical benefit from niacin supplementation.

Vitamin B5

Vitamers: Pantothenic acid; pantethine

Physiologic role: Required for synthesis of coenzyme A (CoA) and acyl carrier protein, both essential in fatty acid and other anabolic/catabolic processes

Dietary sources: Almost all plant/animal-based foods. Richest sources include beef, chicken, organ meats, whole grains, and some vegetables

Pantothenic acid is essential to multiple metabolic processes and readily available in sufficient amounts in most foods.² Although limited RCT data suggest pantethine may improve lipid measures,^12,98,99 pantothenic acid itself does not seem to share this effect.

The takeaway: There is no data that supplementation of any form of vitamin B5 has any patient-oriented clinical benefits.

Continue to: Vitamin B6

Vitamers: Pyridoxine; pyridoxamine; pyridoxal

Physiologic role: Widely involved coenzyme for cognitive development, neurotransmitter biosynthesis, homocysteine and glucose metabolism, immune function, and hemoglobin formation

Dietary sources: Fish, organ meats, potatoes/starchy vegetables, fruit (other than citrus), and fortified cereals

Pyridoxine is required for numerous enzymatic processes in the body, including biosynthesis of neurotransmitters and homeostasis of the amino acid homocysteine.² While overt deficiency is rare, marginal insufficiency may become clinically apparent and has been associated with malabsorption, malignancies, pregnancy, heart disease, alcoholism, and use of drugs such as isoniazid, hydralazine, and levodopa/carbidopa.² Vitamin B6 supplementation is known to decrease plasma homocysteine levels, a theorized intermediary for cardiovascular disease; however, studies have failed to consistently demonstrate patient-­oriented benefits.^100-102 While observational data has suggested a correlation between vitamin B6 status and cancer risk, RCTs have not supported benefit from supplementation.^14-16 Potential effects of vitamin B6 supplementation on cognitive function have also been studied without observed benefit.^17,18

The takeaway: Vitamin B6 is recommended as a potential treatment option for nausea in pregnancy.¹⁹ Otherwise, vitamin B6 is readily available in food, deficiency is rare, and no patient-oriented evidence supports supplementation in the general population.

Vitamin B7

Vitamers: Biotin

Physiologic role: Cofactor in the metabolism of fatty acids, glucose, and amino acids. Also plays key role in histone modifications, gene regulation, and cell signaling

Dietary sources: Widely available; most prevalent in organ meats, fish, meat, seeds, nuts, and vegetables (eg, sweet potatoes). Whole cooked eggs are a major source, but raw eggs contain avidin, which blocks absorption

Biotin serves a key role in metabolism, gene regulation, and cell signaling.² Biotin is known to interfere with laboratory assays— including cardiac enzymes, thyroid studies, and hormone studies—at normal supplementation doses, resulting in both false-positive and false-negative results.¹⁰³

The takeaway: No evidence supports the health benefits of biotin supplementation.

Vitamin B9

Vitamers: Folates; folic acid

Physiologic role: Functions as a coenzyme in the synthesis of DNA/RNA and metabolism of amino acids

Dietary sources: Highest content in spinach, liver, asparagus, and brussels sprouts. Generally found in green leafy vegetables, fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, grains, and fortified cereals.

Continue to: Vitamin B12

Vitamers: Cyanocobalamin; hydroxocobalamin; methylcobalamin; adenosylcobalamin

Physiologic role: Required for red blood cell formation, neurologic function, and DNA synthesis

Dietary sources: Only in animal products: fish, poultry, meat, eggs, and milk/dairy products. Not present in plant foods. Fortified cereals, nutritional yeast are sources for vegans/vegetarians.

Given their linked physiologic roles, vitamins B9 and B12 are frequently studied together. Folate and cobalamins play key roles in nucleic acid synthesis and amino acid metabolism, with their most clinically significant role in hematopoiesis. Vitamin B12 is also essential to normal neurologic function.²

The US Preventive Services Task Force (USPSTF) recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects (grade A).²¹ This is supported by high-quality RCT evidence demonstrating a protective effect of daily folate supplementation in preventing neural tube defects.²² Folate supplementation’s effect on other fetal birth defects has been investigated, but no benefit has been demonstrated. While observational studies have suggested an inverse relationship with folate status and fetal autism spectrum disorder,^23-25 the RCT data is mixed.²⁶

A potential role for folate in cancer prevention has been extensively investigated. An expert panel of the National Toxicology Program (NTP) concluded that folate supplementation does not reduce cancer risk in people with adequate baseline folate status based on high-quality meta-analysis data.^27,104 Conversely, long-term follow-up from RCTs demonstrated an increased risk of colorectal adenomas and cancers,^28,29 leading the NTP panel to conclude there is sufficient concern for adverse effects of folate on cancer growth to justify further research.¹⁰⁴

While observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation.

Given folate and vitamin B12’s ­homocysteine-reducing effects, it has been theorized that supplementation may protect from cardiovascular disease. However, despite extensive research, there remains no consistent patient-oriented outcomes data to support such a benefit.^31,32,105

The evidence is mixed but generally has found no benefit of folate or vitamin B12 supplementation on cognitive function.^18,33-35 Finally, RCT data has failed to demonstrate a reduction in fracture risk with supplementation.^36,106

The takeaway: High-quality RCT evidence demonstrates a protective effect of preconceptual daily folate supplementation in preventing neural tube defects.²² The USPSTF recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects.

Continue to: ANTIOXIDANTS

In addition to their individual roles, vitamins A, E, and C are antioxidants, functioning to protect cells from oxidative damage by free radical species.² Due to this shared role, these vitamins are commonly studied together. Antioxidants are hypothesized to protect from various diseases, including cancer, cardiovascular disease, dementia, autoimmune disorders, depression, cataracts, and age-related vision decline.^2,37,107-112

Though observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation and, in some cases, have found an increased risk of mortality. While several studies have found potential benefit of antioxidant use in reducing colon and breast cancer risk,^38,113-115 vitamins A and E have been associated with increased risk of lung and prostate cancer, respectively.^47,110 Cardiovascular disease and antioxidant vitamin supplementation has similar inconsistent data, ranging from slight benefit to harm.^2,116 After a large Cochrane review in 2012 found a significant increase in all-cause mortality associated with vitamin E and ­beta-carotene,¹¹⁷ the USPSTF made a specific recommendation against supplementation of these vitamins for the prevention of cardiovascular disease or cancer (grade D).¹¹⁸ Given its limited risk for harm, vitamin C was excluded from this recommendation.

Vitamin A

Vitamers: Retinol; retinal; retinyl esters; provitamin A carotenoids (beta-carotene, alpha-carotene, beta-cryptoxanthin)

Physiologic role: Essential for vision and corneal development. Also involved in general cell differentiation and immune function

Dietary sources: Liver, fish oil, dairy, and fortified cereals. Provitamin A sources: leafy green vegetables, orange/yellow vegetables, tomato products, fruits, and vegetable oils

Retinoids and their precursors, carotenoids, serve a critical function in vision, as well as regulating cell differentiation and proliferation throughout the body.² While evidence suggests mortality benefit of supplementation in populations at risk of deficiency,⁴⁵ wide-ranging studies have found either inconsistent benefit or outright harms in the developed world.

The takeaway: Given the USPSTF grade “D” recommendation and concern for potential harms, supplementation is not recommended in healthy patients without risk factors for deficiency.²

Vitamin E

Vitamers: Tocopherols (alpha-, beta-, ­gamma-, delta-); tocotrienol (alpha-, beta-, gamma-, delta-)

Physiologic role: Antioxidant; protects polyunsaturated fats from free radical oxidative damage. Involved in immune function, cell signaling, and regulation of gene expression

Dietary sources: Nuts, seeds, vegetable oil, green leafy vegetables, and fortified cereals

Vitamin E is the collective name of 8 compounds; alpha-tocopherol is the physiologically active form. Vitamin E is involved with cell proliferation as well as endothelial and platelet function.²

The takeaway: Vitamin E supplementation’s effects on cancer, cardiovascular disease, ophthalmologic disorders, and cognition have been investigated; data is either lacking to support a benefit or demonstrates harms as outlined above. Given this and the USPSTF grade “D” recommendation, supplementation is not recommended in healthy patients.²

Vitamin C

Vitamers: Ascorbic acid

Physiologic role: Required for synthesis of collagen, L-carnitine, and some neurotransmitters. Also involved in protein metabolism

Dietary sources: Primarily in fruits and vegetables: citrus, tomato, potatoes, red/green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, cantaloupe, and fortified cereals

Vitamin C supplementation at the onset of illness does not seem to have benefit.

Ascorbic acid is a required cofactor for biosynthesis of collagen, neurotransmitters, and protein metabolism.² In addition to the shared hypothesized benefits of antioxidants, vitamin C supplementation has undergone extensive research into its potential role in augmenting the immune system and preventing the common cold. Systematic reviews have found daily vitamin C supplementation of at least 200 mg did not affect the incidence of the common cold in healthy adults but may shorten duration and could be of benefit in those exposed to extreme physical exercise or cold.⁴⁸ Vitamin C supplementation at the onset of illness does not seem to have benefit.⁴⁸ Data is insufficient to draw conclusions about a potential effect on pneumonia incidence or severity.^119,120

The takeaway: Overall, data remain inconclusive as to potential benefits of vitamin C supplementation, although risks of potential harms are likely low.

Continue to: Vitamin D

Vitamers: Cholecalciferol (D3); ergocalciferol (D2)

Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function

Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure

Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.²

The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.

Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.^49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,^54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.⁵⁷

The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.⁵⁵

Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.^41,58-62

Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer^41,63-66,121 or cardiovascular disease risk.^41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.^{43,72-75,85-90,122}

The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.¹²³ RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.¹²⁴ The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.¹²³ Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.^52,53

Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,^51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).^125,126

Vitamin K

Vitamers: Phylloquinone (K1); menaquinones (K2)

Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism

Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods

Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.²

Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.

Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)⁹¹ and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.¹²⁷ Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.^128,129

Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,^92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.² The FDA considers the evidence insufficient at this time to support such a claim.² Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies⁹⁴ and supplementation was associated with improved disease measures,¹³⁰ but no patient-oriented outcomes have been demonstrated.¹³¹

The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-­oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.

Continue to: MULTIVITAMINS

Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.¹³² Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.¹³³

Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.

A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.⁴¹ Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.^134,135 This benefit appears to disappear at 5 years of follow-up.¹³⁶ RCT data have shown no benefit of multivitamin use on cognitive function,⁹⁵ and high-quality data suggest there is no effect on all-cause mortality.¹³⁷ Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.⁴¹

The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.^138-140 AAP does not recommend multivitamins for children with a well-balanced diet.¹⁴¹ Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.¹⁴²

The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.¹⁴³ Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.¹⁴⁴ Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.²

SUMMARY

Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.

CORRESPONDENCE
Joel Herness, MD, 4700 North Las Vegas Boulevard, Nellis AFB, NV 89191; [email protected]

Since their discovery in the early 1900s as the treatment for life-threatening deficiency syndromes, vitamins have been touted as panaceas for numerous ailments. While observational data have suggested potential correlations between vitamin status and every imaginable disease, randomized controlled trials (RCTs) have generally failed to find benefits from supplementation. Despite this lack of proven efficacy, more than half of older adults reported taking vitamins regularly.¹

While most clinicians consider vitamins to be, at worst, expensive placebos, the potential for harm and dangerous interactions exists. Unlike pharmaceuticals, vitamins are generally unregulated, and the true content of many dietary supplements is often difficult to elucidate. Understanding the physiologic role, foundational evidence, and specific indications for the various vitamins is key to providing the best recommendations to patients.

Vitamins are essential organic nutrients, required in small quantities for normal metabolism. Since they are not synthesized endogenously, they must be ingested via food intake. In the developed world, vitamin deficiency syndromes are rare, thanks to sufficiently balanced diets and availability of fortified foods. The focus of this article will be on vitamin supplementation in healthy patients with well-balanced diets. TABLE W1² (available at mdedge.com/familymedicine) lists the 13 recognized vitamins, their recommended dietary allowances, and any known toxicity risks. TABLE 2² outlines elements of the history to consider when evaluating for deficiency. A summary of the most clinically significant evidence for vitamin supplementation follows; a more comprehensive review can be found in TABLE 3.^3-96

B COMPLEX VITAMINS

Vitamin B1

Vitamers: Thiamine (thiamin)

Physiologic role: Critical in carbohydrate and amino-acid catabolism and energy metabolism

Dietary sources: Whole grains, meat, fish, fortified cereals, and breads

Thiamine serves as an essential cofactor in energy metabolism.² Thiamine deficiency is responsible for beriberi syndrome (rare in the developed world) and Wernicke-Korsakoff syndrome, the latter of which is a relatively common complication of chronic alcohol dependence. Although thiamine’s administration in these conditions can be curative, evidence is lacking to support its use preventively in patients with alcoholism.³ Thiamine has additionally been theorized to play a role in cardiac and cognitive function, but RCT data has not shown consistent patient-oriented benefits.^4,5

The takeaway: Given the lack of evidence, supplementation in the general population is not recommended.

Vitamin B2

Vitamers: Riboflavin

Physiologic role: Essential component of cellular function and growth, energy production, and metabolism of fats and drugs

Dietary sources: Eggs, organ meats, lean meats, milk, green vegetables, fortified cereals and grains

Riboflavin is essential to energy production, cellular growth, and metabolism.²

The takeaway: Its use as migraine prophylaxis has limited data,⁹⁷ but there is otherwise no evidence to support health benefits of riboflavin supplementation.

Vitamin B3

Vitamers: Nicotinic acid (niacin); nicotinamide (niacinamide); nicotinamide riboside

Physiologic role: Converted to nicotinamide adenine dinucleotide (NAD), which is widely required in most cellular metabolic redox processes. Crucial to the synthesis and metabolism of carbohydrates, fatty acids, and proteins

Dietary sources: Poultry, beef, fish, nuts, legumes, grains. (Tryptophan can also be converted to NAD.)

Niacin is readily converted to NAD, an essential coenzyme for multiple catalytic processes in the body. While niacin at doses more than 100 times the recommended dietary allowance (RDA; 1-3 g/d) has been extensively studied for its role in dyslipidemias,² pharmacologic dosing is beyond the scope of this article.

The takeaway: There is no evidence supporting a clinical benefit from niacin supplementation.

Vitamin B5

Vitamers: Pantothenic acid; pantethine

Physiologic role: Required for synthesis of coenzyme A (CoA) and acyl carrier protein, both essential in fatty acid and other anabolic/catabolic processes

Dietary sources: Almost all plant/animal-based foods. Richest sources include beef, chicken, organ meats, whole grains, and some vegetables

Pantothenic acid is essential to multiple metabolic processes and readily available in sufficient amounts in most foods.² Although limited RCT data suggest pantethine may improve lipid measures,^12,98,99 pantothenic acid itself does not seem to share this effect.

The takeaway: There is no data that supplementation of any form of vitamin B5 has any patient-oriented clinical benefits.

Continue to: Vitamin B6

Vitamers: Pyridoxine; pyridoxamine; pyridoxal

Physiologic role: Widely involved coenzyme for cognitive development, neurotransmitter biosynthesis, homocysteine and glucose metabolism, immune function, and hemoglobin formation

Dietary sources: Fish, organ meats, potatoes/starchy vegetables, fruit (other than citrus), and fortified cereals

Pyridoxine is required for numerous enzymatic processes in the body, including biosynthesis of neurotransmitters and homeostasis of the amino acid homocysteine.² While overt deficiency is rare, marginal insufficiency may become clinically apparent and has been associated with malabsorption, malignancies, pregnancy, heart disease, alcoholism, and use of drugs such as isoniazid, hydralazine, and levodopa/carbidopa.² Vitamin B6 supplementation is known to decrease plasma homocysteine levels, a theorized intermediary for cardiovascular disease; however, studies have failed to consistently demonstrate patient-­oriented benefits.^100-102 While observational data has suggested a correlation between vitamin B6 status and cancer risk, RCTs have not supported benefit from supplementation.^14-16 Potential effects of vitamin B6 supplementation on cognitive function have also been studied without observed benefit.^17,18

The takeaway: Vitamin B6 is recommended as a potential treatment option for nausea in pregnancy.¹⁹ Otherwise, vitamin B6 is readily available in food, deficiency is rare, and no patient-oriented evidence supports supplementation in the general population.

Vitamin B7

Vitamers: Biotin

Physiologic role: Cofactor in the metabolism of fatty acids, glucose, and amino acids. Also plays key role in histone modifications, gene regulation, and cell signaling

Dietary sources: Widely available; most prevalent in organ meats, fish, meat, seeds, nuts, and vegetables (eg, sweet potatoes). Whole cooked eggs are a major source, but raw eggs contain avidin, which blocks absorption

Biotin serves a key role in metabolism, gene regulation, and cell signaling.² Biotin is known to interfere with laboratory assays— including cardiac enzymes, thyroid studies, and hormone studies—at normal supplementation doses, resulting in both false-positive and false-negative results.¹⁰³

The takeaway: No evidence supports the health benefits of biotin supplementation.

Vitamin B9

Vitamers: Folates; folic acid

Physiologic role: Functions as a coenzyme in the synthesis of DNA/RNA and metabolism of amino acids

Dietary sources: Highest content in spinach, liver, asparagus, and brussels sprouts. Generally found in green leafy vegetables, fruits, nuts, beans, peas, seafood, eggs, dairy, meat, poultry, grains, and fortified cereals.

Continue to: Vitamin B12

Vitamers: Cyanocobalamin; hydroxocobalamin; methylcobalamin; adenosylcobalamin

Physiologic role: Required for red blood cell formation, neurologic function, and DNA synthesis

Dietary sources: Only in animal products: fish, poultry, meat, eggs, and milk/dairy products. Not present in plant foods. Fortified cereals, nutritional yeast are sources for vegans/vegetarians.

Given their linked physiologic roles, vitamins B9 and B12 are frequently studied together. Folate and cobalamins play key roles in nucleic acid synthesis and amino acid metabolism, with their most clinically significant role in hematopoiesis. Vitamin B12 is also essential to normal neurologic function.²

The US Preventive Services Task Force (USPSTF) recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects (grade A).²¹ This is supported by high-quality RCT evidence demonstrating a protective effect of daily folate supplementation in preventing neural tube defects.²² Folate supplementation’s effect on other fetal birth defects has been investigated, but no benefit has been demonstrated. While observational studies have suggested an inverse relationship with folate status and fetal autism spectrum disorder,^23-25 the RCT data is mixed.²⁶

A potential role for folate in cancer prevention has been extensively investigated. An expert panel of the National Toxicology Program (NTP) concluded that folate supplementation does not reduce cancer risk in people with adequate baseline folate status based on high-quality meta-analysis data.^27,104 Conversely, long-term follow-up from RCTs demonstrated an increased risk of colorectal adenomas and cancers,^28,29 leading the NTP panel to conclude there is sufficient concern for adverse effects of folate on cancer growth to justify further research.¹⁰⁴

While observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation.

Given folate and vitamin B12’s ­homocysteine-reducing effects, it has been theorized that supplementation may protect from cardiovascular disease. However, despite extensive research, there remains no consistent patient-oriented outcomes data to support such a benefit.^31,32,105

The evidence is mixed but generally has found no benefit of folate or vitamin B12 supplementation on cognitive function.^18,33-35 Finally, RCT data has failed to demonstrate a reduction in fracture risk with supplementation.^36,106

The takeaway: High-quality RCT evidence demonstrates a protective effect of preconceptual daily folate supplementation in preventing neural tube defects.²² The USPSTF recommends preconceptual folate supplementation of 0.4-0.8 mg/d in women of childbearing age to decrease the risk of fetal neural tube defects.

Continue to: ANTIOXIDANTS

In addition to their individual roles, vitamins A, E, and C are antioxidants, functioning to protect cells from oxidative damage by free radical species.² Due to this shared role, these vitamins are commonly studied together. Antioxidants are hypothesized to protect from various diseases, including cancer, cardiovascular disease, dementia, autoimmune disorders, depression, cataracts, and age-related vision decline.^2,37,107-112

Though observational studies have found a correlation of increased risk for disease with lower antioxidant serum levels, RCTs have not demonstrated a reduction in disease risk with supplementation and, in some cases, have found an increased risk of mortality. While several studies have found potential benefit of antioxidant use in reducing colon and breast cancer risk,^38,113-115 vitamins A and E have been associated with increased risk of lung and prostate cancer, respectively.^47,110 Cardiovascular disease and antioxidant vitamin supplementation has similar inconsistent data, ranging from slight benefit to harm.^2,116 After a large Cochrane review in 2012 found a significant increase in all-cause mortality associated with vitamin E and ­beta-carotene,¹¹⁷ the USPSTF made a specific recommendation against supplementation of these vitamins for the prevention of cardiovascular disease or cancer (grade D).¹¹⁸ Given its limited risk for harm, vitamin C was excluded from this recommendation.

Vitamin A

Vitamers: Retinol; retinal; retinyl esters; provitamin A carotenoids (beta-carotene, alpha-carotene, beta-cryptoxanthin)

Physiologic role: Essential for vision and corneal development. Also involved in general cell differentiation and immune function

Dietary sources: Liver, fish oil, dairy, and fortified cereals. Provitamin A sources: leafy green vegetables, orange/yellow vegetables, tomato products, fruits, and vegetable oils

Retinoids and their precursors, carotenoids, serve a critical function in vision, as well as regulating cell differentiation and proliferation throughout the body.² While evidence suggests mortality benefit of supplementation in populations at risk of deficiency,⁴⁵ wide-ranging studies have found either inconsistent benefit or outright harms in the developed world.

The takeaway: Given the USPSTF grade “D” recommendation and concern for potential harms, supplementation is not recommended in healthy patients without risk factors for deficiency.²

Vitamin E

Vitamers: Tocopherols (alpha-, beta-, ­gamma-, delta-); tocotrienol (alpha-, beta-, gamma-, delta-)

Physiologic role: Antioxidant; protects polyunsaturated fats from free radical oxidative damage. Involved in immune function, cell signaling, and regulation of gene expression

Dietary sources: Nuts, seeds, vegetable oil, green leafy vegetables, and fortified cereals

Vitamin E is the collective name of 8 compounds; alpha-tocopherol is the physiologically active form. Vitamin E is involved with cell proliferation as well as endothelial and platelet function.²

The takeaway: Vitamin E supplementation’s effects on cancer, cardiovascular disease, ophthalmologic disorders, and cognition have been investigated; data is either lacking to support a benefit or demonstrates harms as outlined above. Given this and the USPSTF grade “D” recommendation, supplementation is not recommended in healthy patients.²

Vitamin C

Vitamers: Ascorbic acid

Physiologic role: Required for synthesis of collagen, L-carnitine, and some neurotransmitters. Also involved in protein metabolism

Dietary sources: Primarily in fruits and vegetables: citrus, tomato, potatoes, red/green peppers, kiwi fruit, broccoli, strawberries, brussels sprouts, cantaloupe, and fortified cereals

Vitamin C supplementation at the onset of illness does not seem to have benefit.

Ascorbic acid is a required cofactor for biosynthesis of collagen, neurotransmitters, and protein metabolism.² In addition to the shared hypothesized benefits of antioxidants, vitamin C supplementation has undergone extensive research into its potential role in augmenting the immune system and preventing the common cold. Systematic reviews have found daily vitamin C supplementation of at least 200 mg did not affect the incidence of the common cold in healthy adults but may shorten duration and could be of benefit in those exposed to extreme physical exercise or cold.⁴⁸ Vitamin C supplementation at the onset of illness does not seem to have benefit.⁴⁸ Data is insufficient to draw conclusions about a potential effect on pneumonia incidence or severity.^119,120

The takeaway: Overall, data remain inconclusive as to potential benefits of vitamin C supplementation, although risks of potential harms are likely low.

Continue to: Vitamin D

Vitamers: Cholecalciferol (D3); ergocalciferol (D2)

Physiologic role: Hydroxylation in liver and kidney required to activate. Promotes dietary calcium absorption, enables normal bone mineralization. Also involved in modulation of cell growth, and neuromuscular and immune function

Dietary sources: Few natural dietary sources, which include fatty fish, fish liver oils; small amount in beef liver, cheese, egg yolks. Primary sources include fortified milk and endogenous synthesis in skin with UV exposure

Calciferol is a fat-soluble vitamin required for calcium and bone homeostasis. It is not naturally available in many foods but is primarily produced endogenously in the skin with ultraviolet light exposure.²

The AAP recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.

Bone density and fracture risk reduction are the most often cited benefits of vitamin D supplementation, but this has not been demonstrated consistently in RCTs. Multiple systematic reviews showing inconsistent benefit of vitamin D (with or without calcium) on fracture risk led the USPSTF to conclude that there is insufficient evidence (grade I) to issue a recommendation on vitamin D and calcium supplementation for primary prevention of fractures in postmenopausal women.^49-51 Despite some initial evidence suggesting a benefit of vitamin D supplementation on falls reduction, 3 recent systematic reviews did not demonstrate this in community-dwelling elders,^54-56 although a separate Cochrane review did suggest a reduction in rate of falls among institutionalized elders.⁵⁷

The takeaway: Given these findings, the USPSTF has recommended against (grade D) vitamin D supplementation to prevent falls in community-dwelling elders.⁵⁵

Beyond falls. While the vitamin D receptor is expressed throughout the body and observational studies have suggested a correlation between vitamin D status and many outcomes, extensive RCT data has generally failed to demonstrate extraskeletal benefits from supplementation. Meta-analysis data have demonstrated potential reductions in acute respiratory infection rates and asthma exacerbations with vitamin D supplementation. There is also limited evidence suggesting a reduction in preeclampsia and low-birthweight infant risk with vitamin D supplementation in pregnancy. However, several large meta-analyses and systematic reviews have investigated vitamin D supplementation’s effect on all-cause mortality and found no consistent data to support an association.^41,58-62

Multiple systematic reviews have investigated and found high-quality evidence demonstrating no association between vitamin D supplementation and cancer^41,63-66,121 or cardiovascular disease risk.^41,70,71 There is high-quality data showing no benefit of vitamin D supplementation for multiple additional diseases, including diabetes, cognitive decline, depression, pain, obesity, and liver disease.^{43,72-75,85-90,122}

The takeaway: Due to poor availability in breastmilk, the American Academy of Pediatrics (AAP) recommends supplementing exclusively breastfed infants with 400 IU/d of vitamin D to prevent rickets.¹²³ RCT data support high-dose supplementation of lactating women (6400 IU/d) as an alternative strategy to supplementation of the infant.¹²⁴ The AAP recommends that all nonbreastfeeding infants and older children ingesting < 1000 mL/d of vitamin D–fortified formula or milk should also be supplemented with 400 IU/d of vitamin D.¹²³ Despite these universal recommendations for supplementation, evidence is mixed on the effect of vitamin D supplementation on bone health in children.^52,53

Although concerns about vitamin D supplementation and increased risk of urolithiasis and hypercalcemia have been raised,^51,62,121 systematic reviews have not demonstrated significant, clinically relevant risks, even with high-dose supplementation (> 2800 IU/d).^125,126

Vitamin K

Vitamers: Phylloquinone (K1); menaquinones (K2)

Physiologic role: Coenzyme for synthesis of proteins involved in hemostasis and bone metabolism

Dietary sources: Phylloquinone is found in green leafy vegetables, vegetable oils, some fruits, meat, dairy, and eggs. Menaquinone is produced by gut bacteria and present in fermented foods

Vitamin K includes 2 groups of similar compounds: phylloquinone and menaquinones. Unlike other fat-soluble vitamins, vitamin K is rapidly metabolized and has low tissue storage.²

Children taking multivitamins were often found to have excess levels of potentially harmful nutrients, such as retinol, zinc, and folic acid.

Administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of vitamin K deficiency bleeding (VKDB). This is supported by RCT data demonstrating a reduction in classic VKDB (occurring within 7 days)⁹¹ and epidemiologic data from various countries showing a reduction in late-onset VKDB with vitamin K prophylaxis programs.¹²⁷ Oral dosing appears to reduce the risk of VKDB in the setting of parental refusal but is less effective than IM dosing.^128,129

Vitamin K’s effects on bone density and fracture risk have also been investigated. Systematic reviews have demonstrated a reduction in fracture risk with vitamin K supplementation,^92,93 and European and Asian regulatory bodies have recognized a potential benefit on bone health.² The FDA considers the evidence insufficient at this time to support such a claim.² Higher dietary vitamin K consumption has been associated with lower risk of cardiovascular disease in observational studies⁹⁴ and supplementation was associated with improved disease measures,¹³⁰ but no patient-oriented outcomes have been demonstrated.¹³¹

The takeaway: The administration of vitamin K 0.5 to 1 mg intramuscularly (IM) to newborns is standard of care for the prevention of VKDB. Vitamin K may lead to a reduction in fracture risk, but the FDA considers the evidence insufficient. Vitamin K’s potential link to a lowered risk of cardiovascular disease has not been demonstrated with patient-­oriented outcomes. Vitamin K has low potential for toxicity, although its interaction with vitamin K antagonists (ie, warfarin) is clinically relevant.

Continue to: MULTIVITAMINS

Multivitamins are often defined as a supplement containing 3 or more vitamins and minerals but without herbs, hormones, or drugs.¹³² Many multivitamins do contain additional substances, and some include levels of vitamins that exceed the RDA or even the established tolerable upper intake level.¹³³

Safe medication storage should be practiced, as multivitamins with iron are a leading cause of poisoning in children.

A 2013 systematic review found limited evidence to support any benefit from multivitamin supplementation.⁴¹ Two included RCTs demonstrated a narrowly significant decrease in cancer rates among men, but saw no effect in women or the combined population.^134,135 This benefit appears to disappear at 5 years of follow-up.¹³⁶ RCT data have shown no benefit of multivitamin use on cognitive function,⁹⁵ and high-quality data suggest there is no effect on all-cause mortality.¹³⁷ Given this lack of supporting evidence, the USPSTF has concluded that there is insufficient evidence (grade I) to recommend vitamin supplementation in general to prevent cardiovascular disease or cancer.⁴¹

The use of prenatal multivitamins is generally recommended in the pregnancy and preconception period and has been associated with reduced risk of autism spectrum disorders, pediatric cancer rates, small-for-gestational-age infants, and multiple birth defects in offspring; however, studies have not examined if this benefit exceeds that of folate supplementation alone.^138-140 AAP does not recommend multivitamins for children with a well-balanced diet.¹⁴¹ Of concern, children taking multivitamins were often found to have excess levels of potentially harmful nutrients such as retinol, zinc, and folic acid.¹⁴²

The takeaway: There is limited evidence to support any benefit from multivitamin supplementation. Prenatal multivitamins are generally recommended in the pregnancy and preconception period. Overall, the risks of multivitamins are minimal, although that risk is dependent on the multivitamin’s constituent components.¹⁴³ Components such as vitamin K may interact with a patient’s medications, and multivitamins have been shown to reduce the circulating levels of antiretrovirals.¹⁴⁴ Specifically, multivitamins with iron should be avoided in men and postmenopausal women, and safe medication storage should be practiced as multivitamins with iron are a leading cause of poisoning in children.²

SUMMARY

Vitamin supplementation in the developed world remains common despite a paucity of RCT data supporting it. Supplementation of folate in women planning to conceive, vitamin D in breastfeeding infants, and vitamin K in newborns are well supported by clinical evidence. Otherwise, there is limited evidence supporting clinically significant benefit from supplementation in healthy patients with well-balanced diets—and in the case of vitamins A and E, there may be outright harms.

CORRESPONDENCE
Joel Herness, MD, 4700 North Las Vegas Boulevard, Nellis AFB, NV 89191; [email protected]