The financial struggles created by the pandemic have eased somewhat, but physicians are still facing an array of challenges, including increased workloads and longer hours. All in all, however, things seem to be looking up.

More than 13,000 physicians in more than 29 specialties shared information about their incomes and other aspects of their careers in a survey conducted by Medscape. The responses showed a trend back to something like normal after the initial blow of the COVID-19 pandemic.

robertsrob/ThinkStock

As the profession began to recover from the pandemic, cardiologists reported that their incomes increased in 2021, reaching an average of $490,000 for the year, up from $459,000 the previous year. This was in keeping with physicians in other specialties. “Compensation for most physicians is trending back up, as demands for physicians accelerates,” said James Taylor, group president and chief operating officer of AMN Healthcare’s Physician & Leadership Solutions Division. “The market for physicians has done a complete 180 over just 7 or 8 months.” And though inflation is on everyone’s mind these days, rising salaries have helped physicians keep up with rising prices.

Despite the increase in income (and the accompanying increased workload), nearly 30% of cardiologists have taken on extra work, most of that being medical work, but a few did report unrelated side hustles. This may be due not to a shortfall in income, but rather to a desire to pad the coffers for the future. Lauren Podnos, a financial planner with Wealth Care, a firm that specializes in working with physicians and other health care professionals, points out that many physicians like to build wealth as quickly as possible as a hedge against possible burnout later on. “With physicians,” she said, “we work to get to the point where they have the freedom to do whatever they want – cut back and work part-time or transition into another career – so if they do burn out, they have other options.”

Though physician pay rose overall, not all cardiologists enjoyed a boost in income. However, those who did lose ground did not always lay the blame on COVID-19: General pay cuts were mentioned, for example. For physicians overall, a gender pay gap still remains, with men averaging $373,000 per year, in contrast to women who make $282,000. With more women moving into higher-paying specialties, the gap has narrowed somewhat in recent years, and industry leaders are making efforts to accelerate that trend. “A great many of the specialty organizations have efforts underway not just to increase the number of women in specialties but also to address gender pay gaps and bias in evaluations during residency and fellowship,” said Ron Holder, chief operating officer of the Medical Group Management Association (MGMA).

Incentive bonuses helped bump up income as well. Overall, 57% of physicians receive some kind of incentive bonus; the average for cardiologists was $85,000 last year, up from $71,000 the prior year. While such bonuses can certainly help the bottom line, they’re not always an unmitigated good. A 2021 study found that incentive programs can cause people to prioritize time spent at work and with work colleagues at the expense of family and personal relationships, a potentially troubling finding with so many physicians struggling with depression and burnout. “There’s been a lot of previous evidence showing that the more time we spend with our loved ones the happier we are,” said Julia Hur, PhD, assistant professor of management and organizations at New York University’s Stern School of Business, and lead author of the study. “The core argument of this study is about attention, and performance incentives create an attentional fixation on money,” she said, “causing people to spend more time with work colleagues and people who are helpful to their careers. And that takes away from time for family and friends.”


 

Still rewarding

Getting paid well is one thing; feeling that you’re being paid well is another. Only 57% of cardiologists who responded to the survey said they felt they were fairly compensated for their work. This puts them at roughly the middle of the pack of specialties. Contrast that with physicians in public health and preventive medicine who topped the charts on this one, with 72% of these doctors feeling that they were being paid fairly for their work.

However, cardiology did rank at the top of specialties whose members said they would choose medicine if they had a chance to do it again, though that number was down from the previous year (81% in 2021 versus 86% in 2020). Of cardiologists surveyed, 88% would choose cardiology if they got a do-over.

Cardiologists spend an average of 16.4 hours each week on paperwork and administration. That’s only slightly higher than the average for all specialties, about 15.5 hours a week. Despite billing hassles and low reimbursement rates, 80% of cardiologists polled say they plan to continue taking new and existing Medicare and Medicaid patients. Though 17% said they could or would drop low-paying insurers, 83% said they could not do that for business, ethical, or other reasons.

Despite its many headaches, medicine is still a rewarding profession. The most rewarding aspects cited by cardiologists were relationships with patients (34%), being good at their work (23%), and knowing they’re making the world a better place (21%). Though this is mostly in line with previous surveys, in recent years physicians have increasingly cited making the world a better place as a key motivation and reward.

The most challenging part of the job? This will not come as a surprise: Having so many rules and regulations. This was the reason given by 26% of respondents. But a close second – at 21% – was having to work long hours. One positive development is that cardiologists are making peace with their EHR systems. Only 10% said this was the most challenging part of the job (the same percentage that cited dealing with difficult patients as most challenging).

The financial struggles created by the pandemic have eased somewhat, but physicians are still facing an array of challenges, including increased workloads and longer hours. All in all, however, things seem to be looking up.

More than 13,000 physicians in more than 29 specialties shared information about their incomes and other aspects of their careers in a survey conducted by Medscape. The responses showed a trend back to something like normal after the initial blow of the COVID-19 pandemic.

robertsrob/ThinkStock

As the profession began to recover from the pandemic, cardiologists reported that their incomes increased in 2021, reaching an average of $490,000 for the year, up from $459,000 the previous year. This was in keeping with physicians in other specialties. “Compensation for most physicians is trending back up, as demands for physicians accelerates,” said James Taylor, group president and chief operating officer of AMN Healthcare’s Physician & Leadership Solutions Division. “The market for physicians has done a complete 180 over just 7 or 8 months.” And though inflation is on everyone’s mind these days, rising salaries have helped physicians keep up with rising prices.

Despite the increase in income (and the accompanying increased workload), nearly 30% of cardiologists have taken on extra work, most of that being medical work, but a few did report unrelated side hustles. This may be due not to a shortfall in income, but rather to a desire to pad the coffers for the future. Lauren Podnos, a financial planner with Wealth Care, a firm that specializes in working with physicians and other health care professionals, points out that many physicians like to build wealth as quickly as possible as a hedge against possible burnout later on. “With physicians,” she said, “we work to get to the point where they have the freedom to do whatever they want – cut back and work part-time or transition into another career – so if they do burn out, they have other options.”

Though physician pay rose overall, not all cardiologists enjoyed a boost in income. However, those who did lose ground did not always lay the blame on COVID-19: General pay cuts were mentioned, for example. For physicians overall, a gender pay gap still remains, with men averaging $373,000 per year, in contrast to women who make $282,000. With more women moving into higher-paying specialties, the gap has narrowed somewhat in recent years, and industry leaders are making efforts to accelerate that trend. “A great many of the specialty organizations have efforts underway not just to increase the number of women in specialties but also to address gender pay gaps and bias in evaluations during residency and fellowship,” said Ron Holder, chief operating officer of the Medical Group Management Association (MGMA).

Incentive bonuses helped bump up income as well. Overall, 57% of physicians receive some kind of incentive bonus; the average for cardiologists was $85,000 last year, up from $71,000 the prior year. While such bonuses can certainly help the bottom line, they’re not always an unmitigated good. A 2021 study found that incentive programs can cause people to prioritize time spent at work and with work colleagues at the expense of family and personal relationships, a potentially troubling finding with so many physicians struggling with depression and burnout. “There’s been a lot of previous evidence showing that the more time we spend with our loved ones the happier we are,” said Julia Hur, PhD, assistant professor of management and organizations at New York University’s Stern School of Business, and lead author of the study. “The core argument of this study is about attention, and performance incentives create an attentional fixation on money,” she said, “causing people to spend more time with work colleagues and people who are helpful to their careers. And that takes away from time for family and friends.”


 

Still rewarding

Getting paid well is one thing; feeling that you’re being paid well is another. Only 57% of cardiologists who responded to the survey said they felt they were fairly compensated for their work. This puts them at roughly the middle of the pack of specialties. Contrast that with physicians in public health and preventive medicine who topped the charts on this one, with 72% of these doctors feeling that they were being paid fairly for their work.

However, cardiology did rank at the top of specialties whose members said they would choose medicine if they had a chance to do it again, though that number was down from the previous year (81% in 2021 versus 86% in 2020). Of cardiologists surveyed, 88% would choose cardiology if they got a do-over.

Cardiologists spend an average of 16.4 hours each week on paperwork and administration. That’s only slightly higher than the average for all specialties, about 15.5 hours a week. Despite billing hassles and low reimbursement rates, 80% of cardiologists polled say they plan to continue taking new and existing Medicare and Medicaid patients. Though 17% said they could or would drop low-paying insurers, 83% said they could not do that for business, ethical, or other reasons.

Despite its many headaches, medicine is still a rewarding profession. The most rewarding aspects cited by cardiologists were relationships with patients (34%), being good at their work (23%), and knowing they’re making the world a better place (21%). Though this is mostly in line with previous surveys, in recent years physicians have increasingly cited making the world a better place as a key motivation and reward.

The most challenging part of the job? This will not come as a surprise: Having so many rules and regulations. This was the reason given by 26% of respondents. But a close second – at 21% – was having to work long hours. One positive development is that cardiologists are making peace with their EHR systems. Only 10% said this was the most challenging part of the job (the same percentage that cited dealing with difficult patients as most challenging).

The financial struggles created by the pandemic have eased somewhat, but physicians are still facing an array of challenges, including increased workloads and longer hours. All in all, however, things seem to be looking up.

More than 13,000 physicians in more than 29 specialties shared information about their incomes and other aspects of their careers in a survey conducted by Medscape. The responses showed a trend back to something like normal after the initial blow of the COVID-19 pandemic.

robertsrob/ThinkStock

As the profession began to recover from the pandemic, cardiologists reported that their incomes increased in 2021, reaching an average of $490,000 for the year, up from $459,000 the previous year. This was in keeping with physicians in other specialties. “Compensation for most physicians is trending back up, as demands for physicians accelerates,” said James Taylor, group president and chief operating officer of AMN Healthcare’s Physician & Leadership Solutions Division. “The market for physicians has done a complete 180 over just 7 or 8 months.” And though inflation is on everyone’s mind these days, rising salaries have helped physicians keep up with rising prices.

Despite the increase in income (and the accompanying increased workload), nearly 30% of cardiologists have taken on extra work, most of that being medical work, but a few did report unrelated side hustles. This may be due not to a shortfall in income, but rather to a desire to pad the coffers for the future. Lauren Podnos, a financial planner with Wealth Care, a firm that specializes in working with physicians and other health care professionals, points out that many physicians like to build wealth as quickly as possible as a hedge against possible burnout later on. “With physicians,” she said, “we work to get to the point where they have the freedom to do whatever they want – cut back and work part-time or transition into another career – so if they do burn out, they have other options.”

Though physician pay rose overall, not all cardiologists enjoyed a boost in income. However, those who did lose ground did not always lay the blame on COVID-19: General pay cuts were mentioned, for example. For physicians overall, a gender pay gap still remains, with men averaging $373,000 per year, in contrast to women who make $282,000. With more women moving into higher-paying specialties, the gap has narrowed somewhat in recent years, and industry leaders are making efforts to accelerate that trend. “A great many of the specialty organizations have efforts underway not just to increase the number of women in specialties but also to address gender pay gaps and bias in evaluations during residency and fellowship,” said Ron Holder, chief operating officer of the Medical Group Management Association (MGMA).

Incentive bonuses helped bump up income as well. Overall, 57% of physicians receive some kind of incentive bonus; the average for cardiologists was $85,000 last year, up from $71,000 the prior year. While such bonuses can certainly help the bottom line, they’re not always an unmitigated good. A 2021 study found that incentive programs can cause people to prioritize time spent at work and with work colleagues at the expense of family and personal relationships, a potentially troubling finding with so many physicians struggling with depression and burnout. “There’s been a lot of previous evidence showing that the more time we spend with our loved ones the happier we are,” said Julia Hur, PhD, assistant professor of management and organizations at New York University’s Stern School of Business, and lead author of the study. “The core argument of this study is about attention, and performance incentives create an attentional fixation on money,” she said, “causing people to spend more time with work colleagues and people who are helpful to their careers. And that takes away from time for family and friends.”


 

Still rewarding

Getting paid well is one thing; feeling that you’re being paid well is another. Only 57% of cardiologists who responded to the survey said they felt they were fairly compensated for their work. This puts them at roughly the middle of the pack of specialties. Contrast that with physicians in public health and preventive medicine who topped the charts on this one, with 72% of these doctors feeling that they were being paid fairly for their work.

However, cardiology did rank at the top of specialties whose members said they would choose medicine if they had a chance to do it again, though that number was down from the previous year (81% in 2021 versus 86% in 2020). Of cardiologists surveyed, 88% would choose cardiology if they got a do-over.

Cardiologists spend an average of 16.4 hours each week on paperwork and administration. That’s only slightly higher than the average for all specialties, about 15.5 hours a week. Despite billing hassles and low reimbursement rates, 80% of cardiologists polled say they plan to continue taking new and existing Medicare and Medicaid patients. Though 17% said they could or would drop low-paying insurers, 83% said they could not do that for business, ethical, or other reasons.

Despite its many headaches, medicine is still a rewarding profession. The most rewarding aspects cited by cardiologists were relationships with patients (34%), being good at their work (23%), and knowing they’re making the world a better place (21%). Though this is mostly in line with previous surveys, in recent years physicians have increasingly cited making the world a better place as a key motivation and reward.

The most challenging part of the job? This will not come as a surprise: Having so many rules and regulations. This was the reason given by 26% of respondents. But a close second – at 21% – was having to work long hours. One positive development is that cardiologists are making peace with their EHR systems. Only 10% said this was the most challenging part of the job (the same percentage that cited dealing with difficult patients as most challenging).

Ordering and interpreting tests is at the heart of what we do as family physicians. Ordering tests judiciously and interpreting them accurately is not easy. The Choosing Wisely campaign¹ has focused our attention on the need to think carefully before ordering tests, whether they be laboratory tests or imaging. Before ordering any test, one should always ask: Is the result of this test going to help me make better decisions about managing this patient?

I would like to highlight and expand on 2 problematic issues Kaminski and Venkat raise in their excellent article on testing in this issue of JFP.²

One should always ask: Is the result of this test going to help me make better decisions?

First, they advise us to know the pretest probability of a disease before we order a test. If we order a test on a patient for whom the probability of disease is very low, a positive result is likely to be a false-positive and mislead us into thinking the patient has the disease when he does not. If we order a test for a patient with a high probability of disease and the result is negative, there is great danger of a false-­negative. We might think the patient does not have the disease, but she does.

There is a deeper problem here, however. Primary care physicians are notorious for overestimating disease probability. In a recent study, primary care clinicians overestimated the pretest probability of disease 2- to 10-fold in scenarios involving 4 common diagnoses: breast cancer, coronary artery disease (CAD), pneumonia, and urinary tract infection.³ Even after receiving a negative test result, clinicians still overestimated the chance of disease in all the scenarios. For example, when presented with a 43-year-old premenopausal woman with atypical chest pain and a normal electrocardiogram, clinicians’ average estimate of the probability of CAD was 10%—considerably higher than true estimates of 1% to 4.4%.³

To improve your accuracy in judging pretest probabilities, see the diagnostic test calculators in Essential Evidence Plus (www.essentialevidenceplus.com/).

Secondly, Kaminski and Venkat advise us to try to avoid the testing cascade.² The associated dangers to patients are considerable. For a cautionary tale, I recommend you read the essay by Michael B. Rothberg, MD, MPH, called “The $50,000 Physical”.⁴ Dr. Rothberg describes the testing cascade his 85-year-old father experienced, which led to a liver biopsy that nearly killed him from post-biopsy bleeding. Always remember: Testing is a double-edged sword. It can help—or harm—your patients.

Ordering and interpreting tests is at the heart of what we do as family physicians. Ordering tests judiciously and interpreting them accurately is not easy. The Choosing Wisely campaign¹ has focused our attention on the need to think carefully before ordering tests, whether they be laboratory tests or imaging. Before ordering any test, one should always ask: Is the result of this test going to help me make better decisions about managing this patient?

I would like to highlight and expand on 2 problematic issues Kaminski and Venkat raise in their excellent article on testing in this issue of JFP.²

One should always ask: Is the result of this test going to help me make better decisions?

First, they advise us to know the pretest probability of a disease before we order a test. If we order a test on a patient for whom the probability of disease is very low, a positive result is likely to be a false-positive and mislead us into thinking the patient has the disease when he does not. If we order a test for a patient with a high probability of disease and the result is negative, there is great danger of a false-­negative. We might think the patient does not have the disease, but she does.

There is a deeper problem here, however. Primary care physicians are notorious for overestimating disease probability. In a recent study, primary care clinicians overestimated the pretest probability of disease 2- to 10-fold in scenarios involving 4 common diagnoses: breast cancer, coronary artery disease (CAD), pneumonia, and urinary tract infection.³ Even after receiving a negative test result, clinicians still overestimated the chance of disease in all the scenarios. For example, when presented with a 43-year-old premenopausal woman with atypical chest pain and a normal electrocardiogram, clinicians’ average estimate of the probability of CAD was 10%—considerably higher than true estimates of 1% to 4.4%.³

To improve your accuracy in judging pretest probabilities, see the diagnostic test calculators in Essential Evidence Plus (www.essentialevidenceplus.com/).

Secondly, Kaminski and Venkat advise us to try to avoid the testing cascade.² The associated dangers to patients are considerable. For a cautionary tale, I recommend you read the essay by Michael B. Rothberg, MD, MPH, called “The $50,000 Physical”.⁴ Dr. Rothberg describes the testing cascade his 85-year-old father experienced, which led to a liver biopsy that nearly killed him from post-biopsy bleeding. Always remember: Testing is a double-edged sword. It can help—or harm—your patients.

Ordering and interpreting tests is at the heart of what we do as family physicians. Ordering tests judiciously and interpreting them accurately is not easy. The Choosing Wisely campaign¹ has focused our attention on the need to think carefully before ordering tests, whether they be laboratory tests or imaging. Before ordering any test, one should always ask: Is the result of this test going to help me make better decisions about managing this patient?

I would like to highlight and expand on 2 problematic issues Kaminski and Venkat raise in their excellent article on testing in this issue of JFP.²

One should always ask: Is the result of this test going to help me make better decisions?

First, they advise us to know the pretest probability of a disease before we order a test. If we order a test on a patient for whom the probability of disease is very low, a positive result is likely to be a false-positive and mislead us into thinking the patient has the disease when he does not. If we order a test for a patient with a high probability of disease and the result is negative, there is great danger of a false-­negative. We might think the patient does not have the disease, but she does.

There is a deeper problem here, however. Primary care physicians are notorious for overestimating disease probability. In a recent study, primary care clinicians overestimated the pretest probability of disease 2- to 10-fold in scenarios involving 4 common diagnoses: breast cancer, coronary artery disease (CAD), pneumonia, and urinary tract infection.³ Even after receiving a negative test result, clinicians still overestimated the chance of disease in all the scenarios. For example, when presented with a 43-year-old premenopausal woman with atypical chest pain and a normal electrocardiogram, clinicians’ average estimate of the probability of CAD was 10%—considerably higher than true estimates of 1% to 4.4%.³

To improve your accuracy in judging pretest probabilities, see the diagnostic test calculators in Essential Evidence Plus (www.essentialevidenceplus.com/).

Secondly, Kaminski and Venkat advise us to try to avoid the testing cascade.² The associated dangers to patients are considerable. For a cautionary tale, I recommend you read the essay by Michael B. Rothberg, MD, MPH, called “The $50,000 Physical”.⁴ Dr. Rothberg describes the testing cascade his 85-year-old father experienced, which led to a liver biopsy that nearly killed him from post-biopsy bleeding. Always remember: Testing is a double-edged sword. It can help—or harm—your patients.

A 55-YEAR-OLD MAN with hypertension and untreated hepatitis C virus (HCV) was referred to the Dermatology Clinic after reporting a 2-year history of photosensitivity and intermittent episodes of blistering and scars on the dorsal side of his hands and feet. No alcohol consumption or drug use was reported.

Physical examination revealed small and shallow erosions on the dorsal aspect of the hands and feet (but no visible blisters) and milium cysts (FIGURE 1A). Additionally, hypertrichosis and hyperpigmentation were observed in the zygomatic areas (FIGURE 1B). Complete blood count and kidney function test results were within normal ranges. Liver function tests showed slightly elevated levels of alanine aminotransferase (79 U/L; normal range, 0-41 U/L), aspartate aminotransferase (62 U/L; normal range, 0-40 U/L), and ferritin (121 ng/mL; normal range, 30-100 ng/mL). Serologies for syphilis, HIV, and hepatitis B virus were negative.

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

The clinical presentation, along with the elevated laboratory values, suggested that this might be a case of porphyria cutanea tarda (PCT). Therefore, a sample of the patient’s urine was examined under Wood lamp and compared to a sample from a healthy control. In the sample of urine from our patient, a vivid red-pink fluorescence could be visualized under the lamp (FIGURE 2), confirming the diagnosis.

The porphyrias are a group of metabolic diseases that affect the heme biosynthesis. They can be classified into 1 of 3 groups, according to clinical features:

• acute hepatic porphyrias, with neurovisceral symptoms (eg, acute intermittent porphyria),
• nonblistering cutaneous porphyrias, with severe photosensitivity but without bullae formation (eg, erythropoietic protoporphyria), or
• blistering cutaneous porphyrias (eg, PCT, hepatoerythropoietic porphyria, and variegate porphyria).

PCT is the most common type of porphyria, with a global prevalence of 1 per 10,000 people.^1,2 It affects adults after the third or fourth decade of life.

Porphyria cutanea tarda has a global prevalance of 1 per 10,000 people.

PCT involves dysfunction of the uroporphyrinogen decarboxylase enzyme (UROD), the fifth enzyme in heme biosynthesis, which catalyzes the conversion of uroporphyrinogen to coproporphyrinogen. This dysfunction causes the accumulation of porphyrinogens that are auto-oxidized to photosensitizing porphyrins.^1-4 PCT can be classified as “sporadic” or “familial” based on the absence or presence of UROD mutation. Approximately 80% of cases of PCT are sporadic.²

In sporadic PCT, triggers for UROD dysfunction include alcohol use, use of estrogens, hemochromatosis or iron overload, chronic HCV infection, and HIV infection.^1-4 HCV (which this patient had) is the most common infection associated with sporadic PCT, with a prevalence of about 50% among these patients.⁵

Continue to: Dermatologic manifestations of PCT

Dermatologic manifestations of PCT include photosensitivity, skin fragility, vesicles, bullae, erosions, and crusts observed in sun-exposed areas. A nonvirilizing type of hypertrichosis may appear prominently on the temples and the cheeks.^2-4 After blisters rupture, atrophy and scarring occur. Milia cysts can form on the dorsal side of the hands and fingers. Less common manifestations include pruritus, scarring alopecia, sclerodermatous changes, and periorbital purple-red suffusion.

Hepatic involvement is demonstrated with elevated serum transaminases and ­gamma-glutamyl transpeptidase. Hepatomegaly is common, and cirrhosis manifests in 30% to 40% of patients.^2-5 On liver biopsy, some degree of siderosis is found in 80% of patients with PCT, and most of them have increased levels of serum iron. The incidence of hepatocellular carcinoma in patients with PCT is greater than in patients with other liver diseases.²

A Wood lamp can be a useful diagnostic first step

Plasma or urine porphyrin lab tests are the gold standard for PCT diagnosis. These tests can be followed by more specific tests (eg, porphyrin fractionation) to exclude other forms of porphyria. However, if plasma or urine porphyrin testing is not readily available, a good first step is a Wood lamp exam, which can be performed on urine or stool. (Plasma or urine porphyrin testing may ultimately be necessary if there is doubt about the diagnosis following the Wood lamp screening.) Histopathologic examination does not confirm the diagnosis of PCT⁴; however, it can be helpful in differential diagnosis.

Wood lamp is a source of long-wave UV light (320 to 400 nm), visualized as a purple or violet light. When porphyrins are present in a urine sample, a red-pink fluorescence may be seen.^3,4,6 The Wood lamp examination should be performed in a completely dark room after the lamp has been warmed up for about 1 minute; time should be allowed for the clinician’s vision to adapt to the dark.⁶ There are no data regarding the sensitivity or specificity of the Wood lamp test in the diagnosis of PCT.

These conditions also cause skin fragility and photosensitivity

The differential diagnosis for PCT includes diseases that also cause skin fragility, blistering, or photosensitivity, such as pseudoporphyria, bullous systemic lupus erythematosus (SLE), and epidermolysis bullosa acquisita (EBA).³

Continue to: In pseudoporphyria

In pseudoporphyria, the clinical findings may be indistinguishable from PCT. Thus, the patient’s history will be especially important; suspect pseudoporphyria if the patient has a history of chronic renal failure or use of a photosensitizing drug.^1,3

Bullous SLE usually manifests with systemic involvement and widespread, tense bullae. Serologic investigation will demonstrate the presence of antinuclear antibodies in high titers (> 1:80), as well as other circulating autoantibodies.

Skin lesions of EBA usually manifest with skin fragility and noninflammatory tense bullae in traumatized skin, such as the extensor surfaces of the hands, feet, and fingers.

None of the above-mentioned diagnoses manifest with hypertrichosis or red-pink fluorescent urine on Wood lamp, and results of porphyrin studies would be normal.³

Address triggers, provide treatment

Once the diagnosis is confirmed, steps must be taken to avoid triggering factors, such as any alcohol consumption, use of estrogen, sun exposure (until plasma porphyrin levels are normal), and potential sources of excessive iron intake.

If plasma or urine porphyrin testing is not readily available, a good first step is a Wood lamp exam.

Two therapeutic options are available for treating PCT—whether it’s sporadic or familial. Phlebotomy sessions reduce iron overload and iron depletion and may prevent the formation of a porphomethene inhibitor of UROD. The other treatment option is antimalarial agents—usually hydroxychloroquine— and is indicated for patients with lower serum ferritin levels.^1-4 In patients with HCV-associated PCT, effective treatment of the infection has resulted in resolution of the PCT, in some cases.³

Treatment involving phlebotomy or an antimalarial agent can be stopped when plasma porphyrins reach normal levels.

Our patient was initially managed with 2 sessions of phlebotomy. He subsequently received treatment for the HCV infection at another hospital.

A 55-YEAR-OLD MAN with hypertension and untreated hepatitis C virus (HCV) was referred to the Dermatology Clinic after reporting a 2-year history of photosensitivity and intermittent episodes of blistering and scars on the dorsal side of his hands and feet. No alcohol consumption or drug use was reported.

Physical examination revealed small and shallow erosions on the dorsal aspect of the hands and feet (but no visible blisters) and milium cysts (FIGURE 1A). Additionally, hypertrichosis and hyperpigmentation were observed in the zygomatic areas (FIGURE 1B). Complete blood count and kidney function test results were within normal ranges. Liver function tests showed slightly elevated levels of alanine aminotransferase (79 U/L; normal range, 0-41 U/L), aspartate aminotransferase (62 U/L; normal range, 0-40 U/L), and ferritin (121 ng/mL; normal range, 30-100 ng/mL). Serologies for syphilis, HIV, and hepatitis B virus were negative.

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

The clinical presentation, along with the elevated laboratory values, suggested that this might be a case of porphyria cutanea tarda (PCT). Therefore, a sample of the patient’s urine was examined under Wood lamp and compared to a sample from a healthy control. In the sample of urine from our patient, a vivid red-pink fluorescence could be visualized under the lamp (FIGURE 2), confirming the diagnosis.

The porphyrias are a group of metabolic diseases that affect the heme biosynthesis. They can be classified into 1 of 3 groups, according to clinical features:

• acute hepatic porphyrias, with neurovisceral symptoms (eg, acute intermittent porphyria),
• nonblistering cutaneous porphyrias, with severe photosensitivity but without bullae formation (eg, erythropoietic protoporphyria), or
• blistering cutaneous porphyrias (eg, PCT, hepatoerythropoietic porphyria, and variegate porphyria).

PCT is the most common type of porphyria, with a global prevalence of 1 per 10,000 people.^1,2 It affects adults after the third or fourth decade of life.

Porphyria cutanea tarda has a global prevalance of 1 per 10,000 people.

PCT involves dysfunction of the uroporphyrinogen decarboxylase enzyme (UROD), the fifth enzyme in heme biosynthesis, which catalyzes the conversion of uroporphyrinogen to coproporphyrinogen. This dysfunction causes the accumulation of porphyrinogens that are auto-oxidized to photosensitizing porphyrins.^1-4 PCT can be classified as “sporadic” or “familial” based on the absence or presence of UROD mutation. Approximately 80% of cases of PCT are sporadic.²

In sporadic PCT, triggers for UROD dysfunction include alcohol use, use of estrogens, hemochromatosis or iron overload, chronic HCV infection, and HIV infection.^1-4 HCV (which this patient had) is the most common infection associated with sporadic PCT, with a prevalence of about 50% among these patients.⁵

Continue to: Dermatologic manifestations of PCT

Dermatologic manifestations of PCT include photosensitivity, skin fragility, vesicles, bullae, erosions, and crusts observed in sun-exposed areas. A nonvirilizing type of hypertrichosis may appear prominently on the temples and the cheeks.^2-4 After blisters rupture, atrophy and scarring occur. Milia cysts can form on the dorsal side of the hands and fingers. Less common manifestations include pruritus, scarring alopecia, sclerodermatous changes, and periorbital purple-red suffusion.

Hepatic involvement is demonstrated with elevated serum transaminases and ­gamma-glutamyl transpeptidase. Hepatomegaly is common, and cirrhosis manifests in 30% to 40% of patients.^2-5 On liver biopsy, some degree of siderosis is found in 80% of patients with PCT, and most of them have increased levels of serum iron. The incidence of hepatocellular carcinoma in patients with PCT is greater than in patients with other liver diseases.²

A Wood lamp can be a useful diagnostic first step

Plasma or urine porphyrin lab tests are the gold standard for PCT diagnosis. These tests can be followed by more specific tests (eg, porphyrin fractionation) to exclude other forms of porphyria. However, if plasma or urine porphyrin testing is not readily available, a good first step is a Wood lamp exam, which can be performed on urine or stool. (Plasma or urine porphyrin testing may ultimately be necessary if there is doubt about the diagnosis following the Wood lamp screening.) Histopathologic examination does not confirm the diagnosis of PCT⁴; however, it can be helpful in differential diagnosis.

Wood lamp is a source of long-wave UV light (320 to 400 nm), visualized as a purple or violet light. When porphyrins are present in a urine sample, a red-pink fluorescence may be seen.^3,4,6 The Wood lamp examination should be performed in a completely dark room after the lamp has been warmed up for about 1 minute; time should be allowed for the clinician’s vision to adapt to the dark.⁶ There are no data regarding the sensitivity or specificity of the Wood lamp test in the diagnosis of PCT.

These conditions also cause skin fragility and photosensitivity

The differential diagnosis for PCT includes diseases that also cause skin fragility, blistering, or photosensitivity, such as pseudoporphyria, bullous systemic lupus erythematosus (SLE), and epidermolysis bullosa acquisita (EBA).³

Continue to: In pseudoporphyria

In pseudoporphyria, the clinical findings may be indistinguishable from PCT. Thus, the patient’s history will be especially important; suspect pseudoporphyria if the patient has a history of chronic renal failure or use of a photosensitizing drug.^1,3

Bullous SLE usually manifests with systemic involvement and widespread, tense bullae. Serologic investigation will demonstrate the presence of antinuclear antibodies in high titers (> 1:80), as well as other circulating autoantibodies.

Skin lesions of EBA usually manifest with skin fragility and noninflammatory tense bullae in traumatized skin, such as the extensor surfaces of the hands, feet, and fingers.

None of the above-mentioned diagnoses manifest with hypertrichosis or red-pink fluorescent urine on Wood lamp, and results of porphyrin studies would be normal.³

Address triggers, provide treatment

Once the diagnosis is confirmed, steps must be taken to avoid triggering factors, such as any alcohol consumption, use of estrogen, sun exposure (until plasma porphyrin levels are normal), and potential sources of excessive iron intake.

If plasma or urine porphyrin testing is not readily available, a good first step is a Wood lamp exam.

Two therapeutic options are available for treating PCT—whether it’s sporadic or familial. Phlebotomy sessions reduce iron overload and iron depletion and may prevent the formation of a porphomethene inhibitor of UROD. The other treatment option is antimalarial agents—usually hydroxychloroquine— and is indicated for patients with lower serum ferritin levels.^1-4 In patients with HCV-associated PCT, effective treatment of the infection has resulted in resolution of the PCT, in some cases.³

Treatment involving phlebotomy or an antimalarial agent can be stopped when plasma porphyrins reach normal levels.

Our patient was initially managed with 2 sessions of phlebotomy. He subsequently received treatment for the HCV infection at another hospital.

A 55-YEAR-OLD MAN with hypertension and untreated hepatitis C virus (HCV) was referred to the Dermatology Clinic after reporting a 2-year history of photosensitivity and intermittent episodes of blistering and scars on the dorsal side of his hands and feet. No alcohol consumption or drug use was reported.

Physical examination revealed small and shallow erosions on the dorsal aspect of the hands and feet (but no visible blisters) and milium cysts (FIGURE 1A). Additionally, hypertrichosis and hyperpigmentation were observed in the zygomatic areas (FIGURE 1B). Complete blood count and kidney function test results were within normal ranges. Liver function tests showed slightly elevated levels of alanine aminotransferase (79 U/L; normal range, 0-41 U/L), aspartate aminotransferase (62 U/L; normal range, 0-40 U/L), and ferritin (121 ng/mL; normal range, 30-100 ng/mL). Serologies for syphilis, HIV, and hepatitis B virus were negative.

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

The clinical presentation, along with the elevated laboratory values, suggested that this might be a case of porphyria cutanea tarda (PCT). Therefore, a sample of the patient’s urine was examined under Wood lamp and compared to a sample from a healthy control. In the sample of urine from our patient, a vivid red-pink fluorescence could be visualized under the lamp (FIGURE 2), confirming the diagnosis.

The porphyrias are a group of metabolic diseases that affect the heme biosynthesis. They can be classified into 1 of 3 groups, according to clinical features:

• acute hepatic porphyrias, with neurovisceral symptoms (eg, acute intermittent porphyria),
• nonblistering cutaneous porphyrias, with severe photosensitivity but without bullae formation (eg, erythropoietic protoporphyria), or
• blistering cutaneous porphyrias (eg, PCT, hepatoerythropoietic porphyria, and variegate porphyria).

PCT is the most common type of porphyria, with a global prevalence of 1 per 10,000 people.^1,2 It affects adults after the third or fourth decade of life.

Porphyria cutanea tarda has a global prevalance of 1 per 10,000 people.

PCT involves dysfunction of the uroporphyrinogen decarboxylase enzyme (UROD), the fifth enzyme in heme biosynthesis, which catalyzes the conversion of uroporphyrinogen to coproporphyrinogen. This dysfunction causes the accumulation of porphyrinogens that are auto-oxidized to photosensitizing porphyrins.^1-4 PCT can be classified as “sporadic” or “familial” based on the absence or presence of UROD mutation. Approximately 80% of cases of PCT are sporadic.²

In sporadic PCT, triggers for UROD dysfunction include alcohol use, use of estrogens, hemochromatosis or iron overload, chronic HCV infection, and HIV infection.^1-4 HCV (which this patient had) is the most common infection associated with sporadic PCT, with a prevalence of about 50% among these patients.⁵

Continue to: Dermatologic manifestations of PCT

Dermatologic manifestations of PCT include photosensitivity, skin fragility, vesicles, bullae, erosions, and crusts observed in sun-exposed areas. A nonvirilizing type of hypertrichosis may appear prominently on the temples and the cheeks.^2-4 After blisters rupture, atrophy and scarring occur. Milia cysts can form on the dorsal side of the hands and fingers. Less common manifestations include pruritus, scarring alopecia, sclerodermatous changes, and periorbital purple-red suffusion.

Hepatic involvement is demonstrated with elevated serum transaminases and ­gamma-glutamyl transpeptidase. Hepatomegaly is common, and cirrhosis manifests in 30% to 40% of patients.^2-5 On liver biopsy, some degree of siderosis is found in 80% of patients with PCT, and most of them have increased levels of serum iron. The incidence of hepatocellular carcinoma in patients with PCT is greater than in patients with other liver diseases.²

A Wood lamp can be a useful diagnostic first step

Plasma or urine porphyrin lab tests are the gold standard for PCT diagnosis. These tests can be followed by more specific tests (eg, porphyrin fractionation) to exclude other forms of porphyria. However, if plasma or urine porphyrin testing is not readily available, a good first step is a Wood lamp exam, which can be performed on urine or stool. (Plasma or urine porphyrin testing may ultimately be necessary if there is doubt about the diagnosis following the Wood lamp screening.) Histopathologic examination does not confirm the diagnosis of PCT⁴; however, it can be helpful in differential diagnosis.

Wood lamp is a source of long-wave UV light (320 to 400 nm), visualized as a purple or violet light. When porphyrins are present in a urine sample, a red-pink fluorescence may be seen.^3,4,6 The Wood lamp examination should be performed in a completely dark room after the lamp has been warmed up for about 1 minute; time should be allowed for the clinician’s vision to adapt to the dark.⁶ There are no data regarding the sensitivity or specificity of the Wood lamp test in the diagnosis of PCT.

These conditions also cause skin fragility and photosensitivity

The differential diagnosis for PCT includes diseases that also cause skin fragility, blistering, or photosensitivity, such as pseudoporphyria, bullous systemic lupus erythematosus (SLE), and epidermolysis bullosa acquisita (EBA).³

Continue to: In pseudoporphyria

In pseudoporphyria, the clinical findings may be indistinguishable from PCT. Thus, the patient’s history will be especially important; suspect pseudoporphyria if the patient has a history of chronic renal failure or use of a photosensitizing drug.^1,3

Bullous SLE usually manifests with systemic involvement and widespread, tense bullae. Serologic investigation will demonstrate the presence of antinuclear antibodies in high titers (> 1:80), as well as other circulating autoantibodies.

Skin lesions of EBA usually manifest with skin fragility and noninflammatory tense bullae in traumatized skin, such as the extensor surfaces of the hands, feet, and fingers.

None of the above-mentioned diagnoses manifest with hypertrichosis or red-pink fluorescent urine on Wood lamp, and results of porphyrin studies would be normal.³

Address triggers, provide treatment

Once the diagnosis is confirmed, steps must be taken to avoid triggering factors, such as any alcohol consumption, use of estrogen, sun exposure (until plasma porphyrin levels are normal), and potential sources of excessive iron intake.

If plasma or urine porphyrin testing is not readily available, a good first step is a Wood lamp exam.

Two therapeutic options are available for treating PCT—whether it’s sporadic or familial. Phlebotomy sessions reduce iron overload and iron depletion and may prevent the formation of a porphomethene inhibitor of UROD. The other treatment option is antimalarial agents—usually hydroxychloroquine— and is indicated for patients with lower serum ferritin levels.^1-4 In patients with HCV-associated PCT, effective treatment of the infection has resulted in resolution of the PCT, in some cases.³

Treatment involving phlebotomy or an antimalarial agent can be stopped when plasma porphyrins reach normal levels.

Our patient was initially managed with 2 sessions of phlebotomy. He subsequently received treatment for the HCV infection at another hospital.

ILLUSTRATIVE CASE

You are seeing a 2-month-old female infant for a routine well-child visit. The birth history was unremarkable. The infant is meeting appropriate developmental milestones. Growth is appropriate at the 40th percentile. The infant is exclusively breastfed. The parents report that they have heard confusing information about when to introduce solid foods, including bread, to their child’s diet. There is no known family history of CD. What anticipatory guidance can you offer regarding gluten introduction and the risk of CD?

CD is an inflammatory disease of the small intestine caused by an immune-based reaction to dietary gluten. The worldwide incidence of CD in children younger than 15 years is 21.3 per 100,000 person-years; this incidence has increased by 7.5% per year over the past several decades.² CD has a range of both gastrointestinal and nongastrointestinal manifestations, including diarrhea, weight loss, abdominal pain, abnormal liver function test results, and iron deficiency anemia.

Diagnosis of CD in adults is based on a combination of clinical symptoms, elevated levels of immunoglobulin A anti-tissue transglutaminase antibody (tTG-IgA), and biopsy-confirmed villous atrophy of the duodenum on upper endoscopy.³ European pediatric guidelines suggest that use of certain criteria, including very high results of tTG-IgA antibody testing (> 10 times the upper limit of normal), can help to avoid endoscopic biopsies and/or human leukocyte antigens (HLA) testing for diagnosis in children.⁴

The mainstay of CD management is strict adherence to a gluten-free diet.³ Because this can be difficult, and yield an incomplete disease response, emphasis has been placed on primary prevention by modifying introduction of dietary gluten. Multiple prior studies examining the risk of CD have failed to demonstrate a significant association between timing of gluten introduction and development of CD among high-risk infants (eg, those with HLA-DR3 alleles or first-degree relatives with CD or type 1 diabetes).^5-7 A 2016 meta-analysis concluded that there was not enough evidence to support early introduction of gluten (at 4-6 months).⁸ RCTs have not previously been conducted to examine the timing of gluten introduction on CD prevalence for infants at average risk, using age-appropriate doses of gluten prior to age 6 months.

Current dietary guidelines in the United States and the United Kingdom recommend introduction of nutrient-dense foods, including potentially allergenic foods, at about age 6 months to complement human milk or infant formula feedings.^9,10 These guidelines do not specify the exact timing or quantity of gluten- containing food introduction for infants. A 2016 position paper by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition indicated that gluten could be introduced into the infant’s diet any time between 4 and 12 months. They did indicate that the amount of gluten introduced into the diet should be low to start and then increased, and that infants at high risk for CD should wait longer for gluten introduction (4 vs 6 months or 6 vs 12 months).¹¹

STUDY SUMMARY

Gluten introduced at 4 months may be linked to lower occurrence of CD

The Enquiring About Tolerance (EAT) Study was an open-label RCT (N = 1303) with children from the general population in England and Wales. The EAT Study sought to test the prevention of food allergy by introducing allergenic foods to infants at age 4 months compared with exclusively breastfeeding until age 6 months. The median age at enrollment was 3.4 months, but allergenic food was not started until age 4 months.^1,12 Most patients were White (84.%-85.4%) and lived in an urban area (77.3%-77.4%). The mean gestational age at delivery was 39.7 to 39.9 weeks.¹²

Infants were exclusively breastfed until age 13 weeks, at which time they were randomized into an early introduction group (EIG) or a standard introduction group (SIG). In addition to breast milk, infants in the EIG consumed 6 allergenic foods (peanut, sesame, hen’s egg, cow’s milk, cod fish, and wheat [gluten]) in a specified pattern per protocol, starting at age 4 months. Wheat (gluten) was introduced during Week 5 of the EIG protocol (median age, 20.6 weeks).¹² The recommended minimum dose of gluten was 3.2 g/wk from age 16 weeks, or 4 g/wk of wheat protein (given as 2 cereal biscuits or the equivalent). Infants in the SIG avoided allergenic foods, following UK infant feeding recommendations for exclusive breastfeeding until about age 6 months. The EIG had a significantly higher rate of cesarean births than the SIG, but the study groups were otherwise balanced.¹³

Continue to: Families completed monthly...

Families completed monthly questionnaires on infant gluten intake and symptoms (eg, gastrointestinal, fatigue) through age 1 year, and then every 3 months through age 3 years. All children were tested for anti-transglutaminase type 2 (anti-TG2) antibodies at age 3 years as a screen for CD. Children with antibody levels > 20 IU/L were referred to independent gastroenterologists for further evaluation, which could include HLA (DQ-2/DQ-8) testing and biopsy in accordance with current European diagnostic guidelines.⁴

Introducing gluten as a complement to breast milk or infant formula from age 4 months may reduce the risk of celiac disease at age 3 years.

In an intention-to-treat analysis for the primary outcome, 595 children in the SIG (91.4%) and 567 in the EIG (87.0%) were included. Between ages 4 and 6 months, the mean (SD) quantity of gluten consumed in the SIG was 0.49 (1.40) g/wk; in the EIG, the mean quantity was 2.66 (1.85) g/wk (P < .001). At age 3 years, of a total of 1004 children tested for anti-TG2 antibodies, 9 had anti-TG2 levels requiring referral (7 in the SIG and 2 in the EIG). A diagnosis of CD was confirmed in 7 of 516 children in the SIG (1.4%) vs none of the 488 children in the EIG (P = .02). Using bootstrap resampling, the risk difference between the groups was 1.4% (95% CI, 0.6%-2.6%).

WHAT’S NEW

Findings have potential to change nutritional guidance

This study demonstrated that introduction of age-appropriate portions of gluten-containing products at age 4 months, in addition to breast milk, may reduce the risk of CD at 3 years in children at average risk. This finding has the potential to change anticipatory guidance given to parents regarding infant nutrition recommendations.

CAVEATS

More studies needed to confirm prevention vs delay of CD

The homogeneous study population may limit generalizability. Infants in this study were from England and Wales (84.3% were White), born at term, and were exclusively breastfed until age 13 weeks. Further studies are required to determine whether these findings can be applied to infants who are no longer breastfeeding, are more racially diverse, or are preterm in gestational age at birth. Additionally, the study followed the participants only until age 3 years. Given that the onset of CD after this age is likely, further research is needed to support that CD is truly prevented rather than delayed.

CHALLENGES TO IMPLEMENTATION

Guidance on allergen introduction may be unclear

The EAT Study protocol required parents in the EIG to sequentially introduce a minimum amount of the 6 allergenic foods specified. Only 42% of the EIG cohort reported adherence to the protocol.¹² It is unclear how important this specific regimen is to the study results and whether introduction of all 6 allergenic foods simultaneously modifies the immune response to gluten. Therefore, there may be challenges to implementation if physicians do not know how to provide anticipatory guidance on the appropriate steps for allergen introduction.

ILLUSTRATIVE CASE

You are seeing a 2-month-old female infant for a routine well-child visit. The birth history was unremarkable. The infant is meeting appropriate developmental milestones. Growth is appropriate at the 40th percentile. The infant is exclusively breastfed. The parents report that they have heard confusing information about when to introduce solid foods, including bread, to their child’s diet. There is no known family history of CD. What anticipatory guidance can you offer regarding gluten introduction and the risk of CD?

CD is an inflammatory disease of the small intestine caused by an immune-based reaction to dietary gluten. The worldwide incidence of CD in children younger than 15 years is 21.3 per 100,000 person-years; this incidence has increased by 7.5% per year over the past several decades.² CD has a range of both gastrointestinal and nongastrointestinal manifestations, including diarrhea, weight loss, abdominal pain, abnormal liver function test results, and iron deficiency anemia.

Diagnosis of CD in adults is based on a combination of clinical symptoms, elevated levels of immunoglobulin A anti-tissue transglutaminase antibody (tTG-IgA), and biopsy-confirmed villous atrophy of the duodenum on upper endoscopy.³ European pediatric guidelines suggest that use of certain criteria, including very high results of tTG-IgA antibody testing (> 10 times the upper limit of normal), can help to avoid endoscopic biopsies and/or human leukocyte antigens (HLA) testing for diagnosis in children.⁴

The mainstay of CD management is strict adherence to a gluten-free diet.³ Because this can be difficult, and yield an incomplete disease response, emphasis has been placed on primary prevention by modifying introduction of dietary gluten. Multiple prior studies examining the risk of CD have failed to demonstrate a significant association between timing of gluten introduction and development of CD among high-risk infants (eg, those with HLA-DR3 alleles or first-degree relatives with CD or type 1 diabetes).^5-7 A 2016 meta-analysis concluded that there was not enough evidence to support early introduction of gluten (at 4-6 months).⁸ RCTs have not previously been conducted to examine the timing of gluten introduction on CD prevalence for infants at average risk, using age-appropriate doses of gluten prior to age 6 months.

Current dietary guidelines in the United States and the United Kingdom recommend introduction of nutrient-dense foods, including potentially allergenic foods, at about age 6 months to complement human milk or infant formula feedings.^9,10 These guidelines do not specify the exact timing or quantity of gluten- containing food introduction for infants. A 2016 position paper by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition indicated that gluten could be introduced into the infant’s diet any time between 4 and 12 months. They did indicate that the amount of gluten introduced into the diet should be low to start and then increased, and that infants at high risk for CD should wait longer for gluten introduction (4 vs 6 months or 6 vs 12 months).¹¹

STUDY SUMMARY

Gluten introduced at 4 months may be linked to lower occurrence of CD

The Enquiring About Tolerance (EAT) Study was an open-label RCT (N = 1303) with children from the general population in England and Wales. The EAT Study sought to test the prevention of food allergy by introducing allergenic foods to infants at age 4 months compared with exclusively breastfeeding until age 6 months. The median age at enrollment was 3.4 months, but allergenic food was not started until age 4 months.^1,12 Most patients were White (84.%-85.4%) and lived in an urban area (77.3%-77.4%). The mean gestational age at delivery was 39.7 to 39.9 weeks.¹²

Infants were exclusively breastfed until age 13 weeks, at which time they were randomized into an early introduction group (EIG) or a standard introduction group (SIG). In addition to breast milk, infants in the EIG consumed 6 allergenic foods (peanut, sesame, hen’s egg, cow’s milk, cod fish, and wheat [gluten]) in a specified pattern per protocol, starting at age 4 months. Wheat (gluten) was introduced during Week 5 of the EIG protocol (median age, 20.6 weeks).¹² The recommended minimum dose of gluten was 3.2 g/wk from age 16 weeks, or 4 g/wk of wheat protein (given as 2 cereal biscuits or the equivalent). Infants in the SIG avoided allergenic foods, following UK infant feeding recommendations for exclusive breastfeeding until about age 6 months. The EIG had a significantly higher rate of cesarean births than the SIG, but the study groups were otherwise balanced.¹³

Continue to: Families completed monthly...

Families completed monthly questionnaires on infant gluten intake and symptoms (eg, gastrointestinal, fatigue) through age 1 year, and then every 3 months through age 3 years. All children were tested for anti-transglutaminase type 2 (anti-TG2) antibodies at age 3 years as a screen for CD. Children with antibody levels > 20 IU/L were referred to independent gastroenterologists for further evaluation, which could include HLA (DQ-2/DQ-8) testing and biopsy in accordance with current European diagnostic guidelines.⁴

Introducing gluten as a complement to breast milk or infant formula from age 4 months may reduce the risk of celiac disease at age 3 years.

In an intention-to-treat analysis for the primary outcome, 595 children in the SIG (91.4%) and 567 in the EIG (87.0%) were included. Between ages 4 and 6 months, the mean (SD) quantity of gluten consumed in the SIG was 0.49 (1.40) g/wk; in the EIG, the mean quantity was 2.66 (1.85) g/wk (P < .001). At age 3 years, of a total of 1004 children tested for anti-TG2 antibodies, 9 had anti-TG2 levels requiring referral (7 in the SIG and 2 in the EIG). A diagnosis of CD was confirmed in 7 of 516 children in the SIG (1.4%) vs none of the 488 children in the EIG (P = .02). Using bootstrap resampling, the risk difference between the groups was 1.4% (95% CI, 0.6%-2.6%).

WHAT’S NEW

Findings have potential to change nutritional guidance

This study demonstrated that introduction of age-appropriate portions of gluten-containing products at age 4 months, in addition to breast milk, may reduce the risk of CD at 3 years in children at average risk. This finding has the potential to change anticipatory guidance given to parents regarding infant nutrition recommendations.

CAVEATS

More studies needed to confirm prevention vs delay of CD

The homogeneous study population may limit generalizability. Infants in this study were from England and Wales (84.3% were White), born at term, and were exclusively breastfed until age 13 weeks. Further studies are required to determine whether these findings can be applied to infants who are no longer breastfeeding, are more racially diverse, or are preterm in gestational age at birth. Additionally, the study followed the participants only until age 3 years. Given that the onset of CD after this age is likely, further research is needed to support that CD is truly prevented rather than delayed.

CHALLENGES TO IMPLEMENTATION

Guidance on allergen introduction may be unclear

The EAT Study protocol required parents in the EIG to sequentially introduce a minimum amount of the 6 allergenic foods specified. Only 42% of the EIG cohort reported adherence to the protocol.¹² It is unclear how important this specific regimen is to the study results and whether introduction of all 6 allergenic foods simultaneously modifies the immune response to gluten. Therefore, there may be challenges to implementation if physicians do not know how to provide anticipatory guidance on the appropriate steps for allergen introduction.

ILLUSTRATIVE CASE

You are seeing a 2-month-old female infant for a routine well-child visit. The birth history was unremarkable. The infant is meeting appropriate developmental milestones. Growth is appropriate at the 40th percentile. The infant is exclusively breastfed. The parents report that they have heard confusing information about when to introduce solid foods, including bread, to their child’s diet. There is no known family history of CD. What anticipatory guidance can you offer regarding gluten introduction and the risk of CD?

CD is an inflammatory disease of the small intestine caused by an immune-based reaction to dietary gluten. The worldwide incidence of CD in children younger than 15 years is 21.3 per 100,000 person-years; this incidence has increased by 7.5% per year over the past several decades.² CD has a range of both gastrointestinal and nongastrointestinal manifestations, including diarrhea, weight loss, abdominal pain, abnormal liver function test results, and iron deficiency anemia.

Diagnosis of CD in adults is based on a combination of clinical symptoms, elevated levels of immunoglobulin A anti-tissue transglutaminase antibody (tTG-IgA), and biopsy-confirmed villous atrophy of the duodenum on upper endoscopy.³ European pediatric guidelines suggest that use of certain criteria, including very high results of tTG-IgA antibody testing (> 10 times the upper limit of normal), can help to avoid endoscopic biopsies and/or human leukocyte antigens (HLA) testing for diagnosis in children.⁴

The mainstay of CD management is strict adherence to a gluten-free diet.³ Because this can be difficult, and yield an incomplete disease response, emphasis has been placed on primary prevention by modifying introduction of dietary gluten. Multiple prior studies examining the risk of CD have failed to demonstrate a significant association between timing of gluten introduction and development of CD among high-risk infants (eg, those with HLA-DR3 alleles or first-degree relatives with CD or type 1 diabetes).^5-7 A 2016 meta-analysis concluded that there was not enough evidence to support early introduction of gluten (at 4-6 months).⁸ RCTs have not previously been conducted to examine the timing of gluten introduction on CD prevalence for infants at average risk, using age-appropriate doses of gluten prior to age 6 months.

Current dietary guidelines in the United States and the United Kingdom recommend introduction of nutrient-dense foods, including potentially allergenic foods, at about age 6 months to complement human milk or infant formula feedings.^9,10 These guidelines do not specify the exact timing or quantity of gluten- containing food introduction for infants. A 2016 position paper by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition indicated that gluten could be introduced into the infant’s diet any time between 4 and 12 months. They did indicate that the amount of gluten introduced into the diet should be low to start and then increased, and that infants at high risk for CD should wait longer for gluten introduction (4 vs 6 months or 6 vs 12 months).¹¹

STUDY SUMMARY

Gluten introduced at 4 months may be linked to lower occurrence of CD

The Enquiring About Tolerance (EAT) Study was an open-label RCT (N = 1303) with children from the general population in England and Wales. The EAT Study sought to test the prevention of food allergy by introducing allergenic foods to infants at age 4 months compared with exclusively breastfeeding until age 6 months. The median age at enrollment was 3.4 months, but allergenic food was not started until age 4 months.^1,12 Most patients were White (84.%-85.4%) and lived in an urban area (77.3%-77.4%). The mean gestational age at delivery was 39.7 to 39.9 weeks.¹²

Infants were exclusively breastfed until age 13 weeks, at which time they were randomized into an early introduction group (EIG) or a standard introduction group (SIG). In addition to breast milk, infants in the EIG consumed 6 allergenic foods (peanut, sesame, hen’s egg, cow’s milk, cod fish, and wheat [gluten]) in a specified pattern per protocol, starting at age 4 months. Wheat (gluten) was introduced during Week 5 of the EIG protocol (median age, 20.6 weeks).¹² The recommended minimum dose of gluten was 3.2 g/wk from age 16 weeks, or 4 g/wk of wheat protein (given as 2 cereal biscuits or the equivalent). Infants in the SIG avoided allergenic foods, following UK infant feeding recommendations for exclusive breastfeeding until about age 6 months. The EIG had a significantly higher rate of cesarean births than the SIG, but the study groups were otherwise balanced.¹³

Continue to: Families completed monthly...

Families completed monthly questionnaires on infant gluten intake and symptoms (eg, gastrointestinal, fatigue) through age 1 year, and then every 3 months through age 3 years. All children were tested for anti-transglutaminase type 2 (anti-TG2) antibodies at age 3 years as a screen for CD. Children with antibody levels > 20 IU/L were referred to independent gastroenterologists for further evaluation, which could include HLA (DQ-2/DQ-8) testing and biopsy in accordance with current European diagnostic guidelines.⁴

Introducing gluten as a complement to breast milk or infant formula from age 4 months may reduce the risk of celiac disease at age 3 years.

In an intention-to-treat analysis for the primary outcome, 595 children in the SIG (91.4%) and 567 in the EIG (87.0%) were included. Between ages 4 and 6 months, the mean (SD) quantity of gluten consumed in the SIG was 0.49 (1.40) g/wk; in the EIG, the mean quantity was 2.66 (1.85) g/wk (P < .001). At age 3 years, of a total of 1004 children tested for anti-TG2 antibodies, 9 had anti-TG2 levels requiring referral (7 in the SIG and 2 in the EIG). A diagnosis of CD was confirmed in 7 of 516 children in the SIG (1.4%) vs none of the 488 children in the EIG (P = .02). Using bootstrap resampling, the risk difference between the groups was 1.4% (95% CI, 0.6%-2.6%).

WHAT’S NEW

Findings have potential to change nutritional guidance

This study demonstrated that introduction of age-appropriate portions of gluten-containing products at age 4 months, in addition to breast milk, may reduce the risk of CD at 3 years in children at average risk. This finding has the potential to change anticipatory guidance given to parents regarding infant nutrition recommendations.

CAVEATS

More studies needed to confirm prevention vs delay of CD

The homogeneous study population may limit generalizability. Infants in this study were from England and Wales (84.3% were White), born at term, and were exclusively breastfed until age 13 weeks. Further studies are required to determine whether these findings can be applied to infants who are no longer breastfeeding, are more racially diverse, or are preterm in gestational age at birth. Additionally, the study followed the participants only until age 3 years. Given that the onset of CD after this age is likely, further research is needed to support that CD is truly prevented rather than delayed.

CHALLENGES TO IMPLEMENTATION

Guidance on allergen introduction may be unclear

The EAT Study protocol required parents in the EIG to sequentially introduce a minimum amount of the 6 allergenic foods specified. Only 42% of the EIG cohort reported adherence to the protocol.¹² It is unclear how important this specific regimen is to the study results and whether introduction of all 6 allergenic foods simultaneously modifies the immune response to gluten. Therefore, there may be challenges to implementation if physicians do not know how to provide anticipatory guidance on the appropriate steps for allergen introduction.

CASE

A 35-year-old man arrives for an annual wellness visit with no specific complaints and no significant personal or family history. His normal exam includes a blood pressure of 110/74 mm Hg and a body mass index (BMI) of 23.6. You order “routine labs” for prevention, which include a comprehensive metabolic panel (CMP), fasting lipid profile, and thyroid-stimulating hormone (TSH) and 25(OH) vitamin D tests. Are you practicing value-based laboratory testing?

The answer to this question appears in the Case discussion at the end of the article.

Value-based care, including care provided through laboratory testing, can achieve the Institute for Healthcare Improvement’s Triple Aim of improving population health, improving the patient experience of care (including quality and satisfaction), and reducing cost: Value = (Quality x Patient experience) / Cost.¹

As quality and patient experience rise and cost falls, the value of care increases. Unnecessary lab testing, however, can negatively impact this equation:

• Error introduced by unnecessary testing can adversely affect quality.
• Patients experience inconvenience and sometimes cascades of testing, in addition to financial responsibility, from unnecessary testing.
• Low-value testing also contributes to work burden and provider burnout by requiring additional review and follow-up.

Rising health care costs are approaching 18% of the US gross domestic product, driven in large part by a wasteful and inefficient care delivery system.² One review of “waste domains” identified by the Institute of Medicine estimates that approximately one-quarter of health care costs represent waste, including overtreatment, breakdowns of care coordination, and pricing that fails to correlate to the level of care received.³ High-volume, low-cost testing contributes more to total cost than low-volume, high-cost tests.⁴

Provider and system factors that contribute to ongoing waste

A lack of awareness of waste and how to reduce it contribute to the problem, as does an underappreciation of the harmful effects caused by incidental abnormal results.

Provider intolerance of diagnostic uncertainty often leads to ordering even more tests.

Continue to: Also, a hope of avoiding...

Do not order tests just to reassure the patient; unnecessary tests with insignificant results do little to reduce patient anxiety.

Also, a hope of avoiding missed diagnoses and potential lawsuits leads to defensive practice and more testing. In addition, patients and family members can exert pressure based on a belief that more testing represents better care. Of course, financial revenues from testing may come into play, with few disincentives to forgo testing. Something that also comes into play is that evidence-based guidance on cost-­effective laboratory testing may be lacking, or there may be a lack of knowledge on how to access existing evidence.

Automated systems can facilitate wasteful laboratory testing, and the heavy testing practices of hospitals and specialists may be inappropriately applied to outpatient primary care.

Factors affecting the cost of laboratory testing

Laboratory test results drive 70% of today’s medical decisions.⁵ Negotiated insurance payment for tests is usually much less than the direct out-of-pocket costs charged to the patient. Without insurance, lab tests can cost patients between $100 and $1000.⁶ If multiple tests are ordered, the costs could likely be many thousands of dollars.

Actual costs typically vary by the testing facility, the patient’s health plan, and location in the United States; hospital-based testing tends to be the most expensive. Insurers will pay for lab tests with appropriate indications that are covered in the contract with the provider.⁶

Choosing Wisely initiative weighs in on lab testing

Choosing Wisely, a prominent initiative of the American Board of Internal Medicine Foundation, promotes appropriate resource utilization through educational campaigns that detail how to avoid unnecessary medical tests, treatments, and procedures.⁷ Recommendations are based largely on specialty society consensus and disease-oriented evidence. Choosing Wisely recommendations advise against the following⁷:

• performing laboratory blood testing unless clinically indicated or necessary for diagnosis or management, in order to avoid iatrogenic anemia. (American Academy of Family Physicians; Society for the Advancement of Patient Blood Management)
• requesting just a serum creatinine to test adult patients with diabetes and/or hypertension for chronic kidney disease. Use the kidney profile: serum creatinine with estimated glomerular filtration rate and urinary albumin-creatinine ratio. (American Society for Clinical Pathology)
• routinely screening for prostate cancer using a prostate-specific antigen test. It should be performed only after engaging in shared decision-making with the patient. (American Academy of Family Physicians; American Urological Association)
• screening for genital herpes simplex virus infectionFrutiger LT Std in asymptomatic adults, including pregnant women. (American Academy of Family Physicians)
• performing preoperative medical tests for eye surgery unless there are specific medical indications. (American Academy of Ophthalmology)

Sequential steps to takefor value-based lab ordering

Ask the question: “How will ordering this specific test change the management of my patient?” From there, take sequential steps using sound, evidence-based pathways. Morgan and colleagues⁸ outline the following practical approaches to rational test ordering:

• Perform a thorough clinical assessment.
• Consider the probability and implications of a positive test result.
• Practice patient-centered communication: address the patient’s concerns and discuss the risks and benefits of tests and how they will influence management.
• Follow clinical guidelines when available.
• Avoid ordering tests to reassure the patient; unnecessary tests with insignificant results do little to reduce patient anxieties.
• Avoid letting uncertainty drive unnecessary testing. Watchful waiting can allow time for the illness to resolve or declare itself.

Let’s consider this approach in the context of 4 areas: preventive care, diagnostic evaluation, ongoing management of chronic conditions, and preoperative testing.

Continue to: Preventive guidance from the USPSTF

An independent volunteer panel of 16 national experts in prevention and evidence-based medicine develop recommendations for the US Preventive Services Task Force (USPSTF).⁹ These guidelines are based on evidence and are updated as new evidence surfaces. Thirteen recommendations, some of which advise avoiding preventive procedures that could cause harm to patients, cover laboratory tests used in screening for conditions such as hyperlipidemia¹⁰ and prostate cancer.¹¹ We review the ones pertinent to our patient later at the end of the Case.

While the target audience for USPSTF recommendations is clinicians who provide preventive care, the recommendations are widely followed by policymakers, managed care organizations, public and private payers, quality improvement organizations, research institutions, and patients.

Take a critical look at how you approach the diagnostic evaluation

To reduce unnecessary testing in the diagnostic evaluation of patients, first consider pretest probability, test sensitivity and specificity, narrowly out-of-range tests, habitually paired tests, and repetitive laboratory testing.

Pretest probability, and test sensitivity and specificity. Pretest probability is the estimated chance that the patient has the disease before the test result is known. In a patient with low pretest probability of a disease, the ability to conclusively arrive at the diagnosis with one positive result is limited. Similarly, for tests in patients with high pretest probability of disease, a negative test cannot be used to firmly rule out a diagnosis.¹²

Reliability also depends on test sensitivity (the proportion of true positive results) and specificity (the proportion of true negative results). A test with high sensitivity but low specificity will generate more false-positive results, with potential harm to patients who do not have a disease.

Reflexively ordering tests together (eg, C-reactive protein with erythrocyte sedimentation rate) often contributes to unnecessary testing.

The pretest probability along with test sensitivity and specificity help a clinician to interpret a test result, and even decide whether to order the test at all. For example, the anti-nuclear antibody (ANA) test for systemic lupus erythematosus (SLE) has a sensitivity of 100% and a specificity of 86%¹³; it will always be positive in a patient with SLE. But when applied to individuals with low likelihood of SLE, false-positives are more common; the ANA is falsely positive in up to 14% of healthy individuals, depending on the population studied.¹³

Ordering a test may be unnecessary if the results will not change the treatment plan. For example, in a female patient with classic symptoms of an uncomplicated urinary tract infection, a urine culture and even a urinalysis may not change treatment.

Continue to: Narrowly out-of-range tests

Narrowly out-of-range tests. Test results that fall just outside the “normal” range may be of questionable significance. When an asymptomatic patient has mildly elevated liver enzymes, should additional tests be ordered to avoid missing a treatable disorder? In these scenarios, a history, including possible contributing factors such as alcohol or substance misuse, must be paired with the clinical presentation to assess pre-test probability of a particular condition.¹⁴ Repeating a narrowly out-of-range test is an option in patients when follow-up is possible. Alternatively, you could pursue watchful waiting and monitor a minor abnormality over time while being vigilant for clinical changes. This whole-patient approach will guide the decision of whether to order additional testing.

Habitually paired tests. Reflexively ordering tests together often contributes to unnecessary testing. Examples of commonly paired tests are serum lipase with amylase, C-reactive protein (CRP) with erythrocyte sedimentation rate (ESR), and TSH with free T4 to monitor patients with treated hypothyroidism. These tests add minimal value together and can be decoupled.^15-17 Evidence supports ordering serum lipase alone, CRP instead of ESR, and TSH alone for monitoring thyroid status.

Unnecessary routine preoperative testing and testing sequelae for cataract surgery was calculated to cost Medicare up to $45.4 million annually

Some commonly paired tests may not even be necessary for diagnosis. The well-established Rotterdam Criteria for diagnosing polycystic ovary syndrome specify clinical features and ovarian ultrasound for diagnosis.¹⁸ They do not require measurement of commonly ordered follicle-­stimulating hormone and luteinizing hormone for diagnosis.

Serial rather than parallel testing, a “2-step approach,” is a strategy made easier with the advent of the electronic medical record (EMR) and computerized lab systems.⁸ These records and lab systems allow providers to order reflex tests, and to add on additional tests, if necessary, to an existing blood specimen.

Repetitive laboratory testing. Repetitive inpatient laboratory testing in patients who are clinically stable is wasteful and potentially harmful. Interventions involving physician education alone show mixed results, but combining education with clinician audit and feedback, along with EMR-enabled restrictive ordering, have resulted in significant and sustained reductions in repetitive laboratory testing.¹⁹

Continue to: Ongoing management of chronic conditions

Ongoing management of chronic conditions

Evidence-based guidelines support choices of tests and testing intervals for ongoing management of chronic conditions such as diabetes, hyperlipidemia, and hypertension.

Diabetes. Guidelines also define quality standards that are applied to value-based contracts. For example, the American Diabetes Association recommends assessing A1C every 6 months in patients whose type 2 diabetes is under stable control.²⁰

Hyperlipidemia. For patients diagnosed with hyperlipidemia, 2018 clinical practice guidelines published by multiple specialty societies recommend assessing adherence and response to lifestyle changes and LDL-C–lowering medications with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed.²¹

Hypertension. With a new diagnosis of hypertension, guidelines advise an initial assessment for comorbidities and end-organ damage with an electrocardiogram, urinalysis, glucose level, blood count, electrolytes, creatinine, calcium, lipids, and urinary albumin/creatinine ratio. For ongoing monitoring, guidelines recommend assessment for end-organ damage through regular measurements of creatinine, glomerular filtration rate, and urinary microalbumin/creatinine ratio. Initiation and alteration of medications should prompt appropriate additional lab follow-up—eg, a measurement of serum potassium after starting a diuretic.²²

Preoperative testing

Preoperative testing is overused in low-risk, ambulatory surgery. And testing, even with abnormal results, does not affect postoperative outcomes.²³

Continue to: The American Society of Anesthesiologists (ASA) Physical Status Classification System

The American Society of Anesthesiologists (ASA) Physical Status Classification System, which has been in use for more than 60 years, considers the patient’s physical status (ASA grades I-VI),²⁴ and when paired with surgery grades of minor, intermediate, and major/complex, can help assess preoperative risk and guide preoperative testing (TABLE).^24-26

Preoperative medical testing did not reduce the risk of medical adverse events during or after cataract surgery when compared with selective or no testing.²⁷ Unnecessary preoperative testing can lead to a nonproductive cascade of additional investigations. In a 2018 study of Medicare beneficiaries, unnecessary routine preoperative testing and testing sequelae for cataract surgery was calculated to cost Medicare up to $45.4 million annually.²⁸

CASE

You would not be practicing value-based laboratory testing, according to the USPSTF, if you ordered a CMP, fasting lipid profile, and TSH and 25(OH) vitamin D tests for this healthy 35-year-old man whose family history, blood pressure, and BMI do not put him at elevated risk. Universal lipid screening (Grade B^a) is recommended for all adults ages 40 to 75. Thyroid screening tests and measurement of 25(OH) vitamin D level (I statements^a) are not recommended. The USPSTF has not evaluated chemistry panels for screening.

The USPSTF would recommend the following actions for this patient:

• Screen for HIV (ages 15 to 65 years; and younger or older if patient is at risk). (A recommendation^a,29)
• Screen for hepatitis C virus (in those ages 18 to 79). (B recommendation³⁰)

The following USPSTF recommendations might have come into play if this patient had certain risk factors, or if the patient had been a woman:

• Screen for diabetes if the patient is overweight or obese (B recommendation).
• Screen for hepatitis B in adults at risk (B recommendation).
• Screen for gonorrhea and chlamydia in women at risk (B recommendation). Such screening has an “I”statement for screening men at risk.

Continue to: As noted, costs of laboratory...

As noted, costs of laboratory testing vary widely, depending upon what tests are ordered, what type of insurance the patient has, and which tests the patient’s insurance covers. Who performs the testing also factors into the cost. Payers negotiate reduced fees for commercial lab testing, but potential out-of-­pocket costs to patients are much higher.

For our healthy 35-year-old man, the cost of the initially proposed testing (CMP, lipid panel, TSH, and 25[OH] vitamin D level) ranges from a negotiated payer cost of $85 to potential patient out-of-pocket cost of more than $400.⁶

Insurance would cover the USPSTF-­recommended testing (HIV and hepatitis C screening tests), which might incur only a patient co-pay, and cost the system about $65.

The USPSTF home page, found at www.uspreventiveservicestaskforce.org/uspstf/ includes recommendations that can be sorted for your patients. A web and mobile device application is also available through the website.

^a USPSTF grade definitions:

A: There is high certainty that the net benefit is substantial. Offer service.

B: There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial. Offer service.

C: There is at least moderate certainty that the net benefit is small. Offer service selectively.

D: There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Don’t offer service.

I: Current evidence is insufficient to assess the balance of benefits and harms of the service.

CORRESPONDENCE
Mitchell Kaminski, MD, MBA, 901 Walnut Street, 10th Floor, Jefferson College of Population Health, Philadelphia, PA 19107; [email protected]

CASE

A 35-year-old man arrives for an annual wellness visit with no specific complaints and no significant personal or family history. His normal exam includes a blood pressure of 110/74 mm Hg and a body mass index (BMI) of 23.6. You order “routine labs” for prevention, which include a comprehensive metabolic panel (CMP), fasting lipid profile, and thyroid-stimulating hormone (TSH) and 25(OH) vitamin D tests. Are you practicing value-based laboratory testing?

The answer to this question appears in the Case discussion at the end of the article.

Value-based care, including care provided through laboratory testing, can achieve the Institute for Healthcare Improvement’s Triple Aim of improving population health, improving the patient experience of care (including quality and satisfaction), and reducing cost: Value = (Quality x Patient experience) / Cost.¹

As quality and patient experience rise and cost falls, the value of care increases. Unnecessary lab testing, however, can negatively impact this equation:

• Error introduced by unnecessary testing can adversely affect quality.
• Patients experience inconvenience and sometimes cascades of testing, in addition to financial responsibility, from unnecessary testing.
• Low-value testing also contributes to work burden and provider burnout by requiring additional review and follow-up.

Rising health care costs are approaching 18% of the US gross domestic product, driven in large part by a wasteful and inefficient care delivery system.² One review of “waste domains” identified by the Institute of Medicine estimates that approximately one-quarter of health care costs represent waste, including overtreatment, breakdowns of care coordination, and pricing that fails to correlate to the level of care received.³ High-volume, low-cost testing contributes more to total cost than low-volume, high-cost tests.⁴

Provider and system factors that contribute to ongoing waste

A lack of awareness of waste and how to reduce it contribute to the problem, as does an underappreciation of the harmful effects caused by incidental abnormal results.

Provider intolerance of diagnostic uncertainty often leads to ordering even more tests.

Continue to: Also, a hope of avoiding...

Do not order tests just to reassure the patient; unnecessary tests with insignificant results do little to reduce patient anxiety.

Also, a hope of avoiding missed diagnoses and potential lawsuits leads to defensive practice and more testing. In addition, patients and family members can exert pressure based on a belief that more testing represents better care. Of course, financial revenues from testing may come into play, with few disincentives to forgo testing. Something that also comes into play is that evidence-based guidance on cost-­effective laboratory testing may be lacking, or there may be a lack of knowledge on how to access existing evidence.

Automated systems can facilitate wasteful laboratory testing, and the heavy testing practices of hospitals and specialists may be inappropriately applied to outpatient primary care.

Factors affecting the cost of laboratory testing

Laboratory test results drive 70% of today’s medical decisions.⁵ Negotiated insurance payment for tests is usually much less than the direct out-of-pocket costs charged to the patient. Without insurance, lab tests can cost patients between $100 and $1000.⁶ If multiple tests are ordered, the costs could likely be many thousands of dollars.

Actual costs typically vary by the testing facility, the patient’s health plan, and location in the United States; hospital-based testing tends to be the most expensive. Insurers will pay for lab tests with appropriate indications that are covered in the contract with the provider.⁶

Choosing Wisely initiative weighs in on lab testing

Choosing Wisely, a prominent initiative of the American Board of Internal Medicine Foundation, promotes appropriate resource utilization through educational campaigns that detail how to avoid unnecessary medical tests, treatments, and procedures.⁷ Recommendations are based largely on specialty society consensus and disease-oriented evidence. Choosing Wisely recommendations advise against the following⁷:

• performing laboratory blood testing unless clinically indicated or necessary for diagnosis or management, in order to avoid iatrogenic anemia. (American Academy of Family Physicians; Society for the Advancement of Patient Blood Management)
• requesting just a serum creatinine to test adult patients with diabetes and/or hypertension for chronic kidney disease. Use the kidney profile: serum creatinine with estimated glomerular filtration rate and urinary albumin-creatinine ratio. (American Society for Clinical Pathology)
• routinely screening for prostate cancer using a prostate-specific antigen test. It should be performed only after engaging in shared decision-making with the patient. (American Academy of Family Physicians; American Urological Association)
• screening for genital herpes simplex virus infectionFrutiger LT Std in asymptomatic adults, including pregnant women. (American Academy of Family Physicians)
• performing preoperative medical tests for eye surgery unless there are specific medical indications. (American Academy of Ophthalmology)

Sequential steps to takefor value-based lab ordering

Ask the question: “How will ordering this specific test change the management of my patient?” From there, take sequential steps using sound, evidence-based pathways. Morgan and colleagues⁸ outline the following practical approaches to rational test ordering:

• Perform a thorough clinical assessment.
• Consider the probability and implications of a positive test result.
• Practice patient-centered communication: address the patient’s concerns and discuss the risks and benefits of tests and how they will influence management.
• Follow clinical guidelines when available.
• Avoid ordering tests to reassure the patient; unnecessary tests with insignificant results do little to reduce patient anxieties.
• Avoid letting uncertainty drive unnecessary testing. Watchful waiting can allow time for the illness to resolve or declare itself.

Let’s consider this approach in the context of 4 areas: preventive care, diagnostic evaluation, ongoing management of chronic conditions, and preoperative testing.

Continue to: Preventive guidance from the USPSTF

An independent volunteer panel of 16 national experts in prevention and evidence-based medicine develop recommendations for the US Preventive Services Task Force (USPSTF).⁹ These guidelines are based on evidence and are updated as new evidence surfaces. Thirteen recommendations, some of which advise avoiding preventive procedures that could cause harm to patients, cover laboratory tests used in screening for conditions such as hyperlipidemia¹⁰ and prostate cancer.¹¹ We review the ones pertinent to our patient later at the end of the Case.

While the target audience for USPSTF recommendations is clinicians who provide preventive care, the recommendations are widely followed by policymakers, managed care organizations, public and private payers, quality improvement organizations, research institutions, and patients.

Take a critical look at how you approach the diagnostic evaluation

To reduce unnecessary testing in the diagnostic evaluation of patients, first consider pretest probability, test sensitivity and specificity, narrowly out-of-range tests, habitually paired tests, and repetitive laboratory testing.

Pretest probability, and test sensitivity and specificity. Pretest probability is the estimated chance that the patient has the disease before the test result is known. In a patient with low pretest probability of a disease, the ability to conclusively arrive at the diagnosis with one positive result is limited. Similarly, for tests in patients with high pretest probability of disease, a negative test cannot be used to firmly rule out a diagnosis.¹²

Reliability also depends on test sensitivity (the proportion of true positive results) and specificity (the proportion of true negative results). A test with high sensitivity but low specificity will generate more false-positive results, with potential harm to patients who do not have a disease.

Reflexively ordering tests together (eg, C-reactive protein with erythrocyte sedimentation rate) often contributes to unnecessary testing.

The pretest probability along with test sensitivity and specificity help a clinician to interpret a test result, and even decide whether to order the test at all. For example, the anti-nuclear antibody (ANA) test for systemic lupus erythematosus (SLE) has a sensitivity of 100% and a specificity of 86%¹³; it will always be positive in a patient with SLE. But when applied to individuals with low likelihood of SLE, false-positives are more common; the ANA is falsely positive in up to 14% of healthy individuals, depending on the population studied.¹³

Ordering a test may be unnecessary if the results will not change the treatment plan. For example, in a female patient with classic symptoms of an uncomplicated urinary tract infection, a urine culture and even a urinalysis may not change treatment.

Continue to: Narrowly out-of-range tests

Narrowly out-of-range tests. Test results that fall just outside the “normal” range may be of questionable significance. When an asymptomatic patient has mildly elevated liver enzymes, should additional tests be ordered to avoid missing a treatable disorder? In these scenarios, a history, including possible contributing factors such as alcohol or substance misuse, must be paired with the clinical presentation to assess pre-test probability of a particular condition.¹⁴ Repeating a narrowly out-of-range test is an option in patients when follow-up is possible. Alternatively, you could pursue watchful waiting and monitor a minor abnormality over time while being vigilant for clinical changes. This whole-patient approach will guide the decision of whether to order additional testing.

Habitually paired tests. Reflexively ordering tests together often contributes to unnecessary testing. Examples of commonly paired tests are serum lipase with amylase, C-reactive protein (CRP) with erythrocyte sedimentation rate (ESR), and TSH with free T4 to monitor patients with treated hypothyroidism. These tests add minimal value together and can be decoupled.^15-17 Evidence supports ordering serum lipase alone, CRP instead of ESR, and TSH alone for monitoring thyroid status.

Unnecessary routine preoperative testing and testing sequelae for cataract surgery was calculated to cost Medicare up to $45.4 million annually

Some commonly paired tests may not even be necessary for diagnosis. The well-established Rotterdam Criteria for diagnosing polycystic ovary syndrome specify clinical features and ovarian ultrasound for diagnosis.¹⁸ They do not require measurement of commonly ordered follicle-­stimulating hormone and luteinizing hormone for diagnosis.

Serial rather than parallel testing, a “2-step approach,” is a strategy made easier with the advent of the electronic medical record (EMR) and computerized lab systems.⁸ These records and lab systems allow providers to order reflex tests, and to add on additional tests, if necessary, to an existing blood specimen.

Repetitive laboratory testing. Repetitive inpatient laboratory testing in patients who are clinically stable is wasteful and potentially harmful. Interventions involving physician education alone show mixed results, but combining education with clinician audit and feedback, along with EMR-enabled restrictive ordering, have resulted in significant and sustained reductions in repetitive laboratory testing.¹⁹

Continue to: Ongoing management of chronic conditions

Ongoing management of chronic conditions

Evidence-based guidelines support choices of tests and testing intervals for ongoing management of chronic conditions such as diabetes, hyperlipidemia, and hypertension.

Diabetes. Guidelines also define quality standards that are applied to value-based contracts. For example, the American Diabetes Association recommends assessing A1C every 6 months in patients whose type 2 diabetes is under stable control.²⁰

Hyperlipidemia. For patients diagnosed with hyperlipidemia, 2018 clinical practice guidelines published by multiple specialty societies recommend assessing adherence and response to lifestyle changes and LDL-C–lowering medications with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed.²¹

Hypertension. With a new diagnosis of hypertension, guidelines advise an initial assessment for comorbidities and end-organ damage with an electrocardiogram, urinalysis, glucose level, blood count, electrolytes, creatinine, calcium, lipids, and urinary albumin/creatinine ratio. For ongoing monitoring, guidelines recommend assessment for end-organ damage through regular measurements of creatinine, glomerular filtration rate, and urinary microalbumin/creatinine ratio. Initiation and alteration of medications should prompt appropriate additional lab follow-up—eg, a measurement of serum potassium after starting a diuretic.²²

Preoperative testing

Preoperative testing is overused in low-risk, ambulatory surgery. And testing, even with abnormal results, does not affect postoperative outcomes.²³

Continue to: The American Society of Anesthesiologists (ASA) Physical Status Classification System

The American Society of Anesthesiologists (ASA) Physical Status Classification System, which has been in use for more than 60 years, considers the patient’s physical status (ASA grades I-VI),²⁴ and when paired with surgery grades of minor, intermediate, and major/complex, can help assess preoperative risk and guide preoperative testing (TABLE).^24-26

Preoperative medical testing did not reduce the risk of medical adverse events during or after cataract surgery when compared with selective or no testing.²⁷ Unnecessary preoperative testing can lead to a nonproductive cascade of additional investigations. In a 2018 study of Medicare beneficiaries, unnecessary routine preoperative testing and testing sequelae for cataract surgery was calculated to cost Medicare up to $45.4 million annually.²⁸

CASE

You would not be practicing value-based laboratory testing, according to the USPSTF, if you ordered a CMP, fasting lipid profile, and TSH and 25(OH) vitamin D tests for this healthy 35-year-old man whose family history, blood pressure, and BMI do not put him at elevated risk. Universal lipid screening (Grade B^a) is recommended for all adults ages 40 to 75. Thyroid screening tests and measurement of 25(OH) vitamin D level (I statements^a) are not recommended. The USPSTF has not evaluated chemistry panels for screening.

The USPSTF would recommend the following actions for this patient:

• Screen for HIV (ages 15 to 65 years; and younger or older if patient is at risk). (A recommendation^a,29)
• Screen for hepatitis C virus (in those ages 18 to 79). (B recommendation³⁰)

The following USPSTF recommendations might have come into play if this patient had certain risk factors, or if the patient had been a woman:

• Screen for diabetes if the patient is overweight or obese (B recommendation).
• Screen for hepatitis B in adults at risk (B recommendation).
• Screen for gonorrhea and chlamydia in women at risk (B recommendation). Such screening has an “I”statement for screening men at risk.

Continue to: As noted, costs of laboratory...

As noted, costs of laboratory testing vary widely, depending upon what tests are ordered, what type of insurance the patient has, and which tests the patient’s insurance covers. Who performs the testing also factors into the cost. Payers negotiate reduced fees for commercial lab testing, but potential out-of-­pocket costs to patients are much higher.

For our healthy 35-year-old man, the cost of the initially proposed testing (CMP, lipid panel, TSH, and 25[OH] vitamin D level) ranges from a negotiated payer cost of $85 to potential patient out-of-pocket cost of more than $400.⁶

Insurance would cover the USPSTF-­recommended testing (HIV and hepatitis C screening tests), which might incur only a patient co-pay, and cost the system about $65.

The USPSTF home page, found at www.uspreventiveservicestaskforce.org/uspstf/ includes recommendations that can be sorted for your patients. A web and mobile device application is also available through the website.

^a USPSTF grade definitions:

A: There is high certainty that the net benefit is substantial. Offer service.

B: There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial. Offer service.

C: There is at least moderate certainty that the net benefit is small. Offer service selectively.

D: There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Don’t offer service.

I: Current evidence is insufficient to assess the balance of benefits and harms of the service.

CORRESPONDENCE
Mitchell Kaminski, MD, MBA, 901 Walnut Street, 10th Floor, Jefferson College of Population Health, Philadelphia, PA 19107; [email protected]

CASE

A 35-year-old man arrives for an annual wellness visit with no specific complaints and no significant personal or family history. His normal exam includes a blood pressure of 110/74 mm Hg and a body mass index (BMI) of 23.6. You order “routine labs” for prevention, which include a comprehensive metabolic panel (CMP), fasting lipid profile, and thyroid-stimulating hormone (TSH) and 25(OH) vitamin D tests. Are you practicing value-based laboratory testing?

The answer to this question appears in the Case discussion at the end of the article.

Value-based care, including care provided through laboratory testing, can achieve the Institute for Healthcare Improvement’s Triple Aim of improving population health, improving the patient experience of care (including quality and satisfaction), and reducing cost: Value = (Quality x Patient experience) / Cost.¹

As quality and patient experience rise and cost falls, the value of care increases. Unnecessary lab testing, however, can negatively impact this equation:

• Error introduced by unnecessary testing can adversely affect quality.
• Patients experience inconvenience and sometimes cascades of testing, in addition to financial responsibility, from unnecessary testing.
• Low-value testing also contributes to work burden and provider burnout by requiring additional review and follow-up.

Rising health care costs are approaching 18% of the US gross domestic product, driven in large part by a wasteful and inefficient care delivery system.² One review of “waste domains” identified by the Institute of Medicine estimates that approximately one-quarter of health care costs represent waste, including overtreatment, breakdowns of care coordination, and pricing that fails to correlate to the level of care received.³ High-volume, low-cost testing contributes more to total cost than low-volume, high-cost tests.⁴

Provider and system factors that contribute to ongoing waste

A lack of awareness of waste and how to reduce it contribute to the problem, as does an underappreciation of the harmful effects caused by incidental abnormal results.

Provider intolerance of diagnostic uncertainty often leads to ordering even more tests.

Continue to: Also, a hope of avoiding...

Do not order tests just to reassure the patient; unnecessary tests with insignificant results do little to reduce patient anxiety.

Also, a hope of avoiding missed diagnoses and potential lawsuits leads to defensive practice and more testing. In addition, patients and family members can exert pressure based on a belief that more testing represents better care. Of course, financial revenues from testing may come into play, with few disincentives to forgo testing. Something that also comes into play is that evidence-based guidance on cost-­effective laboratory testing may be lacking, or there may be a lack of knowledge on how to access existing evidence.

Automated systems can facilitate wasteful laboratory testing, and the heavy testing practices of hospitals and specialists may be inappropriately applied to outpatient primary care.

Factors affecting the cost of laboratory testing

Laboratory test results drive 70% of today’s medical decisions.⁵ Negotiated insurance payment for tests is usually much less than the direct out-of-pocket costs charged to the patient. Without insurance, lab tests can cost patients between $100 and $1000.⁶ If multiple tests are ordered, the costs could likely be many thousands of dollars.

Actual costs typically vary by the testing facility, the patient’s health plan, and location in the United States; hospital-based testing tends to be the most expensive. Insurers will pay for lab tests with appropriate indications that are covered in the contract with the provider.⁶

Choosing Wisely initiative weighs in on lab testing

Choosing Wisely, a prominent initiative of the American Board of Internal Medicine Foundation, promotes appropriate resource utilization through educational campaigns that detail how to avoid unnecessary medical tests, treatments, and procedures.⁷ Recommendations are based largely on specialty society consensus and disease-oriented evidence. Choosing Wisely recommendations advise against the following⁷:

• performing laboratory blood testing unless clinically indicated or necessary for diagnosis or management, in order to avoid iatrogenic anemia. (American Academy of Family Physicians; Society for the Advancement of Patient Blood Management)
• requesting just a serum creatinine to test adult patients with diabetes and/or hypertension for chronic kidney disease. Use the kidney profile: serum creatinine with estimated glomerular filtration rate and urinary albumin-creatinine ratio. (American Society for Clinical Pathology)
• routinely screening for prostate cancer using a prostate-specific antigen test. It should be performed only after engaging in shared decision-making with the patient. (American Academy of Family Physicians; American Urological Association)
• screening for genital herpes simplex virus infectionFrutiger LT Std in asymptomatic adults, including pregnant women. (American Academy of Family Physicians)
• performing preoperative medical tests for eye surgery unless there are specific medical indications. (American Academy of Ophthalmology)

Sequential steps to takefor value-based lab ordering

Ask the question: “How will ordering this specific test change the management of my patient?” From there, take sequential steps using sound, evidence-based pathways. Morgan and colleagues⁸ outline the following practical approaches to rational test ordering:

• Perform a thorough clinical assessment.
• Consider the probability and implications of a positive test result.
• Practice patient-centered communication: address the patient’s concerns and discuss the risks and benefits of tests and how they will influence management.
• Follow clinical guidelines when available.
• Avoid ordering tests to reassure the patient; unnecessary tests with insignificant results do little to reduce patient anxieties.
• Avoid letting uncertainty drive unnecessary testing. Watchful waiting can allow time for the illness to resolve or declare itself.

Let’s consider this approach in the context of 4 areas: preventive care, diagnostic evaluation, ongoing management of chronic conditions, and preoperative testing.

Continue to: Preventive guidance from the USPSTF

An independent volunteer panel of 16 national experts in prevention and evidence-based medicine develop recommendations for the US Preventive Services Task Force (USPSTF).⁹ These guidelines are based on evidence and are updated as new evidence surfaces. Thirteen recommendations, some of which advise avoiding preventive procedures that could cause harm to patients, cover laboratory tests used in screening for conditions such as hyperlipidemia¹⁰ and prostate cancer.¹¹ We review the ones pertinent to our patient later at the end of the Case.

While the target audience for USPSTF recommendations is clinicians who provide preventive care, the recommendations are widely followed by policymakers, managed care organizations, public and private payers, quality improvement organizations, research institutions, and patients.

Take a critical look at how you approach the diagnostic evaluation

To reduce unnecessary testing in the diagnostic evaluation of patients, first consider pretest probability, test sensitivity and specificity, narrowly out-of-range tests, habitually paired tests, and repetitive laboratory testing.

Pretest probability, and test sensitivity and specificity. Pretest probability is the estimated chance that the patient has the disease before the test result is known. In a patient with low pretest probability of a disease, the ability to conclusively arrive at the diagnosis with one positive result is limited. Similarly, for tests in patients with high pretest probability of disease, a negative test cannot be used to firmly rule out a diagnosis.¹²

Reliability also depends on test sensitivity (the proportion of true positive results) and specificity (the proportion of true negative results). A test with high sensitivity but low specificity will generate more false-positive results, with potential harm to patients who do not have a disease.

Reflexively ordering tests together (eg, C-reactive protein with erythrocyte sedimentation rate) often contributes to unnecessary testing.

The pretest probability along with test sensitivity and specificity help a clinician to interpret a test result, and even decide whether to order the test at all. For example, the anti-nuclear antibody (ANA) test for systemic lupus erythematosus (SLE) has a sensitivity of 100% and a specificity of 86%¹³; it will always be positive in a patient with SLE. But when applied to individuals with low likelihood of SLE, false-positives are more common; the ANA is falsely positive in up to 14% of healthy individuals, depending on the population studied.¹³

Ordering a test may be unnecessary if the results will not change the treatment plan. For example, in a female patient with classic symptoms of an uncomplicated urinary tract infection, a urine culture and even a urinalysis may not change treatment.

Continue to: Narrowly out-of-range tests

Narrowly out-of-range tests. Test results that fall just outside the “normal” range may be of questionable significance. When an asymptomatic patient has mildly elevated liver enzymes, should additional tests be ordered to avoid missing a treatable disorder? In these scenarios, a history, including possible contributing factors such as alcohol or substance misuse, must be paired with the clinical presentation to assess pre-test probability of a particular condition.¹⁴ Repeating a narrowly out-of-range test is an option in patients when follow-up is possible. Alternatively, you could pursue watchful waiting and monitor a minor abnormality over time while being vigilant for clinical changes. This whole-patient approach will guide the decision of whether to order additional testing.

Habitually paired tests. Reflexively ordering tests together often contributes to unnecessary testing. Examples of commonly paired tests are serum lipase with amylase, C-reactive protein (CRP) with erythrocyte sedimentation rate (ESR), and TSH with free T4 to monitor patients with treated hypothyroidism. These tests add minimal value together and can be decoupled.^15-17 Evidence supports ordering serum lipase alone, CRP instead of ESR, and TSH alone for monitoring thyroid status.

Unnecessary routine preoperative testing and testing sequelae for cataract surgery was calculated to cost Medicare up to $45.4 million annually

Some commonly paired tests may not even be necessary for diagnosis. The well-established Rotterdam Criteria for diagnosing polycystic ovary syndrome specify clinical features and ovarian ultrasound for diagnosis.¹⁸ They do not require measurement of commonly ordered follicle-­stimulating hormone and luteinizing hormone for diagnosis.

Serial rather than parallel testing, a “2-step approach,” is a strategy made easier with the advent of the electronic medical record (EMR) and computerized lab systems.⁸ These records and lab systems allow providers to order reflex tests, and to add on additional tests, if necessary, to an existing blood specimen.

Repetitive laboratory testing. Repetitive inpatient laboratory testing in patients who are clinically stable is wasteful and potentially harmful. Interventions involving physician education alone show mixed results, but combining education with clinician audit and feedback, along with EMR-enabled restrictive ordering, have resulted in significant and sustained reductions in repetitive laboratory testing.¹⁹

Continue to: Ongoing management of chronic conditions

Ongoing management of chronic conditions

Evidence-based guidelines support choices of tests and testing intervals for ongoing management of chronic conditions such as diabetes, hyperlipidemia, and hypertension.

Diabetes. Guidelines also define quality standards that are applied to value-based contracts. For example, the American Diabetes Association recommends assessing A1C every 6 months in patients whose type 2 diabetes is under stable control.²⁰

Hyperlipidemia. For patients diagnosed with hyperlipidemia, 2018 clinical practice guidelines published by multiple specialty societies recommend assessing adherence and response to lifestyle changes and LDL-C–lowering medications with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed.²¹

Hypertension. With a new diagnosis of hypertension, guidelines advise an initial assessment for comorbidities and end-organ damage with an electrocardiogram, urinalysis, glucose level, blood count, electrolytes, creatinine, calcium, lipids, and urinary albumin/creatinine ratio. For ongoing monitoring, guidelines recommend assessment for end-organ damage through regular measurements of creatinine, glomerular filtration rate, and urinary microalbumin/creatinine ratio. Initiation and alteration of medications should prompt appropriate additional lab follow-up—eg, a measurement of serum potassium after starting a diuretic.²²

Preoperative testing

Preoperative testing is overused in low-risk, ambulatory surgery. And testing, even with abnormal results, does not affect postoperative outcomes.²³

Continue to: The American Society of Anesthesiologists (ASA) Physical Status Classification System

The American Society of Anesthesiologists (ASA) Physical Status Classification System, which has been in use for more than 60 years, considers the patient’s physical status (ASA grades I-VI),²⁴ and when paired with surgery grades of minor, intermediate, and major/complex, can help assess preoperative risk and guide preoperative testing (TABLE).^24-26

Preoperative medical testing did not reduce the risk of medical adverse events during or after cataract surgery when compared with selective or no testing.²⁷ Unnecessary preoperative testing can lead to a nonproductive cascade of additional investigations. In a 2018 study of Medicare beneficiaries, unnecessary routine preoperative testing and testing sequelae for cataract surgery was calculated to cost Medicare up to $45.4 million annually.²⁸

CASE

You would not be practicing value-based laboratory testing, according to the USPSTF, if you ordered a CMP, fasting lipid profile, and TSH and 25(OH) vitamin D tests for this healthy 35-year-old man whose family history, blood pressure, and BMI do not put him at elevated risk. Universal lipid screening (Grade B^a) is recommended for all adults ages 40 to 75. Thyroid screening tests and measurement of 25(OH) vitamin D level (I statements^a) are not recommended. The USPSTF has not evaluated chemistry panels for screening.

The USPSTF would recommend the following actions for this patient:

• Screen for HIV (ages 15 to 65 years; and younger or older if patient is at risk). (A recommendation^a,29)
• Screen for hepatitis C virus (in those ages 18 to 79). (B recommendation³⁰)

The following USPSTF recommendations might have come into play if this patient had certain risk factors, or if the patient had been a woman:

• Screen for diabetes if the patient is overweight or obese (B recommendation).
• Screen for hepatitis B in adults at risk (B recommendation).
• Screen for gonorrhea and chlamydia in women at risk (B recommendation). Such screening has an “I”statement for screening men at risk.

Continue to: As noted, costs of laboratory...

As noted, costs of laboratory testing vary widely, depending upon what tests are ordered, what type of insurance the patient has, and which tests the patient’s insurance covers. Who performs the testing also factors into the cost. Payers negotiate reduced fees for commercial lab testing, but potential out-of-­pocket costs to patients are much higher.

For our healthy 35-year-old man, the cost of the initially proposed testing (CMP, lipid panel, TSH, and 25[OH] vitamin D level) ranges from a negotiated payer cost of $85 to potential patient out-of-pocket cost of more than $400.⁶

Insurance would cover the USPSTF-­recommended testing (HIV and hepatitis C screening tests), which might incur only a patient co-pay, and cost the system about $65.

The USPSTF home page, found at www.uspreventiveservicestaskforce.org/uspstf/ includes recommendations that can be sorted for your patients. A web and mobile device application is also available through the website.

^a USPSTF grade definitions:

A: There is high certainty that the net benefit is substantial. Offer service.

B: There is high certainty that the net benefit is moderate, or there is moderate certainty that the net benefit is moderate to substantial. Offer service.

C: There is at least moderate certainty that the net benefit is small. Offer service selectively.

D: There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Don’t offer service.

I: Current evidence is insufficient to assess the balance of benefits and harms of the service.

CORRESPONDENCE
Mitchell Kaminski, MD, MBA, 901 Walnut Street, 10th Floor, Jefferson College of Population Health, Philadelphia, PA 19107; [email protected]

I was quite sure I had multiple sclerosis when I was a medical student. I first noticed symptoms during my neurology rotation. All the signs were there: Fatigue that was getting worse in the North Carolina heat (Uhthoff sign!). A tingle running down my neck (Lhermitte sign!). Blurry vision late at night while studying pathways in Lange Neurology. “Didn’t cousin Amy have MS?” I asked my Mom. I started researching which medical specialties didn’t require dexterity. My left eyelid began twitching and didn’t stop until I rotated to ob.gyn.

Fortunately, it was not multiple sclerosis I had, but rather nosophobia, also known as Medical Student’s Disease. The combination of intense study of symptoms, spotty knowledge of diagnoses, and grade anxiety makes nosophobia common in med students. Despite its name, it doesn’t afflict only doctors. Patients often come to us convinced they have a disease but without reason. So unshakable is their belief that multiple visits are often required to disabuse them of their self-diagnosis. I sometimes have to remind myself to appear concerned even when a “melanoma” is a freckle so small I can barely see it with a dermatoscope. Or a “genital wart” is a hair follicle that looks exactly like the hundreds on the patient’s scrotum. Tougher though, are the treatment-avoiders: patients whose imagined side effects lead them to stop or refuse treatment.

I recently saw a middle-aged man with erythroderma so severe he looked like a ghillie suit of scale. He had a lifelong history of atopic dermatitis and a 2-year history of avoiding treatments. At some point, he tried all the usual remedies: cyclosporine, methotrexate, azathioprine, light therapy, boxes of topicals. The last treatment had been dupilumab, which he tried for a few weeks. “Why did you stop that one?” I asked. The injections were making him go blind, he explained. “Not blurry? Blind?” I asked. Yes, he could not see at all after each injection. Perhaps he might have dry eyes or keratitis? Sure. But blindness? It seemed an unreasonable concern. Further discussion revealed that intolerance to medication side effects was why he had stopped all his other treatments.

Nocebo, from the Latin “I shall harm,” is the dark counterpart to the placebo. Patients experience imagined, or even real, adverse effects because they believe the treatment is causing them harm. This is true even though that treatment might not be having any unwanted physiologic effect. Statins are a good example. Studies have shown that most patient-reported side effects of statins are in fact nocebo effects rather than a result of pharmacologic causes.

Yet, many patients on statins report muscle pain or other concerns as unbearable. As a consequence, some patients who might have benefited from statins might be missing out on the protective gains. Nocebo effects are exacerbated by a common bias that causes deeper regret when bad outcomes result from an action taken as compared with bad outcomes that occurred from not taking action. It’s frustrating when there’s a standard of care treatment, but our patient can’t get past their fear of harm to try it.

Despite my recommendations, my eczema patient insisted on continuing his nontreatment rather than take any risks with treatments for now. There are ways I might help, but I expect it will require additional visits to build trust. Today, the best I can do is to understand and respect him. At least he doesn’t think he has a genital wart – I’m not sure how I’d treat it if he did.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

I was quite sure I had multiple sclerosis when I was a medical student. I first noticed symptoms during my neurology rotation. All the signs were there: Fatigue that was getting worse in the North Carolina heat (Uhthoff sign!). A tingle running down my neck (Lhermitte sign!). Blurry vision late at night while studying pathways in Lange Neurology. “Didn’t cousin Amy have MS?” I asked my Mom. I started researching which medical specialties didn’t require dexterity. My left eyelid began twitching and didn’t stop until I rotated to ob.gyn.

Fortunately, it was not multiple sclerosis I had, but rather nosophobia, also known as Medical Student’s Disease. The combination of intense study of symptoms, spotty knowledge of diagnoses, and grade anxiety makes nosophobia common in med students. Despite its name, it doesn’t afflict only doctors. Patients often come to us convinced they have a disease but without reason. So unshakable is their belief that multiple visits are often required to disabuse them of their self-diagnosis. I sometimes have to remind myself to appear concerned even when a “melanoma” is a freckle so small I can barely see it with a dermatoscope. Or a “genital wart” is a hair follicle that looks exactly like the hundreds on the patient’s scrotum. Tougher though, are the treatment-avoiders: patients whose imagined side effects lead them to stop or refuse treatment.

I recently saw a middle-aged man with erythroderma so severe he looked like a ghillie suit of scale. He had a lifelong history of atopic dermatitis and a 2-year history of avoiding treatments. At some point, he tried all the usual remedies: cyclosporine, methotrexate, azathioprine, light therapy, boxes of topicals. The last treatment had been dupilumab, which he tried for a few weeks. “Why did you stop that one?” I asked. The injections were making him go blind, he explained. “Not blurry? Blind?” I asked. Yes, he could not see at all after each injection. Perhaps he might have dry eyes or keratitis? Sure. But blindness? It seemed an unreasonable concern. Further discussion revealed that intolerance to medication side effects was why he had stopped all his other treatments.

Nocebo, from the Latin “I shall harm,” is the dark counterpart to the placebo. Patients experience imagined, or even real, adverse effects because they believe the treatment is causing them harm. This is true even though that treatment might not be having any unwanted physiologic effect. Statins are a good example. Studies have shown that most patient-reported side effects of statins are in fact nocebo effects rather than a result of pharmacologic causes.

Yet, many patients on statins report muscle pain or other concerns as unbearable. As a consequence, some patients who might have benefited from statins might be missing out on the protective gains. Nocebo effects are exacerbated by a common bias that causes deeper regret when bad outcomes result from an action taken as compared with bad outcomes that occurred from not taking action. It’s frustrating when there’s a standard of care treatment, but our patient can’t get past their fear of harm to try it.

Despite my recommendations, my eczema patient insisted on continuing his nontreatment rather than take any risks with treatments for now. There are ways I might help, but I expect it will require additional visits to build trust. Today, the best I can do is to understand and respect him. At least he doesn’t think he has a genital wart – I’m not sure how I’d treat it if he did.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

I was quite sure I had multiple sclerosis when I was a medical student. I first noticed symptoms during my neurology rotation. All the signs were there: Fatigue that was getting worse in the North Carolina heat (Uhthoff sign!). A tingle running down my neck (Lhermitte sign!). Blurry vision late at night while studying pathways in Lange Neurology. “Didn’t cousin Amy have MS?” I asked my Mom. I started researching which medical specialties didn’t require dexterity. My left eyelid began twitching and didn’t stop until I rotated to ob.gyn.

Fortunately, it was not multiple sclerosis I had, but rather nosophobia, also known as Medical Student’s Disease. The combination of intense study of symptoms, spotty knowledge of diagnoses, and grade anxiety makes nosophobia common in med students. Despite its name, it doesn’t afflict only doctors. Patients often come to us convinced they have a disease but without reason. So unshakable is their belief that multiple visits are often required to disabuse them of their self-diagnosis. I sometimes have to remind myself to appear concerned even when a “melanoma” is a freckle so small I can barely see it with a dermatoscope. Or a “genital wart” is a hair follicle that looks exactly like the hundreds on the patient’s scrotum. Tougher though, are the treatment-avoiders: patients whose imagined side effects lead them to stop or refuse treatment.

I recently saw a middle-aged man with erythroderma so severe he looked like a ghillie suit of scale. He had a lifelong history of atopic dermatitis and a 2-year history of avoiding treatments. At some point, he tried all the usual remedies: cyclosporine, methotrexate, azathioprine, light therapy, boxes of topicals. The last treatment had been dupilumab, which he tried for a few weeks. “Why did you stop that one?” I asked. The injections were making him go blind, he explained. “Not blurry? Blind?” I asked. Yes, he could not see at all after each injection. Perhaps he might have dry eyes or keratitis? Sure. But blindness? It seemed an unreasonable concern. Further discussion revealed that intolerance to medication side effects was why he had stopped all his other treatments.

Nocebo, from the Latin “I shall harm,” is the dark counterpart to the placebo. Patients experience imagined, or even real, adverse effects because they believe the treatment is causing them harm. This is true even though that treatment might not be having any unwanted physiologic effect. Statins are a good example. Studies have shown that most patient-reported side effects of statins are in fact nocebo effects rather than a result of pharmacologic causes.

Yet, many patients on statins report muscle pain or other concerns as unbearable. As a consequence, some patients who might have benefited from statins might be missing out on the protective gains. Nocebo effects are exacerbated by a common bias that causes deeper regret when bad outcomes result from an action taken as compared with bad outcomes that occurred from not taking action. It’s frustrating when there’s a standard of care treatment, but our patient can’t get past their fear of harm to try it.

Despite my recommendations, my eczema patient insisted on continuing his nontreatment rather than take any risks with treatments for now. There are ways I might help, but I expect it will require additional visits to build trust. Today, the best I can do is to understand and respect him. At least he doesn’t think he has a genital wart – I’m not sure how I’d treat it if he did.

Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. Write to him at [email protected].

NEW YORK – Patients with chronic plaque psoriasis face a nearly twofold increased risk of nonalcoholic fatty liver disease (NAFLD), and the risk climbs higher in those with more severe skin involvement – and probably in those with psoriatic arthritis (PsA) as well, according to a systematic review and meta-analysis presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

“Our findings imply that psoriatic patients should be screened with an ultrasonographic exam in cases where there are metabolic features that are associated with NAFLD,” reported Francesco Bellinato, MD, a researcher in the section of dermatology and venereology, University of Verona (Italy).

In the pooled data, the risk of NAFLD among those with psoriasis relative to healthy controls fell just short of a twofold increase (odds ratio, 1.96; 95% CI, 1.70-2.26; P < .001). When stratified by studies that confirmed NAFLD by biopsy relative to ultrasonography, there was no significant heterogeneity.

Eight of the studies included an analysis of relative risk in the context of skin lesion severity defined by Psoriasis Area and Severity Index (PASI) score. Relative to those without NAFLD, psoriatic patients with NAFLD had a significant greater mean PASI score on a pooled weighted mean difference analysis (OR, 3.93; 95% CI, 2.01-5.84; P < .0001).

courtesy Dr. Francesco Belinato

For PsA relative to no PsA in the five studies that compared risk between these two groups, the risk of NAFLD was again nearly twofold higher. This fell short of conventional definition of statistical significance, but it was associated with a strong trend (OR, 1.83; 95% CI, 0.98-3.43; P = .06).

The risk of NAFLD among patients with psoriasis was not found to vary significantly when assessed by univariable meta-regressions across numerous characteristics, such as sex and body mass index.

In one of the largest of the observational studies included in the meta-analysis by Alexis Ogdie, MD, associate professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, and colleagues, data were analyzed in more than 1.5 million patients, which included 54,251 patients with rheumatoid arthritis. While the hazard ratio of NAFLD was increased for both psoriasis (HR, 2.23) and PsA (HR, 2.11), it was not elevated in those with RA (HR, 0.96).

Risk by severity, possible mechanisms

This study also included an analysis of NAFLD risk according to psoriasis severity. While risk was still significant among those with mild disease (HR, 1.18; 95% CI, 1.07-1.30), it was almost twofold greater in those with moderate to severe psoriasis (HR, 2.23; 95% CI, 1.73-2.87).

Dr. Bellinato conceded that the mechanisms underlying the association between psoriasis and NAFLD are unknown, but he said “metaflammation” is suspected.

“The secretion of proinflammatory, prothrombotic, and oxidative stress mediators in both psoriatic skin and adipose tissue might act systemically and promote insulin resistance and other metabolic derangements that promote the development and progression of NAFLD,” Dr. Bellinato explained.

He thinks that noninvasive screening methods, such as currently used methods to calculate fibrosis score, might be useful for evaluating patients with psoriasis for NAFLD and referring them to a hepatologist when appropriate.

Given the strong association with NAFLD, Dr. Bellinato suggested that “the findings of this meta-analysis pave the way for novel, large, prospective, and histologically based studies.”

Courtesy Dr. Joel M. Gelfand

The association between psoriasis and NAFLD is clinically relevant, agreed Joel M. Gelfand, MD, vice-chair of clinical research and medical director of the clinical studies unit, department of dermatology, University of Pennsylvania, Philadelphia.

“It is not clear if psoriasis causes fatty liver disease or vice versa, but clinicians should be aware of this association,” he said in an interview. Dr. Gelfand was a coauthor of the study by Dr. Ogdie and colleagues and led another more recent population-based study that implicated methotrexate as a factor in psoriasis-related hepatotoxicity.

If NAFLD is identified in a patient with psoriasis, treatments are limited, but Dr. Gelfand suggested that patients should be made aware of the risk. “Clinicians should encourage patients with psoriasis to take measures to protect their liver, such as avoiding drinking alcohol to excess and trying to maintain a healthy body weight,” he said.

Dr. Bellinato reported no conflicts of interest. Dr. Gelfand has financial relationships with more than 10 pharmaceutical companies, including those that make therapies for psoriasis.

NEW YORK – Patients with chronic plaque psoriasis face a nearly twofold increased risk of nonalcoholic fatty liver disease (NAFLD), and the risk climbs higher in those with more severe skin involvement – and probably in those with psoriatic arthritis (PsA) as well, according to a systematic review and meta-analysis presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

“Our findings imply that psoriatic patients should be screened with an ultrasonographic exam in cases where there are metabolic features that are associated with NAFLD,” reported Francesco Bellinato, MD, a researcher in the section of dermatology and venereology, University of Verona (Italy).

In the pooled data, the risk of NAFLD among those with psoriasis relative to healthy controls fell just short of a twofold increase (odds ratio, 1.96; 95% CI, 1.70-2.26; P < .001). When stratified by studies that confirmed NAFLD by biopsy relative to ultrasonography, there was no significant heterogeneity.

Eight of the studies included an analysis of relative risk in the context of skin lesion severity defined by Psoriasis Area and Severity Index (PASI) score. Relative to those without NAFLD, psoriatic patients with NAFLD had a significant greater mean PASI score on a pooled weighted mean difference analysis (OR, 3.93; 95% CI, 2.01-5.84; P < .0001).

courtesy Dr. Francesco Belinato

For PsA relative to no PsA in the five studies that compared risk between these two groups, the risk of NAFLD was again nearly twofold higher. This fell short of conventional definition of statistical significance, but it was associated with a strong trend (OR, 1.83; 95% CI, 0.98-3.43; P = .06).

The risk of NAFLD among patients with psoriasis was not found to vary significantly when assessed by univariable meta-regressions across numerous characteristics, such as sex and body mass index.

In one of the largest of the observational studies included in the meta-analysis by Alexis Ogdie, MD, associate professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, and colleagues, data were analyzed in more than 1.5 million patients, which included 54,251 patients with rheumatoid arthritis. While the hazard ratio of NAFLD was increased for both psoriasis (HR, 2.23) and PsA (HR, 2.11), it was not elevated in those with RA (HR, 0.96).

Risk by severity, possible mechanisms

This study also included an analysis of NAFLD risk according to psoriasis severity. While risk was still significant among those with mild disease (HR, 1.18; 95% CI, 1.07-1.30), it was almost twofold greater in those with moderate to severe psoriasis (HR, 2.23; 95% CI, 1.73-2.87).

Dr. Bellinato conceded that the mechanisms underlying the association between psoriasis and NAFLD are unknown, but he said “metaflammation” is suspected.

“The secretion of proinflammatory, prothrombotic, and oxidative stress mediators in both psoriatic skin and adipose tissue might act systemically and promote insulin resistance and other metabolic derangements that promote the development and progression of NAFLD,” Dr. Bellinato explained.

He thinks that noninvasive screening methods, such as currently used methods to calculate fibrosis score, might be useful for evaluating patients with psoriasis for NAFLD and referring them to a hepatologist when appropriate.

Given the strong association with NAFLD, Dr. Bellinato suggested that “the findings of this meta-analysis pave the way for novel, large, prospective, and histologically based studies.”

Courtesy Dr. Joel M. Gelfand

The association between psoriasis and NAFLD is clinically relevant, agreed Joel M. Gelfand, MD, vice-chair of clinical research and medical director of the clinical studies unit, department of dermatology, University of Pennsylvania, Philadelphia.

“It is not clear if psoriasis causes fatty liver disease or vice versa, but clinicians should be aware of this association,” he said in an interview. Dr. Gelfand was a coauthor of the study by Dr. Ogdie and colleagues and led another more recent population-based study that implicated methotrexate as a factor in psoriasis-related hepatotoxicity.

If NAFLD is identified in a patient with psoriasis, treatments are limited, but Dr. Gelfand suggested that patients should be made aware of the risk. “Clinicians should encourage patients with psoriasis to take measures to protect their liver, such as avoiding drinking alcohol to excess and trying to maintain a healthy body weight,” he said.

Dr. Bellinato reported no conflicts of interest. Dr. Gelfand has financial relationships with more than 10 pharmaceutical companies, including those that make therapies for psoriasis.

NEW YORK – Patients with chronic plaque psoriasis face a nearly twofold increased risk of nonalcoholic fatty liver disease (NAFLD), and the risk climbs higher in those with more severe skin involvement – and probably in those with psoriatic arthritis (PsA) as well, according to a systematic review and meta-analysis presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

“Our findings imply that psoriatic patients should be screened with an ultrasonographic exam in cases where there are metabolic features that are associated with NAFLD,” reported Francesco Bellinato, MD, a researcher in the section of dermatology and venereology, University of Verona (Italy).

In the pooled data, the risk of NAFLD among those with psoriasis relative to healthy controls fell just short of a twofold increase (odds ratio, 1.96; 95% CI, 1.70-2.26; P < .001). When stratified by studies that confirmed NAFLD by biopsy relative to ultrasonography, there was no significant heterogeneity.

Eight of the studies included an analysis of relative risk in the context of skin lesion severity defined by Psoriasis Area and Severity Index (PASI) score. Relative to those without NAFLD, psoriatic patients with NAFLD had a significant greater mean PASI score on a pooled weighted mean difference analysis (OR, 3.93; 95% CI, 2.01-5.84; P < .0001).

courtesy Dr. Francesco Belinato

For PsA relative to no PsA in the five studies that compared risk between these two groups, the risk of NAFLD was again nearly twofold higher. This fell short of conventional definition of statistical significance, but it was associated with a strong trend (OR, 1.83; 95% CI, 0.98-3.43; P = .06).

The risk of NAFLD among patients with psoriasis was not found to vary significantly when assessed by univariable meta-regressions across numerous characteristics, such as sex and body mass index.

In one of the largest of the observational studies included in the meta-analysis by Alexis Ogdie, MD, associate professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, and colleagues, data were analyzed in more than 1.5 million patients, which included 54,251 patients with rheumatoid arthritis. While the hazard ratio of NAFLD was increased for both psoriasis (HR, 2.23) and PsA (HR, 2.11), it was not elevated in those with RA (HR, 0.96).

Risk by severity, possible mechanisms

This study also included an analysis of NAFLD risk according to psoriasis severity. While risk was still significant among those with mild disease (HR, 1.18; 95% CI, 1.07-1.30), it was almost twofold greater in those with moderate to severe psoriasis (HR, 2.23; 95% CI, 1.73-2.87).

Dr. Bellinato conceded that the mechanisms underlying the association between psoriasis and NAFLD are unknown, but he said “metaflammation” is suspected.

“The secretion of proinflammatory, prothrombotic, and oxidative stress mediators in both psoriatic skin and adipose tissue might act systemically and promote insulin resistance and other metabolic derangements that promote the development and progression of NAFLD,” Dr. Bellinato explained.

He thinks that noninvasive screening methods, such as currently used methods to calculate fibrosis score, might be useful for evaluating patients with psoriasis for NAFLD and referring them to a hepatologist when appropriate.

Given the strong association with NAFLD, Dr. Bellinato suggested that “the findings of this meta-analysis pave the way for novel, large, prospective, and histologically based studies.”

Courtesy Dr. Joel M. Gelfand

The association between psoriasis and NAFLD is clinically relevant, agreed Joel M. Gelfand, MD, vice-chair of clinical research and medical director of the clinical studies unit, department of dermatology, University of Pennsylvania, Philadelphia.

“It is not clear if psoriasis causes fatty liver disease or vice versa, but clinicians should be aware of this association,” he said in an interview. Dr. Gelfand was a coauthor of the study by Dr. Ogdie and colleagues and led another more recent population-based study that implicated methotrexate as a factor in psoriasis-related hepatotoxicity.

If NAFLD is identified in a patient with psoriasis, treatments are limited, but Dr. Gelfand suggested that patients should be made aware of the risk. “Clinicians should encourage patients with psoriasis to take measures to protect their liver, such as avoiding drinking alcohol to excess and trying to maintain a healthy body weight,” he said.

Dr. Bellinato reported no conflicts of interest. Dr. Gelfand has financial relationships with more than 10 pharmaceutical companies, including those that make therapies for psoriasis.

As states grapple with the future of abortion in the United States, Michigan, California, and Vermont could become the first states to let voters decide whether the right to abortion should be written into the state constitution.

In Michigan, a proposed constitutional amendment would override a 90-year-old state law that makes abortion a felony even in cases of rape or incest. The U.S. Supreme Court’s overturning of Roe v. Wade could revive that abortion ban – and has galvanized abortion-rights advocates to secure new protections.

Some of the momentum is coming from activists getting involved for the first time.

“I wanted to do something, but I had no political experience or really any experience in activism,” said Amanda Mazur, who lives in rural northwestern Michigan. “But I thought, ‘Maybe I can volunteer and just offer something tangible to the movement.’”

Michigan organizers like Ms. Mazur submitted more than 750,000 signatures – a record number, they said – to state election officials in hopes of having the amendment appear on the November ballot.

If just over half those signatures are validated, Michigan voters will decide whether to amend the state’s constitution to guarantee broad individual rights to “reproductive freedom” that would cover abortion, contraception, and fertility treatments. It would also prevent the state from regulating abortions later in pregnancy if the patient’s “physical or mental health” is at risk.

The ballot initiative has the backing of medical groups like the American College of Obstetricians and Gynecologists, while conservative groups have called it radical and dangerous, claiming it would “allow late-term abortions for practically any reason.”

In California, the push to expand abortion access starts from a very different vantage point: The right to abortion is protected in state statute. And voters will be asked whether they want to enshrine it in the constitution. Proposition 1, which will be on the ballot in November, would prohibit the state from interfering with Californians’ reproductive health decisions, including those related to abortion or contraception.

“I want to know for sure that that right is protected,” state Sen. Toni Atkins (D-Calif.), the Democratic leader in the Senate and lead author of the amendment, said at a legislative hearing in June. “We are protecting ourselves from future courts and future politicians.”

The amendment is one strategy that several California lawmakers are pursuing to protect abortion access in the state. Gov. Gavin Newsom, a Democrat, has signed legislation to eliminate out-of-pocket expenses for abortion for most Californians and to protect California providers that offer abortion services from lawsuits in other states. The recent state budget deal also includes $200 million for reproductive and abortion care.

Earlier in July, Vermont Gov. Phil Scott, a Republican, announced that Proposal 5 will be on the November ballot. He said in a statement: “In Vermont, we solidified the right to choose in law, and now Vermonters have the opportunity to further protect that right in our constitution.”

For Ms. Mazur, the desire to “do something” started in 2017, when she and her husband gave their daughter, then 2 years old, some happy news: She was going to be a big sister. The family was thrilled.

But then doctors told Ms. Mazur something was wrong.

“I found out halfway through the pregnancy that the baby my husband and I hoped for suffered from a rare and life-limiting genetic condition,” Ms. Mazur said. “We ultimately made the compassionate choice to end the pregnancy for my well-being, and for the well-being of our family, and the life of what we thought would be our child.”

Devastated, Ms. Mazur turned to a national online support group and met people having similar experiences. But many group members said they were having a tough time finding a way to terminate their pregnancies.

“It really broke my heart that you’re going through this already devastating experience but have to travel far away from your home across the country ... [and] advocate for yourself like crazy just to get care that you have decided with your doctor is best for you,” Ms. Mazur said.

At the time, abortion rights in Michigan seemed pretty stable, but Ms. Mazur’s political awakening found an outlet this year.

Reproductive Freedom for All, a petition group backed by the American Civil Liberties Union of Michigan and Planned Parenthood Advocates of Michigan, was gathering signatures for the constitutional amendment to enshrine abortion protections in state law. The effort took on new urgency in May after a draft of the Supreme Court’s decision in Dobbs v. Jackson Women’s Health Organization was leaked and then published.

“Folks realized that this big, scary thing that they did not think would happen might actually happen,” said Jessica Ayoub, a field organizer with the ACLU of Michigan.

Some Michiganders were registering to vote just to be eligible to sign the petition. Jaynie Hoerauf, a 62-year-old attorney in Farwell, drove 40 miles to attend a rally where she knew she could sign it.

“A bunch of us were so ticked off [about Roe being overturned], and we were talking about it. And I was like, ‘I’m just going to go on and find where I can sign the stupid petition,’” Ms. Hoerauf said.

Activists on both sides of the abortion-rights debate expect to spend millions of dollars. They predict that donations will pour in from outside Michigan and that voters in other states will be watching.

“This is just the start of our fight,” Ms. Ayoub said. “We know that it is a long road to November.”

KHN correspondent Rachel Bluth contributed to this report. This story is part of a partnership that includes Michigan Radio, NPR, and KHN. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

As states grapple with the future of abortion in the United States, Michigan, California, and Vermont could become the first states to let voters decide whether the right to abortion should be written into the state constitution.

In Michigan, a proposed constitutional amendment would override a 90-year-old state law that makes abortion a felony even in cases of rape or incest. The U.S. Supreme Court’s overturning of Roe v. Wade could revive that abortion ban – and has galvanized abortion-rights advocates to secure new protections.

Some of the momentum is coming from activists getting involved for the first time.

“I wanted to do something, but I had no political experience or really any experience in activism,” said Amanda Mazur, who lives in rural northwestern Michigan. “But I thought, ‘Maybe I can volunteer and just offer something tangible to the movement.’”

Michigan organizers like Ms. Mazur submitted more than 750,000 signatures – a record number, they said – to state election officials in hopes of having the amendment appear on the November ballot.

If just over half those signatures are validated, Michigan voters will decide whether to amend the state’s constitution to guarantee broad individual rights to “reproductive freedom” that would cover abortion, contraception, and fertility treatments. It would also prevent the state from regulating abortions later in pregnancy if the patient’s “physical or mental health” is at risk.

The ballot initiative has the backing of medical groups like the American College of Obstetricians and Gynecologists, while conservative groups have called it radical and dangerous, claiming it would “allow late-term abortions for practically any reason.”

In California, the push to expand abortion access starts from a very different vantage point: The right to abortion is protected in state statute. And voters will be asked whether they want to enshrine it in the constitution. Proposition 1, which will be on the ballot in November, would prohibit the state from interfering with Californians’ reproductive health decisions, including those related to abortion or contraception.

“I want to know for sure that that right is protected,” state Sen. Toni Atkins (D-Calif.), the Democratic leader in the Senate and lead author of the amendment, said at a legislative hearing in June. “We are protecting ourselves from future courts and future politicians.”

The amendment is one strategy that several California lawmakers are pursuing to protect abortion access in the state. Gov. Gavin Newsom, a Democrat, has signed legislation to eliminate out-of-pocket expenses for abortion for most Californians and to protect California providers that offer abortion services from lawsuits in other states. The recent state budget deal also includes $200 million for reproductive and abortion care.

Earlier in July, Vermont Gov. Phil Scott, a Republican, announced that Proposal 5 will be on the November ballot. He said in a statement: “In Vermont, we solidified the right to choose in law, and now Vermonters have the opportunity to further protect that right in our constitution.”

For Ms. Mazur, the desire to “do something” started in 2017, when she and her husband gave their daughter, then 2 years old, some happy news: She was going to be a big sister. The family was thrilled.

But then doctors told Ms. Mazur something was wrong.

“I found out halfway through the pregnancy that the baby my husband and I hoped for suffered from a rare and life-limiting genetic condition,” Ms. Mazur said. “We ultimately made the compassionate choice to end the pregnancy for my well-being, and for the well-being of our family, and the life of what we thought would be our child.”

Devastated, Ms. Mazur turned to a national online support group and met people having similar experiences. But many group members said they were having a tough time finding a way to terminate their pregnancies.

“It really broke my heart that you’re going through this already devastating experience but have to travel far away from your home across the country ... [and] advocate for yourself like crazy just to get care that you have decided with your doctor is best for you,” Ms. Mazur said.

At the time, abortion rights in Michigan seemed pretty stable, but Ms. Mazur’s political awakening found an outlet this year.

Reproductive Freedom for All, a petition group backed by the American Civil Liberties Union of Michigan and Planned Parenthood Advocates of Michigan, was gathering signatures for the constitutional amendment to enshrine abortion protections in state law. The effort took on new urgency in May after a draft of the Supreme Court’s decision in Dobbs v. Jackson Women’s Health Organization was leaked and then published.

“Folks realized that this big, scary thing that they did not think would happen might actually happen,” said Jessica Ayoub, a field organizer with the ACLU of Michigan.

Some Michiganders were registering to vote just to be eligible to sign the petition. Jaynie Hoerauf, a 62-year-old attorney in Farwell, drove 40 miles to attend a rally where she knew she could sign it.

“A bunch of us were so ticked off [about Roe being overturned], and we were talking about it. And I was like, ‘I’m just going to go on and find where I can sign the stupid petition,’” Ms. Hoerauf said.

Activists on both sides of the abortion-rights debate expect to spend millions of dollars. They predict that donations will pour in from outside Michigan and that voters in other states will be watching.

“This is just the start of our fight,” Ms. Ayoub said. “We know that it is a long road to November.”

KHN correspondent Rachel Bluth contributed to this report. This story is part of a partnership that includes Michigan Radio, NPR, and KHN. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

As states grapple with the future of abortion in the United States, Michigan, California, and Vermont could become the first states to let voters decide whether the right to abortion should be written into the state constitution.

In Michigan, a proposed constitutional amendment would override a 90-year-old state law that makes abortion a felony even in cases of rape or incest. The U.S. Supreme Court’s overturning of Roe v. Wade could revive that abortion ban – and has galvanized abortion-rights advocates to secure new protections.

Some of the momentum is coming from activists getting involved for the first time.

“I wanted to do something, but I had no political experience or really any experience in activism,” said Amanda Mazur, who lives in rural northwestern Michigan. “But I thought, ‘Maybe I can volunteer and just offer something tangible to the movement.’”

Michigan organizers like Ms. Mazur submitted more than 750,000 signatures – a record number, they said – to state election officials in hopes of having the amendment appear on the November ballot.

If just over half those signatures are validated, Michigan voters will decide whether to amend the state’s constitution to guarantee broad individual rights to “reproductive freedom” that would cover abortion, contraception, and fertility treatments. It would also prevent the state from regulating abortions later in pregnancy if the patient’s “physical or mental health” is at risk.

The ballot initiative has the backing of medical groups like the American College of Obstetricians and Gynecologists, while conservative groups have called it radical and dangerous, claiming it would “allow late-term abortions for practically any reason.”

In California, the push to expand abortion access starts from a very different vantage point: The right to abortion is protected in state statute. And voters will be asked whether they want to enshrine it in the constitution. Proposition 1, which will be on the ballot in November, would prohibit the state from interfering with Californians’ reproductive health decisions, including those related to abortion or contraception.

“I want to know for sure that that right is protected,” state Sen. Toni Atkins (D-Calif.), the Democratic leader in the Senate and lead author of the amendment, said at a legislative hearing in June. “We are protecting ourselves from future courts and future politicians.”

The amendment is one strategy that several California lawmakers are pursuing to protect abortion access in the state. Gov. Gavin Newsom, a Democrat, has signed legislation to eliminate out-of-pocket expenses for abortion for most Californians and to protect California providers that offer abortion services from lawsuits in other states. The recent state budget deal also includes $200 million for reproductive and abortion care.

Earlier in July, Vermont Gov. Phil Scott, a Republican, announced that Proposal 5 will be on the November ballot. He said in a statement: “In Vermont, we solidified the right to choose in law, and now Vermonters have the opportunity to further protect that right in our constitution.”

For Ms. Mazur, the desire to “do something” started in 2017, when she and her husband gave their daughter, then 2 years old, some happy news: She was going to be a big sister. The family was thrilled.

But then doctors told Ms. Mazur something was wrong.

“I found out halfway through the pregnancy that the baby my husband and I hoped for suffered from a rare and life-limiting genetic condition,” Ms. Mazur said. “We ultimately made the compassionate choice to end the pregnancy for my well-being, and for the well-being of our family, and the life of what we thought would be our child.”

Devastated, Ms. Mazur turned to a national online support group and met people having similar experiences. But many group members said they were having a tough time finding a way to terminate their pregnancies.

“It really broke my heart that you’re going through this already devastating experience but have to travel far away from your home across the country ... [and] advocate for yourself like crazy just to get care that you have decided with your doctor is best for you,” Ms. Mazur said.

At the time, abortion rights in Michigan seemed pretty stable, but Ms. Mazur’s political awakening found an outlet this year.

Reproductive Freedom for All, a petition group backed by the American Civil Liberties Union of Michigan and Planned Parenthood Advocates of Michigan, was gathering signatures for the constitutional amendment to enshrine abortion protections in state law. The effort took on new urgency in May after a draft of the Supreme Court’s decision in Dobbs v. Jackson Women’s Health Organization was leaked and then published.

“Folks realized that this big, scary thing that they did not think would happen might actually happen,” said Jessica Ayoub, a field organizer with the ACLU of Michigan.

Some Michiganders were registering to vote just to be eligible to sign the petition. Jaynie Hoerauf, a 62-year-old attorney in Farwell, drove 40 miles to attend a rally where she knew she could sign it.

“A bunch of us were so ticked off [about Roe being overturned], and we were talking about it. And I was like, ‘I’m just going to go on and find where I can sign the stupid petition,’” Ms. Hoerauf said.

Activists on both sides of the abortion-rights debate expect to spend millions of dollars. They predict that donations will pour in from outside Michigan and that voters in other states will be watching.

“This is just the start of our fight,” Ms. Ayoub said. “We know that it is a long road to November.”

KHN correspondent Rachel Bluth contributed to this report. This story is part of a partnership that includes Michigan Radio, NPR, and KHN. KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

To the Editor:

Focal palmoplantar keratoderma and gingival keratosis (FPGK)(Online Mendelian Inheritance in Man [OMIM] 148730) is a rare autosomal-dominant syndrome featuring focal, pressure-related, painful palmoplantar keratoderma and gingival hyperkeratosis presenting as leukokeratosis. Focal palmoplantar keratoderma and gingival keratosis was first defined by Gorlin¹ in 1976. Since then, only a few cases have been reported, but no causative mutations have been identified.²

Focal pressure-related palmoplantar keratoderma (PPK) and oral hyperkeratosis also are seen in pachyonychia congenita (PC)(OMIM 167200, 615726, 615728, 167210), a rare autosomal-dominant disorder of keratinization characterized by PPK and nail dystrophy. Patients with PC often present with plantar pain; more variable features include oral leukokeratosis, follicular hyperkeratosis, pilosebaceous and epidermal inclusion cysts, hoarseness, hyperhidrosis, and natal teeth. Pachyonychia congenita is caused by mutation in keratin genes KRT6A, KRT6B, KRT16, or KRT17.

Focal palmoplantar keratoderma and gingival keratosis as well as PC are distinct from other forms of PPK with gingival involvement such as Papillon-Lefèvre syndrome (OMIM 245000) and Olmsted syndrome (OMIM 614594). Papillon-Lefèvre syndrome is a rare autosomal-recessive disorder caused by mutations in the cathepsin C, CTSC, gene that exhibits erythematous, diffuse, transgradient PPK and early severe periodontitis. Olmsted syndrome is caused by autosomal-dominant gene mutations in transient receptor potential cation channel, subfamily V, member 3, TRPV3, and is characterized by severe bilateral transgradient PPK with leukoplakia of the tongue and buccal mucosa but also usually exhibits marked periorificial keratotic plaques, which facilitate exclusion of other phenotypically similar syndromes.³

Despite the common features of FPGK and PC, they are considered distinct disorders due to absence of nail changes in FPGK and no prior evidence of a common genetic cause. We present a patient with familial FPGK found by whole exome sequencing to be caused by a mutation in KRT16.

The proband was a 57-year-old man born to unrelated parents (Figure 1). He had no skin problems at birth, and his development was normal. He had painful focal keratoderma since childhood that were most prominent at pressure points on the soles and toes (Figure 2A), in addition to gingival hyperkeratosis and oral leukokeratosis (Figure 2B). He had no associated abnormalities of the skin, hair, or teeth and no nail findings (Figure 2C). He reported that his father and 2 of his 3 sisters were affected with similar symptoms. A punch biopsy of the right fifth toe was consistent with verrucous epidermal hyperplasia with perinuclear keratinization in the spinous layer (Figure 3A). A gingival biopsy showed perinuclear eosinophilic globules and basophilic stranding in the cytoplasm (Figure 3B). His older sister had more severe and painful focal keratoderma of the soles, punctate keratoderma of the palms, gingival hyperkeratosis, and leukokeratosis of the tongue.

Whole exome sequencing of the proband revealed a heterozygous missense mutation in KRT16 (c.380G>A, p.R127H, rs57424749). Sanger sequencing confirmed this mutation and showed that it was heterozygous in both of his affected sisters and absent in his unaffected niece (Figure 1). The patient was treated with topical and systemic retinoids, keratolytics, and mechanical removal to moderate effect, with noted improvement in the appearance and associated pain of the plantar keratoderma.

Phenotypic heterogeneity is common in PC, though PC due to KRT6A mutations demonstrates more severe nail disease with oral lesions, cysts, and follicular hyperkeratosis, while PC caused by KRT16 mutations generally presents with more extensive and painful PPK.⁴KRT16 mutations affecting p.R127 are frequent causes of PC, and genotype-phenotype correlations have been observed. Individuals with p.R127P mutations exhibit more severe disease with earlier age of onset, more extensive nail involvement and oral leukokeratosis, and greater impact on daily quality of life than in individuals with p.R127C mutations.⁵ Cases of PC with KRT16 p.R127S and p.R127G mutations also have been observed. The KRT16 c.380G>A, p.R127H mutation we documented has been reported in one kindred with PC who presented with PPK, oral leukokeratosis, toenail thickening, and pilosebaceous and follicular hyperkeratosis.⁶

Although patients with FPGK lack the thickening of fingernails and/or toenails considered a defining feature of PC, the disorders otherwise are phenotypically similar, suggesting the possibility of common pathogenesis. One linkage study of familial FPGK excluded genetic intervals containing type I and type II keratins but was limited to a single small kindred.² This study and our data together suggest that, similar to PC, there are multiple genes in which mutations cause FPGK.

Murine Krt16 knockouts show distinct phenotypes depending on the mouse strain in which they are propagated, ranging from perinatal lethality to differences in the severity of oral and PPK lesions.⁷ These observations provide evidence that additional genetic variants contribute to Krt16 phenotypes in mice and suggest the same could be true for humans.

We propose that some cases of FPGK are due to mutations in KRT16 and thus share a genetic pathogenesis with PC, underscoring the utility of whole exome sequencing in providing genetic diagnoses for disorders that are genetically and clinically heterogeneous. Further biologic investigation of phenotypes caused by KRT16 mutation may reveal respective contributions of additional genetic variation and environmental effects to the variable clinical presentations.

To the Editor:

Focal palmoplantar keratoderma and gingival keratosis (FPGK)(Online Mendelian Inheritance in Man [OMIM] 148730) is a rare autosomal-dominant syndrome featuring focal, pressure-related, painful palmoplantar keratoderma and gingival hyperkeratosis presenting as leukokeratosis. Focal palmoplantar keratoderma and gingival keratosis was first defined by Gorlin¹ in 1976. Since then, only a few cases have been reported, but no causative mutations have been identified.²

Focal pressure-related palmoplantar keratoderma (PPK) and oral hyperkeratosis also are seen in pachyonychia congenita (PC)(OMIM 167200, 615726, 615728, 167210), a rare autosomal-dominant disorder of keratinization characterized by PPK and nail dystrophy. Patients with PC often present with plantar pain; more variable features include oral leukokeratosis, follicular hyperkeratosis, pilosebaceous and epidermal inclusion cysts, hoarseness, hyperhidrosis, and natal teeth. Pachyonychia congenita is caused by mutation in keratin genes KRT6A, KRT6B, KRT16, or KRT17.

Focal palmoplantar keratoderma and gingival keratosis as well as PC are distinct from other forms of PPK with gingival involvement such as Papillon-Lefèvre syndrome (OMIM 245000) and Olmsted syndrome (OMIM 614594). Papillon-Lefèvre syndrome is a rare autosomal-recessive disorder caused by mutations in the cathepsin C, CTSC, gene that exhibits erythematous, diffuse, transgradient PPK and early severe periodontitis. Olmsted syndrome is caused by autosomal-dominant gene mutations in transient receptor potential cation channel, subfamily V, member 3, TRPV3, and is characterized by severe bilateral transgradient PPK with leukoplakia of the tongue and buccal mucosa but also usually exhibits marked periorificial keratotic plaques, which facilitate exclusion of other phenotypically similar syndromes.³

Despite the common features of FPGK and PC, they are considered distinct disorders due to absence of nail changes in FPGK and no prior evidence of a common genetic cause. We present a patient with familial FPGK found by whole exome sequencing to be caused by a mutation in KRT16.

The proband was a 57-year-old man born to unrelated parents (Figure 1). He had no skin problems at birth, and his development was normal. He had painful focal keratoderma since childhood that were most prominent at pressure points on the soles and toes (Figure 2A), in addition to gingival hyperkeratosis and oral leukokeratosis (Figure 2B). He had no associated abnormalities of the skin, hair, or teeth and no nail findings (Figure 2C). He reported that his father and 2 of his 3 sisters were affected with similar symptoms. A punch biopsy of the right fifth toe was consistent with verrucous epidermal hyperplasia with perinuclear keratinization in the spinous layer (Figure 3A). A gingival biopsy showed perinuclear eosinophilic globules and basophilic stranding in the cytoplasm (Figure 3B). His older sister had more severe and painful focal keratoderma of the soles, punctate keratoderma of the palms, gingival hyperkeratosis, and leukokeratosis of the tongue.

Whole exome sequencing of the proband revealed a heterozygous missense mutation in KRT16 (c.380G>A, p.R127H, rs57424749). Sanger sequencing confirmed this mutation and showed that it was heterozygous in both of his affected sisters and absent in his unaffected niece (Figure 1). The patient was treated with topical and systemic retinoids, keratolytics, and mechanical removal to moderate effect, with noted improvement in the appearance and associated pain of the plantar keratoderma.

Phenotypic heterogeneity is common in PC, though PC due to KRT6A mutations demonstrates more severe nail disease with oral lesions, cysts, and follicular hyperkeratosis, while PC caused by KRT16 mutations generally presents with more extensive and painful PPK.⁴KRT16 mutations affecting p.R127 are frequent causes of PC, and genotype-phenotype correlations have been observed. Individuals with p.R127P mutations exhibit more severe disease with earlier age of onset, more extensive nail involvement and oral leukokeratosis, and greater impact on daily quality of life than in individuals with p.R127C mutations.⁵ Cases of PC with KRT16 p.R127S and p.R127G mutations also have been observed. The KRT16 c.380G>A, p.R127H mutation we documented has been reported in one kindred with PC who presented with PPK, oral leukokeratosis, toenail thickening, and pilosebaceous and follicular hyperkeratosis.⁶

Although patients with FPGK lack the thickening of fingernails and/or toenails considered a defining feature of PC, the disorders otherwise are phenotypically similar, suggesting the possibility of common pathogenesis. One linkage study of familial FPGK excluded genetic intervals containing type I and type II keratins but was limited to a single small kindred.² This study and our data together suggest that, similar to PC, there are multiple genes in which mutations cause FPGK.

Murine Krt16 knockouts show distinct phenotypes depending on the mouse strain in which they are propagated, ranging from perinatal lethality to differences in the severity of oral and PPK lesions.⁷ These observations provide evidence that additional genetic variants contribute to Krt16 phenotypes in mice and suggest the same could be true for humans.

We propose that some cases of FPGK are due to mutations in KRT16 and thus share a genetic pathogenesis with PC, underscoring the utility of whole exome sequencing in providing genetic diagnoses for disorders that are genetically and clinically heterogeneous. Further biologic investigation of phenotypes caused by KRT16 mutation may reveal respective contributions of additional genetic variation and environmental effects to the variable clinical presentations.

To the Editor:

Focal palmoplantar keratoderma and gingival keratosis (FPGK)(Online Mendelian Inheritance in Man [OMIM] 148730) is a rare autosomal-dominant syndrome featuring focal, pressure-related, painful palmoplantar keratoderma and gingival hyperkeratosis presenting as leukokeratosis. Focal palmoplantar keratoderma and gingival keratosis was first defined by Gorlin¹ in 1976. Since then, only a few cases have been reported, but no causative mutations have been identified.²

Focal pressure-related palmoplantar keratoderma (PPK) and oral hyperkeratosis also are seen in pachyonychia congenita (PC)(OMIM 167200, 615726, 615728, 167210), a rare autosomal-dominant disorder of keratinization characterized by PPK and nail dystrophy. Patients with PC often present with plantar pain; more variable features include oral leukokeratosis, follicular hyperkeratosis, pilosebaceous and epidermal inclusion cysts, hoarseness, hyperhidrosis, and natal teeth. Pachyonychia congenita is caused by mutation in keratin genes KRT6A, KRT6B, KRT16, or KRT17.

Focal palmoplantar keratoderma and gingival keratosis as well as PC are distinct from other forms of PPK with gingival involvement such as Papillon-Lefèvre syndrome (OMIM 245000) and Olmsted syndrome (OMIM 614594). Papillon-Lefèvre syndrome is a rare autosomal-recessive disorder caused by mutations in the cathepsin C, CTSC, gene that exhibits erythematous, diffuse, transgradient PPK and early severe periodontitis. Olmsted syndrome is caused by autosomal-dominant gene mutations in transient receptor potential cation channel, subfamily V, member 3, TRPV3, and is characterized by severe bilateral transgradient PPK with leukoplakia of the tongue and buccal mucosa but also usually exhibits marked periorificial keratotic plaques, which facilitate exclusion of other phenotypically similar syndromes.³

Despite the common features of FPGK and PC, they are considered distinct disorders due to absence of nail changes in FPGK and no prior evidence of a common genetic cause. We present a patient with familial FPGK found by whole exome sequencing to be caused by a mutation in KRT16.

The proband was a 57-year-old man born to unrelated parents (Figure 1). He had no skin problems at birth, and his development was normal. He had painful focal keratoderma since childhood that were most prominent at pressure points on the soles and toes (Figure 2A), in addition to gingival hyperkeratosis and oral leukokeratosis (Figure 2B). He had no associated abnormalities of the skin, hair, or teeth and no nail findings (Figure 2C). He reported that his father and 2 of his 3 sisters were affected with similar symptoms. A punch biopsy of the right fifth toe was consistent with verrucous epidermal hyperplasia with perinuclear keratinization in the spinous layer (Figure 3A). A gingival biopsy showed perinuclear eosinophilic globules and basophilic stranding in the cytoplasm (Figure 3B). His older sister had more severe and painful focal keratoderma of the soles, punctate keratoderma of the palms, gingival hyperkeratosis, and leukokeratosis of the tongue.

Whole exome sequencing of the proband revealed a heterozygous missense mutation in KRT16 (c.380G>A, p.R127H, rs57424749). Sanger sequencing confirmed this mutation and showed that it was heterozygous in both of his affected sisters and absent in his unaffected niece (Figure 1). The patient was treated with topical and systemic retinoids, keratolytics, and mechanical removal to moderate effect, with noted improvement in the appearance and associated pain of the plantar keratoderma.

Phenotypic heterogeneity is common in PC, though PC due to KRT6A mutations demonstrates more severe nail disease with oral lesions, cysts, and follicular hyperkeratosis, while PC caused by KRT16 mutations generally presents with more extensive and painful PPK.⁴KRT16 mutations affecting p.R127 are frequent causes of PC, and genotype-phenotype correlations have been observed. Individuals with p.R127P mutations exhibit more severe disease with earlier age of onset, more extensive nail involvement and oral leukokeratosis, and greater impact on daily quality of life than in individuals with p.R127C mutations.⁵ Cases of PC with KRT16 p.R127S and p.R127G mutations also have been observed. The KRT16 c.380G>A, p.R127H mutation we documented has been reported in one kindred with PC who presented with PPK, oral leukokeratosis, toenail thickening, and pilosebaceous and follicular hyperkeratosis.⁶

Although patients with FPGK lack the thickening of fingernails and/or toenails considered a defining feature of PC, the disorders otherwise are phenotypically similar, suggesting the possibility of common pathogenesis. One linkage study of familial FPGK excluded genetic intervals containing type I and type II keratins but was limited to a single small kindred.² This study and our data together suggest that, similar to PC, there are multiple genes in which mutations cause FPGK.

Murine Krt16 knockouts show distinct phenotypes depending on the mouse strain in which they are propagated, ranging from perinatal lethality to differences in the severity of oral and PPK lesions.⁷ These observations provide evidence that additional genetic variants contribute to Krt16 phenotypes in mice and suggest the same could be true for humans.

We propose that some cases of FPGK are due to mutations in KRT16 and thus share a genetic pathogenesis with PC, underscoring the utility of whole exome sequencing in providing genetic diagnoses for disorders that are genetically and clinically heterogeneous. Further biologic investigation of phenotypes caused by KRT16 mutation may reveal respective contributions of additional genetic variation and environmental effects to the variable clinical presentations.

Use of cholesterol-lowering statins was linked to a lower risk of developing a subtype of diabetes that occurs after acute pancreatitis, according to a new report.

The benefits of statins depended on the consistency of usage, with regular users having a lower risk of developing postpancreatitis diabetes than irregular users. The results were similar with low, moderate, and high statin doses, as well as in cases of both mild and severe acute pancreatitis.

“About 15% of patients with acute pancreatitis will develop diabetes mellitus in the next 5 years, and although we can monitor for it, we can’t do anything to prevent it,” Nikhil Thiruvengadam, MD, the lead study author and a gastroenterologist at Loma Linda (Calif.) University, told this news organization.

iStock/ThinkStock

“This could push you as a clinician to prescribe [a statin if you have a reason to] because it could provide two benefits instead of just one,” he said.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Steady use mattered, not dose

Patients with acute pancreatitis face at least a twofold increased risk of developing postpancreatitis diabetes, the study authors write. Although previous studies have shown that statins can lower the incidence and severity of acute pancreatitis, they haven’t been studied for the prevention of postpancreatitis diabetes.

In a collaborative study with several other universities, Dr. Thiruvengadam and colleagues examined commercial insurance claims from the Optum Clinformatics database to assess the impact of statins on 118,479 patients without preexisting diabetes admitted for a first episode of acute pancreatitis between 2008 and 2020.

They compared patients who consistently used statins with irregular users and nonusers. Regular statin usage was defined as patients who had statin prescriptions filled for at least 80% of the year prior to their acute pancreatitis diagnosis. The analysis included 9,048 patients (7.6%) who used statins regularly, 27,272 (23%) who used statins irregularly, and 82,159 (69.3%) nonusers.

With a median follow-up of 3.5 years, the 5-year cumulative incidence of postpancreatitis diabetes was 7.5% among regular statin users and 12.7% among nonusers. Regular statin users had a 42% lower risk of developing postpancreatitis diabetes, compared with nonusers. Irregular statin users had a 15% lower risk of postpancreatitis diabetes.

In addition, the 5-year cumulative incidence of insulin-dependent postpancreatitis diabetes was 2.4% among regular statin users and 6.6% among nonusers. Regular statin users had a 52% lower risk of developing insulin-dependent diabetes as compared with nonusers.

Daily dosage didn’t demonstrate a linear dose-response relationship. That means high-dose statins may not be more effective in preventing diabetes as compared with lower doses, the study authors write.

Statin usage was effective across additional analyses, including sex, etiologies of pancreatitis, and in both mild and severe acute pancreatitis. According to the study authors, this suggests that a broad population of these patients may benefit from statins.

“We were pleasantly surprised by the variety of findings,” Dr. Thiruvengadam said. “We’re seeing strong signals, especially with consistency of usage.”
 

Ongoing studies

The results may seem paradoxical, the study authors write, given an epidemiologic association with a slight increase in new-onset diabetes with statin initiation. But, as other researchers have reported, postpancreatitis diabetes and type 2 diabetes have different clinical features and underlying pathophysiology. For example, patients with postpancreatitis diabetes have much higher rates of requiring insulin, hospitalization, and all-cause mortality, the study authors write.

In fact, postpancreatitis diabetes is thought to be driven by chronic low-grade inflammation attributable to interleukin-6 and tumor necrosis factor–alpha. Statins have been shown to reduce tumor necrosis factor–alpha secretion and the production of C-reactive protein in response to circulating interleukin-6 in hepatocytes, they write.

The results should inform long-term prospective studies of acute pancreatitis, the study authors write, as well as randomized controlled trials of statins.

In the meantime, gastroenterologists and primary care physicians who see outpatients after hospitalization for acute pancreatitis may consider using statins, particularly in those who may have another possible indication for statin therapy, such as mild hyperlipidemia.

“There appears to be a low-dose benefit, which is another reason why providers may consider using statins, though it’s not for everyone with pancreatitis,” Dr. Thiruvengadam said. “This could be an exploratory pathway and suggested for use in the right setting.”

The Type 1 Diabetes in Acute Pancreatitis Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, is conducting an observational cohort study at more than a dozen locations across the country to investigate the incidence, etiology, and pathophysiology of diabetes after acute pancreatitis.

“Diabetes is surprisingly common after even a single attack of acute pancreatitis,” Chris Forsmark, MD, professor of medicine and chief of the division of gastroenterology, hepatology, and nutrition at the University of Florida, Gainesville, told this news organization.

Dr. Forsmark, who wasn’t involved with this study, is a member of T1DAPC and one of the principal investigators in Florida.

“The reduction of risk by 42% is quite substantial,” he said. “Like all such studies, there is risk of bias and confounding in determining the actual risk. Nonetheless, the results provide a strong reason for confirmation in other datasets and for further study.”

The study didn’t report funding support. Dr. Thiruvengadam and Dr. Forsmark report no relevant financial relationships.

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

Use of cholesterol-lowering statins was linked to a lower risk of developing a subtype of diabetes that occurs after acute pancreatitis, according to a new report.

The benefits of statins depended on the consistency of usage, with regular users having a lower risk of developing postpancreatitis diabetes than irregular users. The results were similar with low, moderate, and high statin doses, as well as in cases of both mild and severe acute pancreatitis.

“About 15% of patients with acute pancreatitis will develop diabetes mellitus in the next 5 years, and although we can monitor for it, we can’t do anything to prevent it,” Nikhil Thiruvengadam, MD, the lead study author and a gastroenterologist at Loma Linda (Calif.) University, told this news organization.

iStock/ThinkStock

“This could push you as a clinician to prescribe [a statin if you have a reason to] because it could provide two benefits instead of just one,” he said.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Steady use mattered, not dose

Patients with acute pancreatitis face at least a twofold increased risk of developing postpancreatitis diabetes, the study authors write. Although previous studies have shown that statins can lower the incidence and severity of acute pancreatitis, they haven’t been studied for the prevention of postpancreatitis diabetes.

In a collaborative study with several other universities, Dr. Thiruvengadam and colleagues examined commercial insurance claims from the Optum Clinformatics database to assess the impact of statins on 118,479 patients without preexisting diabetes admitted for a first episode of acute pancreatitis between 2008 and 2020.

They compared patients who consistently used statins with irregular users and nonusers. Regular statin usage was defined as patients who had statin prescriptions filled for at least 80% of the year prior to their acute pancreatitis diagnosis. The analysis included 9,048 patients (7.6%) who used statins regularly, 27,272 (23%) who used statins irregularly, and 82,159 (69.3%) nonusers.

With a median follow-up of 3.5 years, the 5-year cumulative incidence of postpancreatitis diabetes was 7.5% among regular statin users and 12.7% among nonusers. Regular statin users had a 42% lower risk of developing postpancreatitis diabetes, compared with nonusers. Irregular statin users had a 15% lower risk of postpancreatitis diabetes.

In addition, the 5-year cumulative incidence of insulin-dependent postpancreatitis diabetes was 2.4% among regular statin users and 6.6% among nonusers. Regular statin users had a 52% lower risk of developing insulin-dependent diabetes as compared with nonusers.

Daily dosage didn’t demonstrate a linear dose-response relationship. That means high-dose statins may not be more effective in preventing diabetes as compared with lower doses, the study authors write.

Statin usage was effective across additional analyses, including sex, etiologies of pancreatitis, and in both mild and severe acute pancreatitis. According to the study authors, this suggests that a broad population of these patients may benefit from statins.

“We were pleasantly surprised by the variety of findings,” Dr. Thiruvengadam said. “We’re seeing strong signals, especially with consistency of usage.”
 

Ongoing studies

The results may seem paradoxical, the study authors write, given an epidemiologic association with a slight increase in new-onset diabetes with statin initiation. But, as other researchers have reported, postpancreatitis diabetes and type 2 diabetes have different clinical features and underlying pathophysiology. For example, patients with postpancreatitis diabetes have much higher rates of requiring insulin, hospitalization, and all-cause mortality, the study authors write.

In fact, postpancreatitis diabetes is thought to be driven by chronic low-grade inflammation attributable to interleukin-6 and tumor necrosis factor–alpha. Statins have been shown to reduce tumor necrosis factor–alpha secretion and the production of C-reactive protein in response to circulating interleukin-6 in hepatocytes, they write.

The results should inform long-term prospective studies of acute pancreatitis, the study authors write, as well as randomized controlled trials of statins.

In the meantime, gastroenterologists and primary care physicians who see outpatients after hospitalization for acute pancreatitis may consider using statins, particularly in those who may have another possible indication for statin therapy, such as mild hyperlipidemia.

“There appears to be a low-dose benefit, which is another reason why providers may consider using statins, though it’s not for everyone with pancreatitis,” Dr. Thiruvengadam said. “This could be an exploratory pathway and suggested for use in the right setting.”

The Type 1 Diabetes in Acute Pancreatitis Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, is conducting an observational cohort study at more than a dozen locations across the country to investigate the incidence, etiology, and pathophysiology of diabetes after acute pancreatitis.

“Diabetes is surprisingly common after even a single attack of acute pancreatitis,” Chris Forsmark, MD, professor of medicine and chief of the division of gastroenterology, hepatology, and nutrition at the University of Florida, Gainesville, told this news organization.

Dr. Forsmark, who wasn’t involved with this study, is a member of T1DAPC and one of the principal investigators in Florida.

“The reduction of risk by 42% is quite substantial,” he said. “Like all such studies, there is risk of bias and confounding in determining the actual risk. Nonetheless, the results provide a strong reason for confirmation in other datasets and for further study.”

The study didn’t report funding support. Dr. Thiruvengadam and Dr. Forsmark report no relevant financial relationships.

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

Use of cholesterol-lowering statins was linked to a lower risk of developing a subtype of diabetes that occurs after acute pancreatitis, according to a new report.

The benefits of statins depended on the consistency of usage, with regular users having a lower risk of developing postpancreatitis diabetes than irregular users. The results were similar with low, moderate, and high statin doses, as well as in cases of both mild and severe acute pancreatitis.

“About 15% of patients with acute pancreatitis will develop diabetes mellitus in the next 5 years, and although we can monitor for it, we can’t do anything to prevent it,” Nikhil Thiruvengadam, MD, the lead study author and a gastroenterologist at Loma Linda (Calif.) University, told this news organization.

iStock/ThinkStock

“This could push you as a clinician to prescribe [a statin if you have a reason to] because it could provide two benefits instead of just one,” he said.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Steady use mattered, not dose

Patients with acute pancreatitis face at least a twofold increased risk of developing postpancreatitis diabetes, the study authors write. Although previous studies have shown that statins can lower the incidence and severity of acute pancreatitis, they haven’t been studied for the prevention of postpancreatitis diabetes.

In a collaborative study with several other universities, Dr. Thiruvengadam and colleagues examined commercial insurance claims from the Optum Clinformatics database to assess the impact of statins on 118,479 patients without preexisting diabetes admitted for a first episode of acute pancreatitis between 2008 and 2020.

They compared patients who consistently used statins with irregular users and nonusers. Regular statin usage was defined as patients who had statin prescriptions filled for at least 80% of the year prior to their acute pancreatitis diagnosis. The analysis included 9,048 patients (7.6%) who used statins regularly, 27,272 (23%) who used statins irregularly, and 82,159 (69.3%) nonusers.

With a median follow-up of 3.5 years, the 5-year cumulative incidence of postpancreatitis diabetes was 7.5% among regular statin users and 12.7% among nonusers. Regular statin users had a 42% lower risk of developing postpancreatitis diabetes, compared with nonusers. Irregular statin users had a 15% lower risk of postpancreatitis diabetes.

In addition, the 5-year cumulative incidence of insulin-dependent postpancreatitis diabetes was 2.4% among regular statin users and 6.6% among nonusers. Regular statin users had a 52% lower risk of developing insulin-dependent diabetes as compared with nonusers.

Daily dosage didn’t demonstrate a linear dose-response relationship. That means high-dose statins may not be more effective in preventing diabetes as compared with lower doses, the study authors write.

Statin usage was effective across additional analyses, including sex, etiologies of pancreatitis, and in both mild and severe acute pancreatitis. According to the study authors, this suggests that a broad population of these patients may benefit from statins.

“We were pleasantly surprised by the variety of findings,” Dr. Thiruvengadam said. “We’re seeing strong signals, especially with consistency of usage.”
 

Ongoing studies

The results may seem paradoxical, the study authors write, given an epidemiologic association with a slight increase in new-onset diabetes with statin initiation. But, as other researchers have reported, postpancreatitis diabetes and type 2 diabetes have different clinical features and underlying pathophysiology. For example, patients with postpancreatitis diabetes have much higher rates of requiring insulin, hospitalization, and all-cause mortality, the study authors write.

In fact, postpancreatitis diabetes is thought to be driven by chronic low-grade inflammation attributable to interleukin-6 and tumor necrosis factor–alpha. Statins have been shown to reduce tumor necrosis factor–alpha secretion and the production of C-reactive protein in response to circulating interleukin-6 in hepatocytes, they write.

The results should inform long-term prospective studies of acute pancreatitis, the study authors write, as well as randomized controlled trials of statins.

In the meantime, gastroenterologists and primary care physicians who see outpatients after hospitalization for acute pancreatitis may consider using statins, particularly in those who may have another possible indication for statin therapy, such as mild hyperlipidemia.

“There appears to be a low-dose benefit, which is another reason why providers may consider using statins, though it’s not for everyone with pancreatitis,” Dr. Thiruvengadam said. “This could be an exploratory pathway and suggested for use in the right setting.”

The Type 1 Diabetes in Acute Pancreatitis Consortium, sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, is conducting an observational cohort study at more than a dozen locations across the country to investigate the incidence, etiology, and pathophysiology of diabetes after acute pancreatitis.

“Diabetes is surprisingly common after even a single attack of acute pancreatitis,” Chris Forsmark, MD, professor of medicine and chief of the division of gastroenterology, hepatology, and nutrition at the University of Florida, Gainesville, told this news organization.

Dr. Forsmark, who wasn’t involved with this study, is a member of T1DAPC and one of the principal investigators in Florida.

“The reduction of risk by 42% is quite substantial,” he said. “Like all such studies, there is risk of bias and confounding in determining the actual risk. Nonetheless, the results provide a strong reason for confirmation in other datasets and for further study.”

The study didn’t report funding support. Dr. Thiruvengadam and Dr. Forsmark report no relevant financial relationships.

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