MDedge Dermatology

Andrea Partida, DO, an obstetrician and gynecologist in Enid, Okla., loves her new assistant.

The 15 or 20 minutes she used to spend on documentation for each patient visit is now 3. The 2-3 hours she’d spend charting outside clinic hours is maybe 1.

All that time saved allows her to see two to five more patients a day, provide better care to each patient, and get more involved in hospital leadership at Integris Health, where she works.

“I have a better work-life balance with my family,” Dr. Partida said. “I leave work at work and get home earlier.”

You’ve probably figured out the plot twist: Dr. Partida’s assistant is not a person – it’s artificial intelligence (AI).

Dr. Partida uses IRIS, a tool from OnPoint Healthcare Partners, part of a fast-growing niche of AI medical scribes designed to automate onerous data entry. The evolution of generative AI – specifically, large language models, such as ChatGPT – has led to a rapid explosion of these tools. Other companies in the space include Abridge, Ambience Healthcare, Augmedix, DeepScribe, Nuance (part of Microsoft), and Suki. The newest kid on the block, Amazon Web Services, announced the launch of HealthScribe in July.

These tools – some of which are already on the market, with more on the way – record patient visits and generate notes for treatment and billing. Earlier iterations combine AI with offsite human scribes who provide quality control. But more and more are fully automated, no human required. Some also offer video recording and foreign language translation.

The promise is alluring: Ease your workload and reclaim hours in your day so you can spend more time with patients or try that “work-life balance” thing you’ve heard so much about.

But do these tools fulfill that promise?

According to Dr. Partida and other doctors who spoke with this news organization, the answer is a resounding yes.
 

A tech solution for a tech problem

“I believe a lot of doctors see patients for free. They get paid to do paperwork,” said Anthony J. Mazzarelli, MD, JD, MBE, co-president and CEO of Cooper University Health Care, in Camden, N.J.

Indeed, for every hour U.S. clinicians spend with their patients, they may spend 2 more hours documenting in electronic health records (EHRs), estimates show. About half of doctors, especially those in primary care, report feeling burned out, and some 42% say they want to quit clinical practice.

Enter AI scribes.

“The holy grail in medicine right now is improving burnout while also maintaining or improving productivity and quality,” said Patricia Garcia, MD, associate clinical information officer for ambulatory care at Stanford (Calif.) Health Care. “These ambient digital scribes have the potential to do just that.”

While anyone can buy these products, their use has been mostly limited to pilot programs and early adopters so far, said Dr. Garcia, who has been helping to pilot Nuance’s digital scribe, DAX, at Stanford.

But that’s expected to change quickly. “I don’t think the time horizon is a decade,” Dr. Garcia said. “I think within a matter of 2 or 3 years, these tools will be pervasive throughout health care.”

Since introducing these tools at Cooper, “our doctors’ paperwork burden is significantly lighter,” said Dr. Mazzarelli, who decides which technologies Cooper should invest in and who monitors their results. In Cooper studies, physicians who used DAX more than half the time spent 43% less time working on notes.

“They spend more time connecting with their patients, talking with them, and looking them in the eye,” Dr. Mazzarelli said. That, in turn, seems to improve patient outcomes, reduce doctor burnout and turnover, and lower costs.

The AI scribes, by virtue of eliminating the distraction of note taking, also allow doctors to give their full attention to the patient. “The patient relationship is the most important aspect of medicine,” said Raul Ayala, MD, MHCM, a family medicine physician at Adventist Health, in Hanford, Calif., who uses Augmedix. The digital scribe “helps us strengthen that relationship.”
 

What’s it like to use an AI medical scribe?

The scribes feature hardware (typically a smartphone or tablet) and software built on automatic speech recognition, natural language processing, and machine learning. Download an app to your device, and you’re ready to go. Use it to record in-person or telehealth visits.

In the first week, a company may help train you to use the hardware and software. You’ll likely start by using it for a few patient visits per day, ramping up gradually. Dr. Partida said she was comfortable using the system for all her patients in 6 weeks.

Each day, Dr. Partida logs in to a dedicated smartphone or tablet, opens the app, and reviews her schedule, including details she needs to prepare for each patient.

At the start of each patient visit, Dr. Partida taps the app icon to begin recording and lays the device nearby. She can pause as needed. At the end of the visit, she taps the icon again to stop recording.

The AI listens, creates the note, and updates relevant data in the EHR. The note includes patient problems, assessment, treatment plan, patient history, orders, and tasks for staff, along with medications, referrals, and preauthorizations. A human scribe, who is also a physician, reviews the information for accuracy and edits it as needed. By the next morning, the data are ready for Dr. Partida to review.

Fully automated versions can generate notes much faster. Jack Shilling, MD, MBA, an orthopedic surgeon at Cooper University Health Care, in Voorhees, N.J., uses DAX. A new feature called DAX Express – which uses OpenAI’s GPT-4 but no humans – provides him with a draft of his clinical notes in just seconds.
 

How accurate are AI notes?

The accuracy of those notes remains an open question, Dr. Garcia said – mostly because accuracy can be hard to define.

“If you asked five docs to write a note based on the same patient encounter, you’d get five different notes,” Dr. Garcia said. “That makes it hard to assess these technologies in a scientifically rigorous way.”

Still, the onus is on the physician to review the notes and edit them as needed, Dr. Garcia said. How light or heavy those edits are can depend on your unique preferences.

Dr. Shilling said he may need to lightly edit transcripts of his conversations with patients. “When someone tells me how long their knee hurts, slight variability in their transcribed words is tolerable,” he said. But for some things – such as physical exam notes and x-ray readings – he dictates directly into the device, speaking at a closer range and being less conversational, more exact in his speech.
 

Should you let patients know they’re being recorded?

The federal Health Insurance Portability and Accountability Act (HIPAA) does not require providers to inform patients that their face-to-face conversations are being recorded, said Daniel Lebovic, JD, corporate legal counsel at Compliancy Group, in Greenlawn, N.Y., a company that helps providers adhere to HIPAA rules.

But make sure you know the laws in your state and the policies at your health care practice. State laws may require providers to inform patients and to get patients’ consent in advance of being recorded.

All the doctors who spoke to this news organization said their patients are informed that they’ll be recorded and that they can opt out if they wish.
 

How much do AI scribes cost?

As the marketplace for these tools expands, companies are offering more products and services at different price points that target a range of organizations, from large health care systems to small private practices.

Price models vary, said Dr. Garcia. Some are based on the number of users, others on the number of notes, and still others on minutes.

Amazon’s HealthScribe is priced at 10 cents per minute. For 1,000 consultation transcripts per month, with each call averaging 15 minutes, it would take 15,000 minutes at a total cost of $1,500 for the month.

In general, the rapidly growing competition in this space could mean prices become more affordable, Dr. Garcia said. “It’s good that so many are getting into this game, because that means the price will come down and it will be a lot more accessible to everybody.”

A version of this article appeared on Medscape.com.

Andrea Partida, DO, an obstetrician and gynecologist in Enid, Okla., loves her new assistant.

The 15 or 20 minutes she used to spend on documentation for each patient visit is now 3. The 2-3 hours she’d spend charting outside clinic hours is maybe 1.

All that time saved allows her to see two to five more patients a day, provide better care to each patient, and get more involved in hospital leadership at Integris Health, where she works.

“I have a better work-life balance with my family,” Dr. Partida said. “I leave work at work and get home earlier.”

You’ve probably figured out the plot twist: Dr. Partida’s assistant is not a person – it’s artificial intelligence (AI).

Dr. Partida uses IRIS, a tool from OnPoint Healthcare Partners, part of a fast-growing niche of AI medical scribes designed to automate onerous data entry. The evolution of generative AI – specifically, large language models, such as ChatGPT – has led to a rapid explosion of these tools. Other companies in the space include Abridge, Ambience Healthcare, Augmedix, DeepScribe, Nuance (part of Microsoft), and Suki. The newest kid on the block, Amazon Web Services, announced the launch of HealthScribe in July.

These tools – some of which are already on the market, with more on the way – record patient visits and generate notes for treatment and billing. Earlier iterations combine AI with offsite human scribes who provide quality control. But more and more are fully automated, no human required. Some also offer video recording and foreign language translation.

The promise is alluring: Ease your workload and reclaim hours in your day so you can spend more time with patients or try that “work-life balance” thing you’ve heard so much about.

But do these tools fulfill that promise?

According to Dr. Partida and other doctors who spoke with this news organization, the answer is a resounding yes.
 

A tech solution for a tech problem

“I believe a lot of doctors see patients for free. They get paid to do paperwork,” said Anthony J. Mazzarelli, MD, JD, MBE, co-president and CEO of Cooper University Health Care, in Camden, N.J.

Indeed, for every hour U.S. clinicians spend with their patients, they may spend 2 more hours documenting in electronic health records (EHRs), estimates show. About half of doctors, especially those in primary care, report feeling burned out, and some 42% say they want to quit clinical practice.

Enter AI scribes.

“The holy grail in medicine right now is improving burnout while also maintaining or improving productivity and quality,” said Patricia Garcia, MD, associate clinical information officer for ambulatory care at Stanford (Calif.) Health Care. “These ambient digital scribes have the potential to do just that.”

While anyone can buy these products, their use has been mostly limited to pilot programs and early adopters so far, said Dr. Garcia, who has been helping to pilot Nuance’s digital scribe, DAX, at Stanford.

But that’s expected to change quickly. “I don’t think the time horizon is a decade,” Dr. Garcia said. “I think within a matter of 2 or 3 years, these tools will be pervasive throughout health care.”

Since introducing these tools at Cooper, “our doctors’ paperwork burden is significantly lighter,” said Dr. Mazzarelli, who decides which technologies Cooper should invest in and who monitors their results. In Cooper studies, physicians who used DAX more than half the time spent 43% less time working on notes.

“They spend more time connecting with their patients, talking with them, and looking them in the eye,” Dr. Mazzarelli said. That, in turn, seems to improve patient outcomes, reduce doctor burnout and turnover, and lower costs.

The AI scribes, by virtue of eliminating the distraction of note taking, also allow doctors to give their full attention to the patient. “The patient relationship is the most important aspect of medicine,” said Raul Ayala, MD, MHCM, a family medicine physician at Adventist Health, in Hanford, Calif., who uses Augmedix. The digital scribe “helps us strengthen that relationship.”
 

What’s it like to use an AI medical scribe?

The scribes feature hardware (typically a smartphone or tablet) and software built on automatic speech recognition, natural language processing, and machine learning. Download an app to your device, and you’re ready to go. Use it to record in-person or telehealth visits.

In the first week, a company may help train you to use the hardware and software. You’ll likely start by using it for a few patient visits per day, ramping up gradually. Dr. Partida said she was comfortable using the system for all her patients in 6 weeks.

Each day, Dr. Partida logs in to a dedicated smartphone or tablet, opens the app, and reviews her schedule, including details she needs to prepare for each patient.

At the start of each patient visit, Dr. Partida taps the app icon to begin recording and lays the device nearby. She can pause as needed. At the end of the visit, she taps the icon again to stop recording.

The AI listens, creates the note, and updates relevant data in the EHR. The note includes patient problems, assessment, treatment plan, patient history, orders, and tasks for staff, along with medications, referrals, and preauthorizations. A human scribe, who is also a physician, reviews the information for accuracy and edits it as needed. By the next morning, the data are ready for Dr. Partida to review.

Fully automated versions can generate notes much faster. Jack Shilling, MD, MBA, an orthopedic surgeon at Cooper University Health Care, in Voorhees, N.J., uses DAX. A new feature called DAX Express – which uses OpenAI’s GPT-4 but no humans – provides him with a draft of his clinical notes in just seconds.
 

How accurate are AI notes?

The accuracy of those notes remains an open question, Dr. Garcia said – mostly because accuracy can be hard to define.

“If you asked five docs to write a note based on the same patient encounter, you’d get five different notes,” Dr. Garcia said. “That makes it hard to assess these technologies in a scientifically rigorous way.”

Still, the onus is on the physician to review the notes and edit them as needed, Dr. Garcia said. How light or heavy those edits are can depend on your unique preferences.

Dr. Shilling said he may need to lightly edit transcripts of his conversations with patients. “When someone tells me how long their knee hurts, slight variability in their transcribed words is tolerable,” he said. But for some things – such as physical exam notes and x-ray readings – he dictates directly into the device, speaking at a closer range and being less conversational, more exact in his speech.
 

Should you let patients know they’re being recorded?

The federal Health Insurance Portability and Accountability Act (HIPAA) does not require providers to inform patients that their face-to-face conversations are being recorded, said Daniel Lebovic, JD, corporate legal counsel at Compliancy Group, in Greenlawn, N.Y., a company that helps providers adhere to HIPAA rules.

But make sure you know the laws in your state and the policies at your health care practice. State laws may require providers to inform patients and to get patients’ consent in advance of being recorded.

All the doctors who spoke to this news organization said their patients are informed that they’ll be recorded and that they can opt out if they wish.
 

How much do AI scribes cost?

As the marketplace for these tools expands, companies are offering more products and services at different price points that target a range of organizations, from large health care systems to small private practices.

Price models vary, said Dr. Garcia. Some are based on the number of users, others on the number of notes, and still others on minutes.

Amazon’s HealthScribe is priced at 10 cents per minute. For 1,000 consultation transcripts per month, with each call averaging 15 minutes, it would take 15,000 minutes at a total cost of $1,500 for the month.

In general, the rapidly growing competition in this space could mean prices become more affordable, Dr. Garcia said. “It’s good that so many are getting into this game, because that means the price will come down and it will be a lot more accessible to everybody.”

A version of this article appeared on Medscape.com.

Andrea Partida, DO, an obstetrician and gynecologist in Enid, Okla., loves her new assistant.

The 15 or 20 minutes she used to spend on documentation for each patient visit is now 3. The 2-3 hours she’d spend charting outside clinic hours is maybe 1.

All that time saved allows her to see two to five more patients a day, provide better care to each patient, and get more involved in hospital leadership at Integris Health, where she works.

“I have a better work-life balance with my family,” Dr. Partida said. “I leave work at work and get home earlier.”

You’ve probably figured out the plot twist: Dr. Partida’s assistant is not a person – it’s artificial intelligence (AI).

Dr. Partida uses IRIS, a tool from OnPoint Healthcare Partners, part of a fast-growing niche of AI medical scribes designed to automate onerous data entry. The evolution of generative AI – specifically, large language models, such as ChatGPT – has led to a rapid explosion of these tools. Other companies in the space include Abridge, Ambience Healthcare, Augmedix, DeepScribe, Nuance (part of Microsoft), and Suki. The newest kid on the block, Amazon Web Services, announced the launch of HealthScribe in July.

These tools – some of which are already on the market, with more on the way – record patient visits and generate notes for treatment and billing. Earlier iterations combine AI with offsite human scribes who provide quality control. But more and more are fully automated, no human required. Some also offer video recording and foreign language translation.

The promise is alluring: Ease your workload and reclaim hours in your day so you can spend more time with patients or try that “work-life balance” thing you’ve heard so much about.

But do these tools fulfill that promise?

According to Dr. Partida and other doctors who spoke with this news organization, the answer is a resounding yes.
 

A tech solution for a tech problem

“I believe a lot of doctors see patients for free. They get paid to do paperwork,” said Anthony J. Mazzarelli, MD, JD, MBE, co-president and CEO of Cooper University Health Care, in Camden, N.J.

Indeed, for every hour U.S. clinicians spend with their patients, they may spend 2 more hours documenting in electronic health records (EHRs), estimates show. About half of doctors, especially those in primary care, report feeling burned out, and some 42% say they want to quit clinical practice.

Enter AI scribes.

“The holy grail in medicine right now is improving burnout while also maintaining or improving productivity and quality,” said Patricia Garcia, MD, associate clinical information officer for ambulatory care at Stanford (Calif.) Health Care. “These ambient digital scribes have the potential to do just that.”

While anyone can buy these products, their use has been mostly limited to pilot programs and early adopters so far, said Dr. Garcia, who has been helping to pilot Nuance’s digital scribe, DAX, at Stanford.

But that’s expected to change quickly. “I don’t think the time horizon is a decade,” Dr. Garcia said. “I think within a matter of 2 or 3 years, these tools will be pervasive throughout health care.”

Since introducing these tools at Cooper, “our doctors’ paperwork burden is significantly lighter,” said Dr. Mazzarelli, who decides which technologies Cooper should invest in and who monitors their results. In Cooper studies, physicians who used DAX more than half the time spent 43% less time working on notes.

“They spend more time connecting with their patients, talking with them, and looking them in the eye,” Dr. Mazzarelli said. That, in turn, seems to improve patient outcomes, reduce doctor burnout and turnover, and lower costs.

The AI scribes, by virtue of eliminating the distraction of note taking, also allow doctors to give their full attention to the patient. “The patient relationship is the most important aspect of medicine,” said Raul Ayala, MD, MHCM, a family medicine physician at Adventist Health, in Hanford, Calif., who uses Augmedix. The digital scribe “helps us strengthen that relationship.”
 

What’s it like to use an AI medical scribe?

The scribes feature hardware (typically a smartphone or tablet) and software built on automatic speech recognition, natural language processing, and machine learning. Download an app to your device, and you’re ready to go. Use it to record in-person or telehealth visits.

In the first week, a company may help train you to use the hardware and software. You’ll likely start by using it for a few patient visits per day, ramping up gradually. Dr. Partida said she was comfortable using the system for all her patients in 6 weeks.

Each day, Dr. Partida logs in to a dedicated smartphone or tablet, opens the app, and reviews her schedule, including details she needs to prepare for each patient.

At the start of each patient visit, Dr. Partida taps the app icon to begin recording and lays the device nearby. She can pause as needed. At the end of the visit, she taps the icon again to stop recording.

The AI listens, creates the note, and updates relevant data in the EHR. The note includes patient problems, assessment, treatment plan, patient history, orders, and tasks for staff, along with medications, referrals, and preauthorizations. A human scribe, who is also a physician, reviews the information for accuracy and edits it as needed. By the next morning, the data are ready for Dr. Partida to review.

Fully automated versions can generate notes much faster. Jack Shilling, MD, MBA, an orthopedic surgeon at Cooper University Health Care, in Voorhees, N.J., uses DAX. A new feature called DAX Express – which uses OpenAI’s GPT-4 but no humans – provides him with a draft of his clinical notes in just seconds.
 

How accurate are AI notes?

The accuracy of those notes remains an open question, Dr. Garcia said – mostly because accuracy can be hard to define.

“If you asked five docs to write a note based on the same patient encounter, you’d get five different notes,” Dr. Garcia said. “That makes it hard to assess these technologies in a scientifically rigorous way.”

Still, the onus is on the physician to review the notes and edit them as needed, Dr. Garcia said. How light or heavy those edits are can depend on your unique preferences.

Dr. Shilling said he may need to lightly edit transcripts of his conversations with patients. “When someone tells me how long their knee hurts, slight variability in their transcribed words is tolerable,” he said. But for some things – such as physical exam notes and x-ray readings – he dictates directly into the device, speaking at a closer range and being less conversational, more exact in his speech.
 

Should you let patients know they’re being recorded?

The federal Health Insurance Portability and Accountability Act (HIPAA) does not require providers to inform patients that their face-to-face conversations are being recorded, said Daniel Lebovic, JD, corporate legal counsel at Compliancy Group, in Greenlawn, N.Y., a company that helps providers adhere to HIPAA rules.

But make sure you know the laws in your state and the policies at your health care practice. State laws may require providers to inform patients and to get patients’ consent in advance of being recorded.

All the doctors who spoke to this news organization said their patients are informed that they’ll be recorded and that they can opt out if they wish.
 

How much do AI scribes cost?

As the marketplace for these tools expands, companies are offering more products and services at different price points that target a range of organizations, from large health care systems to small private practices.

Price models vary, said Dr. Garcia. Some are based on the number of users, others on the number of notes, and still others on minutes.

Amazon’s HealthScribe is priced at 10 cents per minute. For 1,000 consultation transcripts per month, with each call averaging 15 minutes, it would take 15,000 minutes at a total cost of $1,500 for the month.

In general, the rapidly growing competition in this space could mean prices become more affordable, Dr. Garcia said. “It’s good that so many are getting into this game, because that means the price will come down and it will be a lot more accessible to everybody.”

A version of this article appeared on Medscape.com.

In a specialty dermatology clinic, pediatric lichen sclerosus (LS) was difficult to differentiate from vitiligo, especially in patients with medium to dark skin tones, according to a retrospective review of cases.

Researchers who tallied symptoms and physical exam findings observed fewer statistically significant differences between LS and vitiligo patients than expected, and LS and vitiligo were sometimes misdiagnosed as each other.

“LS must be treated aggressively to prevent long-term sequelae such as permanent scarring and vulvar squamous cell carcinoma, making an accurate diagnosis crucial,” the authors write in a poster they presented at the annual meeting of the Society for Pediatric Dermatology.

The researchers found that pruritus, constipation, and dysuria were the most common symptoms experienced by both LS and vitiligo patients. All were experienced more frequently by LS patients, but only pruritus reached statistical significance (P = .040). Other symptoms experienced only by LS patients included vulvar pain, bleeding, and pain with defecation.

Meanwhile, apart from hypopigmentation and erythema, all physical exam findings were more frequent in LS patients, compared with vitiligo patients, including fissures and purpura/petechiae, but only epidermal atrophy and figure-of-8 distribution of hypopigmentation reached statistical significance (P values of .047 and .036, respectively).

In other findings, LS and vitiligo were misdiagnosed as each other 15 times. Nearly half of the misdiagnoses (46.7%) were made in Black patients, who composed 38.8% of all patients in the study.

“I suspect that some vitiligo cases that were previously ‘misdiagnosed’ as LS were actually LS that just didn’t repigment and then were labeled as vitiligo in the chart,” Dr. Habeshian said.

“And some of those LS cases that previously were misdiagnosed as vitiligo likely had other more subtle LS findings that were missed (shininess and wrinkling of the skin, small fissures, constipation) or that were attributed to comorbid irritant contact dermatitis or another condition,” she said. “It was interesting to see that even in a vulvar dermatology clinic there can be confusion between these diagnoses because the literature on pediatric LS in darker skin tones is so sparse.”

She emphasized that a close exam and detailed history are needed to properly diagnose patients with anogenital skin conditions.

“Don’t forget to ask about constipation and urinary symptoms as well as psychosocial and, in the appropriate patient, sexual and reproductive function,” Dr. Habeshian said. “Based on my experience, pediatric LS is much more common in our community than the literature would suggest. Its psychosocial impact is tremendous but not well documented, particularly in pediatric patients. In my experience, the longer LS is misdiagnosed or mistreated, the more challenging it becomes to manage. You don’t want to miss LS.”

She acknowledged certain limitations of the study, including the fact that photographs were not available for review for many of the earlier years of the clinic. “Therefore, we had to depend on the diagnosis given at the time of the visit,” she said. “This likely accounts in part for the smaller number than expected of significant exam and history findings between LS and vitiligo. We need further studies utilizing a standardized approach to accurate diagnosis.”

Her coauthors were Nikita Menta, Aneka Khilnani, MS, and Tazim Dowlut-McElroy, MD. The researchers reported having no financial disclosures.

 

In a specialty dermatology clinic, pediatric lichen sclerosus (LS) was difficult to differentiate from vitiligo, especially in patients with medium to dark skin tones, according to a retrospective review of cases.

Researchers who tallied symptoms and physical exam findings observed fewer statistically significant differences between LS and vitiligo patients than expected, and LS and vitiligo were sometimes misdiagnosed as each other.

“LS must be treated aggressively to prevent long-term sequelae such as permanent scarring and vulvar squamous cell carcinoma, making an accurate diagnosis crucial,” the authors write in a poster they presented at the annual meeting of the Society for Pediatric Dermatology.

The researchers found that pruritus, constipation, and dysuria were the most common symptoms experienced by both LS and vitiligo patients. All were experienced more frequently by LS patients, but only pruritus reached statistical significance (P = .040). Other symptoms experienced only by LS patients included vulvar pain, bleeding, and pain with defecation.

Meanwhile, apart from hypopigmentation and erythema, all physical exam findings were more frequent in LS patients, compared with vitiligo patients, including fissures and purpura/petechiae, but only epidermal atrophy and figure-of-8 distribution of hypopigmentation reached statistical significance (P values of .047 and .036, respectively).

In other findings, LS and vitiligo were misdiagnosed as each other 15 times. Nearly half of the misdiagnoses (46.7%) were made in Black patients, who composed 38.8% of all patients in the study.

“I suspect that some vitiligo cases that were previously ‘misdiagnosed’ as LS were actually LS that just didn’t repigment and then were labeled as vitiligo in the chart,” Dr. Habeshian said.

“And some of those LS cases that previously were misdiagnosed as vitiligo likely had other more subtle LS findings that were missed (shininess and wrinkling of the skin, small fissures, constipation) or that were attributed to comorbid irritant contact dermatitis or another condition,” she said. “It was interesting to see that even in a vulvar dermatology clinic there can be confusion between these diagnoses because the literature on pediatric LS in darker skin tones is so sparse.”

She emphasized that a close exam and detailed history are needed to properly diagnose patients with anogenital skin conditions.

“Don’t forget to ask about constipation and urinary symptoms as well as psychosocial and, in the appropriate patient, sexual and reproductive function,” Dr. Habeshian said. “Based on my experience, pediatric LS is much more common in our community than the literature would suggest. Its psychosocial impact is tremendous but not well documented, particularly in pediatric patients. In my experience, the longer LS is misdiagnosed or mistreated, the more challenging it becomes to manage. You don’t want to miss LS.”

She acknowledged certain limitations of the study, including the fact that photographs were not available for review for many of the earlier years of the clinic. “Therefore, we had to depend on the diagnosis given at the time of the visit,” she said. “This likely accounts in part for the smaller number than expected of significant exam and history findings between LS and vitiligo. We need further studies utilizing a standardized approach to accurate diagnosis.”

Her coauthors were Nikita Menta, Aneka Khilnani, MS, and Tazim Dowlut-McElroy, MD. The researchers reported having no financial disclosures.

 

In a specialty dermatology clinic, pediatric lichen sclerosus (LS) was difficult to differentiate from vitiligo, especially in patients with medium to dark skin tones, according to a retrospective review of cases.

Researchers who tallied symptoms and physical exam findings observed fewer statistically significant differences between LS and vitiligo patients than expected, and LS and vitiligo were sometimes misdiagnosed as each other.

“LS must be treated aggressively to prevent long-term sequelae such as permanent scarring and vulvar squamous cell carcinoma, making an accurate diagnosis crucial,” the authors write in a poster they presented at the annual meeting of the Society for Pediatric Dermatology.

The researchers found that pruritus, constipation, and dysuria were the most common symptoms experienced by both LS and vitiligo patients. All were experienced more frequently by LS patients, but only pruritus reached statistical significance (P = .040). Other symptoms experienced only by LS patients included vulvar pain, bleeding, and pain with defecation.

Meanwhile, apart from hypopigmentation and erythema, all physical exam findings were more frequent in LS patients, compared with vitiligo patients, including fissures and purpura/petechiae, but only epidermal atrophy and figure-of-8 distribution of hypopigmentation reached statistical significance (P values of .047 and .036, respectively).

In other findings, LS and vitiligo were misdiagnosed as each other 15 times. Nearly half of the misdiagnoses (46.7%) were made in Black patients, who composed 38.8% of all patients in the study.

“I suspect that some vitiligo cases that were previously ‘misdiagnosed’ as LS were actually LS that just didn’t repigment and then were labeled as vitiligo in the chart,” Dr. Habeshian said.

“And some of those LS cases that previously were misdiagnosed as vitiligo likely had other more subtle LS findings that were missed (shininess and wrinkling of the skin, small fissures, constipation) or that were attributed to comorbid irritant contact dermatitis or another condition,” she said. “It was interesting to see that even in a vulvar dermatology clinic there can be confusion between these diagnoses because the literature on pediatric LS in darker skin tones is so sparse.”

She emphasized that a close exam and detailed history are needed to properly diagnose patients with anogenital skin conditions.

“Don’t forget to ask about constipation and urinary symptoms as well as psychosocial and, in the appropriate patient, sexual and reproductive function,” Dr. Habeshian said. “Based on my experience, pediatric LS is much more common in our community than the literature would suggest. Its psychosocial impact is tremendous but not well documented, particularly in pediatric patients. In my experience, the longer LS is misdiagnosed or mistreated, the more challenging it becomes to manage. You don’t want to miss LS.”

She acknowledged certain limitations of the study, including the fact that photographs were not available for review for many of the earlier years of the clinic. “Therefore, we had to depend on the diagnosis given at the time of the visit,” she said. “This likely accounts in part for the smaller number than expected of significant exam and history findings between LS and vitiligo. We need further studies utilizing a standardized approach to accurate diagnosis.”

Her coauthors were Nikita Menta, Aneka Khilnani, MS, and Tazim Dowlut-McElroy, MD. The researchers reported having no financial disclosures.

 

As we navigate the ever-evolving landscape of diabetic foot disease management, I’d like to discuss the updated 2023 International Working Group on the Diabetic Foot guidelines and their implications for our practice. The goal is to create a common language of risk that is easily related from clinician to clinician to patient.

Whatever language we use, though, the problem we face is vast:

• Diabetic foot ulcers affect approximately 18.6 million people worldwide and 1.6 million in the United States each year.
• They are associated with high rates of premature death, with a 5-year mortality rate of 30%. This rate is greater than 70% for those with above-foot amputations, worse than all but the most aggressive cancers.
• The direct costs of treating diabetic foot ulcers in the United States is estimated at $9 billion-$13 billion annually.
• Over 550 million people worldwide have diabetes, with 18.6 million developing foot ulcers annually. Up to 34% of those with diabetes will develop a foot ulcer.
• About 20% of those with a diabetic foot ulcer will undergo amputation, a major cause of which is infection, which affects 50% of foot ulcers.
• Up to 20% of those with a foot ulcer require hospitalization, with 15%-20% undergoing amputation. Inequities exist in diabetes-related foot complications:
• –Rates of major amputation are higher in non-Hispanic Black, Hispanic, and Native American populations, compared with non-Hispanic White populations.
• –Non-Hispanic Black and Hispanic populations present with more advanced ulcers and peripheral artery disease, and are more likely to undergo amputation without revascularization attempt.

The IWGDF, a multidisciplinary team of international experts, has recently updated its guidelines. This team, comprising endocrinologists, internal medicine physicians, physiatrists, podiatrists, and vascular surgeons from across the globe, has worked tirelessly to provide us with a comprehensive guide to managing diabetes-related foot ulcers.

The updated guidelines address five critical clinical questions, each with up to 13 important outcomes. The systematic review that underpins these guidelines identified 149 eligible studies, assessing 28 different systems. This exhaustive research has led to the development of seven key recommendations that address the clinical questions and consider the existence of different clinical settings.

One of the significant updates in the 2023 guidelines is the recommendation of SINBAD – site, ischemia, neuropathy, bacterial infection, area, and depth – as the priority wound classification system for people with diabetes and a foot ulcer. This system is particularly useful for interprofessional communication, describing each composite variable, and conducting clinical audits using the full score. However, the guidelines also recommend the use of other, more specific assessment systems for infection and peripheral artery disease from the Infectious Diseases Society of America/IWGDF when resources and an appropriate level of expertise exist.

The introduction of the Wound, Ischemia and Foot Infection (WIfI) classification system in the guidelines is also a noteworthy development. This system is crucial in assessing perfusion and the likely benefit of revascularization in a person with diabetes and a foot ulcer. By assessing the level of wound ischemia and infection, we can make informed decisions about the need for vascular intervention, which can significantly affect the patient’s outcome. This can be done simply by classifying each of the three categories of wound, ischemia, or foot infection as none, mild, moderate, or severe. By simplifying the very dynamic comorbidities of tissue loss, ischemia, and infection into a usable and predictive scale, it helps us to communicate risk across disciplines. This has been found to be highly predictive of healing, amputation, and mortality.

We use WIfI every day across our system. An example might include a patient we recently treated:

A 76-year-old woman presented with a wound to her left foot. Her past medical history revealed type 2 diabetes, peripheral neuropathy, and documented peripheral artery disease with prior bilateral femoral-popliteal bypass conducted at an external facility. In addition to gangrenous changes to her fourth toe, she displayed erythema and lymphangitic streaking up her dorsal foot. While she was afebrile, her white cell count was 13,000/mcL. Radiographic examinations did not show signs of osteomyelitis. Noninvasive vascular evaluations revealed an ankle brachial index of 0.4 and a toe pressure of 10 mm Hg. An aortogram with a lower-extremity runoff arteriogram confirmed the obstruction of her left femoral-popliteal bypass.

Taking these results into account, her WIfI score was determined as: wound 2 (moderate), ischemia 3 (severe), foot infection 2 (moderate, no sepsis), translating to a clinical stage 4. This denotes a high risk for major amputation.

Following a team discussion, she was taken to the operating room for an initial debridement of her infection which consisted of a partial fourth ray resection to the level of the mid-metatarsal. Following control of the infection, she received a vascular assessment which ultimately constituted a femoral to distal anterior tibial bypass. Following both of these, she was discharged on a negative-pressure wound therapy device, receiving a split-thickness skin graft 4 weeks later.

The guidelines also emphasize the need for specific training, skills, and experience to ensure the accuracy of the recommended systems for characterizing foot ulcers. The person applying these systems should be appropriately trained and, according to their national or regional standards, should have the knowledge, expertise, and skills necessary to manage people with a diabetes-related foot ulcer.

As we continue to navigate the complexities of diabetes-related foot disease, these guidelines serve as a valuable compass, guiding our decisions and actions. They remind us of the importance of continuous learning, collaboration, and the application of evidence-based practice in our work.

I encourage you to delve into these guidelines. Let’s use them to improve our practice, enhance our communication, and, ultimately, provide better care for our patients.

Dr. Armstrong is professor of surgery, director of limb preservation, University of Southern California, Los Angeles. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

As we navigate the ever-evolving landscape of diabetic foot disease management, I’d like to discuss the updated 2023 International Working Group on the Diabetic Foot guidelines and their implications for our practice. The goal is to create a common language of risk that is easily related from clinician to clinician to patient.

Whatever language we use, though, the problem we face is vast:

• Diabetic foot ulcers affect approximately 18.6 million people worldwide and 1.6 million in the United States each year.
• They are associated with high rates of premature death, with a 5-year mortality rate of 30%. This rate is greater than 70% for those with above-foot amputations, worse than all but the most aggressive cancers.
• The direct costs of treating diabetic foot ulcers in the United States is estimated at $9 billion-$13 billion annually.
• Over 550 million people worldwide have diabetes, with 18.6 million developing foot ulcers annually. Up to 34% of those with diabetes will develop a foot ulcer.
• About 20% of those with a diabetic foot ulcer will undergo amputation, a major cause of which is infection, which affects 50% of foot ulcers.
• Up to 20% of those with a foot ulcer require hospitalization, with 15%-20% undergoing amputation. Inequities exist in diabetes-related foot complications:
• –Rates of major amputation are higher in non-Hispanic Black, Hispanic, and Native American populations, compared with non-Hispanic White populations.
• –Non-Hispanic Black and Hispanic populations present with more advanced ulcers and peripheral artery disease, and are more likely to undergo amputation without revascularization attempt.

The IWGDF, a multidisciplinary team of international experts, has recently updated its guidelines. This team, comprising endocrinologists, internal medicine physicians, physiatrists, podiatrists, and vascular surgeons from across the globe, has worked tirelessly to provide us with a comprehensive guide to managing diabetes-related foot ulcers.

The updated guidelines address five critical clinical questions, each with up to 13 important outcomes. The systematic review that underpins these guidelines identified 149 eligible studies, assessing 28 different systems. This exhaustive research has led to the development of seven key recommendations that address the clinical questions and consider the existence of different clinical settings.

One of the significant updates in the 2023 guidelines is the recommendation of SINBAD – site, ischemia, neuropathy, bacterial infection, area, and depth – as the priority wound classification system for people with diabetes and a foot ulcer. This system is particularly useful for interprofessional communication, describing each composite variable, and conducting clinical audits using the full score. However, the guidelines also recommend the use of other, more specific assessment systems for infection and peripheral artery disease from the Infectious Diseases Society of America/IWGDF when resources and an appropriate level of expertise exist.

The introduction of the Wound, Ischemia and Foot Infection (WIfI) classification system in the guidelines is also a noteworthy development. This system is crucial in assessing perfusion and the likely benefit of revascularization in a person with diabetes and a foot ulcer. By assessing the level of wound ischemia and infection, we can make informed decisions about the need for vascular intervention, which can significantly affect the patient’s outcome. This can be done simply by classifying each of the three categories of wound, ischemia, or foot infection as none, mild, moderate, or severe. By simplifying the very dynamic comorbidities of tissue loss, ischemia, and infection into a usable and predictive scale, it helps us to communicate risk across disciplines. This has been found to be highly predictive of healing, amputation, and mortality.

We use WIfI every day across our system. An example might include a patient we recently treated:

A 76-year-old woman presented with a wound to her left foot. Her past medical history revealed type 2 diabetes, peripheral neuropathy, and documented peripheral artery disease with prior bilateral femoral-popliteal bypass conducted at an external facility. In addition to gangrenous changes to her fourth toe, she displayed erythema and lymphangitic streaking up her dorsal foot. While she was afebrile, her white cell count was 13,000/mcL. Radiographic examinations did not show signs of osteomyelitis. Noninvasive vascular evaluations revealed an ankle brachial index of 0.4 and a toe pressure of 10 mm Hg. An aortogram with a lower-extremity runoff arteriogram confirmed the obstruction of her left femoral-popliteal bypass.

Taking these results into account, her WIfI score was determined as: wound 2 (moderate), ischemia 3 (severe), foot infection 2 (moderate, no sepsis), translating to a clinical stage 4. This denotes a high risk for major amputation.

Following a team discussion, she was taken to the operating room for an initial debridement of her infection which consisted of a partial fourth ray resection to the level of the mid-metatarsal. Following control of the infection, she received a vascular assessment which ultimately constituted a femoral to distal anterior tibial bypass. Following both of these, she was discharged on a negative-pressure wound therapy device, receiving a split-thickness skin graft 4 weeks later.

The guidelines also emphasize the need for specific training, skills, and experience to ensure the accuracy of the recommended systems for characterizing foot ulcers. The person applying these systems should be appropriately trained and, according to their national or regional standards, should have the knowledge, expertise, and skills necessary to manage people with a diabetes-related foot ulcer.

As we continue to navigate the complexities of diabetes-related foot disease, these guidelines serve as a valuable compass, guiding our decisions and actions. They remind us of the importance of continuous learning, collaboration, and the application of evidence-based practice in our work.

I encourage you to delve into these guidelines. Let’s use them to improve our practice, enhance our communication, and, ultimately, provide better care for our patients.

Dr. Armstrong is professor of surgery, director of limb preservation, University of Southern California, Los Angeles. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

As we navigate the ever-evolving landscape of diabetic foot disease management, I’d like to discuss the updated 2023 International Working Group on the Diabetic Foot guidelines and their implications for our practice. The goal is to create a common language of risk that is easily related from clinician to clinician to patient.

Whatever language we use, though, the problem we face is vast:

• Diabetic foot ulcers affect approximately 18.6 million people worldwide and 1.6 million in the United States each year.
• They are associated with high rates of premature death, with a 5-year mortality rate of 30%. This rate is greater than 70% for those with above-foot amputations, worse than all but the most aggressive cancers.
• The direct costs of treating diabetic foot ulcers in the United States is estimated at $9 billion-$13 billion annually.
• Over 550 million people worldwide have diabetes, with 18.6 million developing foot ulcers annually. Up to 34% of those with diabetes will develop a foot ulcer.
• About 20% of those with a diabetic foot ulcer will undergo amputation, a major cause of which is infection, which affects 50% of foot ulcers.
• Up to 20% of those with a foot ulcer require hospitalization, with 15%-20% undergoing amputation. Inequities exist in diabetes-related foot complications:
• –Rates of major amputation are higher in non-Hispanic Black, Hispanic, and Native American populations, compared with non-Hispanic White populations.
• –Non-Hispanic Black and Hispanic populations present with more advanced ulcers and peripheral artery disease, and are more likely to undergo amputation without revascularization attempt.

The IWGDF, a multidisciplinary team of international experts, has recently updated its guidelines. This team, comprising endocrinologists, internal medicine physicians, physiatrists, podiatrists, and vascular surgeons from across the globe, has worked tirelessly to provide us with a comprehensive guide to managing diabetes-related foot ulcers.

The updated guidelines address five critical clinical questions, each with up to 13 important outcomes. The systematic review that underpins these guidelines identified 149 eligible studies, assessing 28 different systems. This exhaustive research has led to the development of seven key recommendations that address the clinical questions and consider the existence of different clinical settings.

One of the significant updates in the 2023 guidelines is the recommendation of SINBAD – site, ischemia, neuropathy, bacterial infection, area, and depth – as the priority wound classification system for people with diabetes and a foot ulcer. This system is particularly useful for interprofessional communication, describing each composite variable, and conducting clinical audits using the full score. However, the guidelines also recommend the use of other, more specific assessment systems for infection and peripheral artery disease from the Infectious Diseases Society of America/IWGDF when resources and an appropriate level of expertise exist.

The introduction of the Wound, Ischemia and Foot Infection (WIfI) classification system in the guidelines is also a noteworthy development. This system is crucial in assessing perfusion and the likely benefit of revascularization in a person with diabetes and a foot ulcer. By assessing the level of wound ischemia and infection, we can make informed decisions about the need for vascular intervention, which can significantly affect the patient’s outcome. This can be done simply by classifying each of the three categories of wound, ischemia, or foot infection as none, mild, moderate, or severe. By simplifying the very dynamic comorbidities of tissue loss, ischemia, and infection into a usable and predictive scale, it helps us to communicate risk across disciplines. This has been found to be highly predictive of healing, amputation, and mortality.

We use WIfI every day across our system. An example might include a patient we recently treated:

A 76-year-old woman presented with a wound to her left foot. Her past medical history revealed type 2 diabetes, peripheral neuropathy, and documented peripheral artery disease with prior bilateral femoral-popliteal bypass conducted at an external facility. In addition to gangrenous changes to her fourth toe, she displayed erythema and lymphangitic streaking up her dorsal foot. While she was afebrile, her white cell count was 13,000/mcL. Radiographic examinations did not show signs of osteomyelitis. Noninvasive vascular evaluations revealed an ankle brachial index of 0.4 and a toe pressure of 10 mm Hg. An aortogram with a lower-extremity runoff arteriogram confirmed the obstruction of her left femoral-popliteal bypass.

Taking these results into account, her WIfI score was determined as: wound 2 (moderate), ischemia 3 (severe), foot infection 2 (moderate, no sepsis), translating to a clinical stage 4. This denotes a high risk for major amputation.

Following a team discussion, she was taken to the operating room for an initial debridement of her infection which consisted of a partial fourth ray resection to the level of the mid-metatarsal. Following control of the infection, she received a vascular assessment which ultimately constituted a femoral to distal anterior tibial bypass. Following both of these, she was discharged on a negative-pressure wound therapy device, receiving a split-thickness skin graft 4 weeks later.

The guidelines also emphasize the need for specific training, skills, and experience to ensure the accuracy of the recommended systems for characterizing foot ulcers. The person applying these systems should be appropriately trained and, according to their national or regional standards, should have the knowledge, expertise, and skills necessary to manage people with a diabetes-related foot ulcer.

As we continue to navigate the complexities of diabetes-related foot disease, these guidelines serve as a valuable compass, guiding our decisions and actions. They remind us of the importance of continuous learning, collaboration, and the application of evidence-based practice in our work.

I encourage you to delve into these guidelines. Let’s use them to improve our practice, enhance our communication, and, ultimately, provide better care for our patients.

Dr. Armstrong is professor of surgery, director of limb preservation, University of Southern California, Los Angeles. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Antigephyrin autoantibodies have been tied to lower gastrointestinal dysfunction, such as severe constipation and distention, in patients with systemic sclerosis (SSc), new research suggests. Researchers also found that gephyrin is expressed in the patient’s enteric nervous system (ENS), which regulates gut motility.

University of Texas Health Science Center at Houston

“While there are many antibodies that are helpful in identifying patients at risk for extraintestinal complications of this disease, markers that identify patients at higher risk for gastrointestinal complications are limited. Furthermore, the biological mechanisms that cause and perpetuate the progression of gastrointestinal disease in scleroderma are not well understood, making it challenging to distinguish between patients whose gastrointestinal disease will progress from those whose GI disease will remain stable/mild,” Zsuzsanna H. McMahan, MD, MHS, told this news organization in an email. Dr. McMahan is co–first author on the study along with Subhash Kulkarni, PhD. They conducted the research with colleagues when they both worked at Johns Hopkins University in Baltimore, Md.

Hospital for Special Surgery

When asked for comment, Kimberly Lakin, MD, MS, assistant professor of medicine at Weill Cornell Medicine and a rheumatologist at Hospital for Special Surgery, New York, called the study “interesting and novel.”

“Not only did [antigephyrin antibodies] correlate with the presence of lower GI symptoms, but also higher levels of antibodies correlated with worse lower GI symptoms. This suggests that not only could this antibody be used to predict who may have constipation and potentially need more aggressive GI interventions, but it may also be useful in quantifying GI severity in systemic sclerosis, although more research is still needed,” said Dr. Lakin, who was not involved with the research.

The study was published online in Arthritis & Rheumatology.

In the cross-sectional study, researchers identified gephyrin as an autoantigen in sera from a single patient with SSc by isolating it from immunoprecipitations performed with murine myenteric plexus neuron lysates, and then characterizing it by mass spectrometry and validating it in further assays. That patient had GI dysfunction but no defined SSc-associated autoantibodies.

Dr. McMahan and colleagues then investigated the prevalence of the autoantibody by screening the sera of 188 patients with SSc who presented consecutively to the Johns Hopkins Scleroderma Center between April 2016 and August 2017, as well as 40 controls, and compared GI symptom severity between antibody-positive and antibody-negative patients with SSc.

A total of 16 (8.5%) of the 188 patients with SSc had antigephyrin antibodies, compared with none of the controls. Of these 16 patients, 4 had no other defined SSc antibodies. In the SSc cohort, severe constipation was more common in antigephyrin antibody–positive patients, compared with antibody-negative patients (46% vs. 15%). Antibody-positive patients also had higher constipation scores, and severe distension and bloating occurred in the antibody-positive group more than twice as often (54% vs. 25%).

Patients with severe constipation, distention, and bloating had higher antigephyrin antibody levels. After adjusting for confounders such as disease duration, patients with severe constipation were nearly five times as likely (odds ratio, 4.74; P = .010) to be antigephyrin antibody–positive, and patients with severe distention and bloating were nearly four times as likely (OR, 3.71; P = .027) to be antibody-positive.

Last, the authors showed via immunohistochemistry that gephyrin is expressed in the myenteric ganglia of human GI tissue.

“Gastrointestinal function is highly regulated by the ENS, so it is interesting that antibodies that target a protein expressed by ENS cells (gephyrin) were identified in patients with scleroderma who have severe lower bowel dysfunction,” said Dr. McMahan, who is associate professor in the division of rheumatology and codirector of the scleroderma program at the University of Texas Health Science Center at Houston. “Gephyrin is a key mediator of normal communications between nerves in the gut, so it is tantalizing to speculate that autoimmune-mediated disruption (e.g., an inhibitory or blocking antibody) in neural (ENS) communications in the gut might lead to impaired bowel transit and prominent constipation.”

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and other NIH grants, as well as the Scleroderma Research Foundation, Rheumatology Research Foundation, Jerome L. Greene Foundation, Martha McCrory Professorship, and Chresanthe Stauraluakis Memorial Discovery Fund. The study authors and Dr. Lakin report no relevant financial relationships.
 

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

Antigephyrin autoantibodies have been tied to lower gastrointestinal dysfunction, such as severe constipation and distention, in patients with systemic sclerosis (SSc), new research suggests. Researchers also found that gephyrin is expressed in the patient’s enteric nervous system (ENS), which regulates gut motility.

University of Texas Health Science Center at Houston

“While there are many antibodies that are helpful in identifying patients at risk for extraintestinal complications of this disease, markers that identify patients at higher risk for gastrointestinal complications are limited. Furthermore, the biological mechanisms that cause and perpetuate the progression of gastrointestinal disease in scleroderma are not well understood, making it challenging to distinguish between patients whose gastrointestinal disease will progress from those whose GI disease will remain stable/mild,” Zsuzsanna H. McMahan, MD, MHS, told this news organization in an email. Dr. McMahan is co–first author on the study along with Subhash Kulkarni, PhD. They conducted the research with colleagues when they both worked at Johns Hopkins University in Baltimore, Md.

Hospital for Special Surgery

When asked for comment, Kimberly Lakin, MD, MS, assistant professor of medicine at Weill Cornell Medicine and a rheumatologist at Hospital for Special Surgery, New York, called the study “interesting and novel.”

“Not only did [antigephyrin antibodies] correlate with the presence of lower GI symptoms, but also higher levels of antibodies correlated with worse lower GI symptoms. This suggests that not only could this antibody be used to predict who may have constipation and potentially need more aggressive GI interventions, but it may also be useful in quantifying GI severity in systemic sclerosis, although more research is still needed,” said Dr. Lakin, who was not involved with the research.

The study was published online in Arthritis & Rheumatology.

In the cross-sectional study, researchers identified gephyrin as an autoantigen in sera from a single patient with SSc by isolating it from immunoprecipitations performed with murine myenteric plexus neuron lysates, and then characterizing it by mass spectrometry and validating it in further assays. That patient had GI dysfunction but no defined SSc-associated autoantibodies.

Dr. McMahan and colleagues then investigated the prevalence of the autoantibody by screening the sera of 188 patients with SSc who presented consecutively to the Johns Hopkins Scleroderma Center between April 2016 and August 2017, as well as 40 controls, and compared GI symptom severity between antibody-positive and antibody-negative patients with SSc.

A total of 16 (8.5%) of the 188 patients with SSc had antigephyrin antibodies, compared with none of the controls. Of these 16 patients, 4 had no other defined SSc antibodies. In the SSc cohort, severe constipation was more common in antigephyrin antibody–positive patients, compared with antibody-negative patients (46% vs. 15%). Antibody-positive patients also had higher constipation scores, and severe distension and bloating occurred in the antibody-positive group more than twice as often (54% vs. 25%).

Patients with severe constipation, distention, and bloating had higher antigephyrin antibody levels. After adjusting for confounders such as disease duration, patients with severe constipation were nearly five times as likely (odds ratio, 4.74; P = .010) to be antigephyrin antibody–positive, and patients with severe distention and bloating were nearly four times as likely (OR, 3.71; P = .027) to be antibody-positive.

Last, the authors showed via immunohistochemistry that gephyrin is expressed in the myenteric ganglia of human GI tissue.

“Gastrointestinal function is highly regulated by the ENS, so it is interesting that antibodies that target a protein expressed by ENS cells (gephyrin) were identified in patients with scleroderma who have severe lower bowel dysfunction,” said Dr. McMahan, who is associate professor in the division of rheumatology and codirector of the scleroderma program at the University of Texas Health Science Center at Houston. “Gephyrin is a key mediator of normal communications between nerves in the gut, so it is tantalizing to speculate that autoimmune-mediated disruption (e.g., an inhibitory or blocking antibody) in neural (ENS) communications in the gut might lead to impaired bowel transit and prominent constipation.”

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and other NIH grants, as well as the Scleroderma Research Foundation, Rheumatology Research Foundation, Jerome L. Greene Foundation, Martha McCrory Professorship, and Chresanthe Stauraluakis Memorial Discovery Fund. The study authors and Dr. Lakin report no relevant financial relationships.
 

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

Antigephyrin autoantibodies have been tied to lower gastrointestinal dysfunction, such as severe constipation and distention, in patients with systemic sclerosis (SSc), new research suggests. Researchers also found that gephyrin is expressed in the patient’s enteric nervous system (ENS), which regulates gut motility.

University of Texas Health Science Center at Houston

“While there are many antibodies that are helpful in identifying patients at risk for extraintestinal complications of this disease, markers that identify patients at higher risk for gastrointestinal complications are limited. Furthermore, the biological mechanisms that cause and perpetuate the progression of gastrointestinal disease in scleroderma are not well understood, making it challenging to distinguish between patients whose gastrointestinal disease will progress from those whose GI disease will remain stable/mild,” Zsuzsanna H. McMahan, MD, MHS, told this news organization in an email. Dr. McMahan is co–first author on the study along with Subhash Kulkarni, PhD. They conducted the research with colleagues when they both worked at Johns Hopkins University in Baltimore, Md.

Hospital for Special Surgery

When asked for comment, Kimberly Lakin, MD, MS, assistant professor of medicine at Weill Cornell Medicine and a rheumatologist at Hospital for Special Surgery, New York, called the study “interesting and novel.”

“Not only did [antigephyrin antibodies] correlate with the presence of lower GI symptoms, but also higher levels of antibodies correlated with worse lower GI symptoms. This suggests that not only could this antibody be used to predict who may have constipation and potentially need more aggressive GI interventions, but it may also be useful in quantifying GI severity in systemic sclerosis, although more research is still needed,” said Dr. Lakin, who was not involved with the research.

The study was published online in Arthritis & Rheumatology.

In the cross-sectional study, researchers identified gephyrin as an autoantigen in sera from a single patient with SSc by isolating it from immunoprecipitations performed with murine myenteric plexus neuron lysates, and then characterizing it by mass spectrometry and validating it in further assays. That patient had GI dysfunction but no defined SSc-associated autoantibodies.

Dr. McMahan and colleagues then investigated the prevalence of the autoantibody by screening the sera of 188 patients with SSc who presented consecutively to the Johns Hopkins Scleroderma Center between April 2016 and August 2017, as well as 40 controls, and compared GI symptom severity between antibody-positive and antibody-negative patients with SSc.

A total of 16 (8.5%) of the 188 patients with SSc had antigephyrin antibodies, compared with none of the controls. Of these 16 patients, 4 had no other defined SSc antibodies. In the SSc cohort, severe constipation was more common in antigephyrin antibody–positive patients, compared with antibody-negative patients (46% vs. 15%). Antibody-positive patients also had higher constipation scores, and severe distension and bloating occurred in the antibody-positive group more than twice as often (54% vs. 25%).

Patients with severe constipation, distention, and bloating had higher antigephyrin antibody levels. After adjusting for confounders such as disease duration, patients with severe constipation were nearly five times as likely (odds ratio, 4.74; P = .010) to be antigephyrin antibody–positive, and patients with severe distention and bloating were nearly four times as likely (OR, 3.71; P = .027) to be antibody-positive.

Last, the authors showed via immunohistochemistry that gephyrin is expressed in the myenteric ganglia of human GI tissue.

“Gastrointestinal function is highly regulated by the ENS, so it is interesting that antibodies that target a protein expressed by ENS cells (gephyrin) were identified in patients with scleroderma who have severe lower bowel dysfunction,” said Dr. McMahan, who is associate professor in the division of rheumatology and codirector of the scleroderma program at the University of Texas Health Science Center at Houston. “Gephyrin is a key mediator of normal communications between nerves in the gut, so it is tantalizing to speculate that autoimmune-mediated disruption (e.g., an inhibitory or blocking antibody) in neural (ENS) communications in the gut might lead to impaired bowel transit and prominent constipation.”

The study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and other NIH grants, as well as the Scleroderma Research Foundation, Rheumatology Research Foundation, Jerome L. Greene Foundation, Martha McCrory Professorship, and Chresanthe Stauraluakis Memorial Discovery Fund. The study authors and Dr. Lakin report no relevant financial relationships.
 

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

Zolpidem (Ambien) is a well-known sedative for sleep. Letairis (Ambrisentan) is a vasodilator for the treatment of pulmonary arterial hypertension. Citalopram (Celexa) is an antidepressant; escitalopram (Lexapro) is prescribed for anxiety and depression.
 

Those are just 4 of the more than 80 pairs of drug names that the Institute for Safe Medication Practices recently added to its list of confusing drug names. The aim is to increase awareness about the potential for a serious medication mistake when the wrong drug is given because of drug names that look and sound similar.

Awareness of these drug names, however, is just the first step in preventing medication mistakes. Health care providers should take a number of other steps as well, experts said.

ISMP launched its confusing drug names list, previously called look-alike, sound-alike (LASA) drugs, in 2008. The new list is an update of the 2019 version, said Michael J. Gaunt, PharmD, senior manager of error reporting programs for the ISMP, which focuses on the prevention of medication mistakes. The new entries were chosen on the basis of a number of factors, including ISMP’s analysis of recent medication mishap reports that were submitted to it.

The ISMP list now includes about 528 drug pairs, Dr. Gaunt said. The list is long, he said, partly because each pair is listed twice, so readers can cross reference. For instance, hydralazine and hydroxyzine are listed in one entry in the list, and hydroxyzine and hydralazine are listed in another.

Brand Institute in Miami has named, among other drugs, Entresto, Rybelsus, and Lunesta. The regulatory arm of the company, the Drug Safety Institute, “considers drug names that have been confused as an important part of our comprehensive drug name assessments,” Todd Bridges, global president of the institute, said in an emailed statement. Information on the confusing drug names are incorporated into the company’s proprietary algorithm and is used when developing brand names for drugs. “We continually update this algorithm as new drug names that are often confused are identified,” Mr. Bridges said.
 

Confusing drug names: Ongoing issue

The length of the list, as well as the latest additions, are not surprising, said Mary Ann Kliethermes, PharmD, director of medication safety and quality for the American Society of Health-System Pharmacists, a membership organization of about 60,000 pharmacists who practice in inpatient and outpatient settings.

“I’ve been in practice over 45 years,” she said, “and this has been a problem ever since I have been in practice.” The sheer volume of new drugs is one reason, she said. From 2013 through 2022, the U.S. Food and Drug Administration approved an average of 43 novel drugs per year, according to a report from its Center for Drug Evaluation and Research. “Since the 90s, this [confusion about similar drug names] has happened,” Dr. Kliethermes said.

According to a 2023 report, about 7,000-9,000 people die each year in the United States as the result of a medication error. However, it’s impossible to say for sure what percentage of those errors involve name confusion, Dr. Gaunt said.

Not all the mistakes are reported. Some that are reported are dramatic and deadly. In 2022, a Tennessee nurse was convicted of gross neglect and negligent homicide. She was sentenced to 3 years’ probation after she mistakenly gave vercuronium, an anesthetic agent, instead of the sedative Versed to a patient, and the woman died.
 

Updated list: A closer look

Many of the new drug pairs that are listed in the update are cephalosporins, said Dr. Kliethermes, who reviewed the new list for this news organization. In all, 20 of the latest 82 additions are cephalosporins. These include drugs such as cefazolin, which can be confused with cefotetan, and vice versa. These drugs have been around since the 1980s, she said, but “they needed to be on there.” Even in the 1980s, it was becoming difficult to differentiate them, and there were fewer drugs in that class then, she said.

Influenza vaccines made the new list, too. Fluzone High-Dose Quadrivalent can be confused with fluzone quadrivalent. Other new additions: hydrochlorothiazide and hydroxychloroquine, Lasik and Wakix, Pitressin and Pitocin, Remeron and Rozerem.
 

Beyond the list

While it’s not possible to pinpoint how big a problem name confusion is in causing medication mistakes, “it is certainly still an issue,” Dr. Gaunt said. A variety of practices can reduce that risk substantially, Dr. Gaunt and Dr. Kliethermes agreed.

Tall-man lettering. Both the FDA and the ISMP recommend the use of so-called tall-man lettering (TML), which involves the use of uppercase letters, sometimes in boldface, to distinguish similar names on product labels and elsewhere. Examples include vinBLAStine and vinCRIStine.

Electronic prescribing. “It eliminates the risk of handwriting confusion,” Dr. Gaunt said. However, electronic prescribing can have a downside, Dr. Kliethermes said. When ordering medication, a person may type in a few letters and may then be presented with a prompt that lists several drug names, and it can be easy to click the wrong one. For that reason, ISMP and other experts recommend typing at least five letters when searching for a medication in an electronic system.

Use both brand and generic names on labels and prescriptions.

Write the indication. That can serve as a double check. If a prescription for Ambien says “For sleep,” there’s probably less risk of filling a prescription for ambrisentan, the vasodilator.

Smart formulary additions. When hospitals add medications to their formularies, “part of that formulary assessment should include looking at the potential risk for errors,” Dr. Gaunt said. This involves keeping an eye out for confusing names and similar packaging. “Do that analysis up front and put in strategies to minimize that. Maybe you look for a different drug [for the same use] that has a different name.” Or choose a different manufacturer, so the medication would at least have a different container.

Use bar code scanning. Suppose a pharmacist goes to the shelf and pulls the wrong drug. “Bar code scanning provides the opportunity to catch the error,” Dr. Gaunt said. Many community pharmacies now have bar code scanning. ISMP just issued best practices for community pharmacies, Dr. Gaunt said, and these include the use of bar code scanning and other measures.

Educate consumers. Health care providers can educate consumers on how to minimize the risk of getting the wrong drug, Dr. Gaunt said. When patients are picking up a prescription, suggest they look at the container label; if it looks different from previous prescriptions of the same medicine, ask the pharmacist for an explanation. Some patients just pass it off, Dr. Gaunt said, figuring the pharmacist or health plan switched manufacturers of their medication.

Access the list. The entire list is on the ISMP site and is accessible after free registration.
 

Goal: Preventing confusion

The FDA has provided guidance for industry on naming drugs not yet approved so that the proposed names are not too similar in sound or appearance to those already on the market. Included in the lengthy document are checklists, such as, “Across a range of dialects, are the names consistently pronounced differently?” and “Are the lengths of the names dissimilar when scripted?” (Lengths are considered different if they differ by two or more letters.)

The FDA also offers the phonetic and orthographic computer analysis (POCA) program, a software tool that employs an advanced algorithm to evaluate similarities between two drug names. The data sources are updated regularly as new drugs are approved.
 

Liability update

The problem may be decreasing. In a 2020 report, researchers used pharmacists’ professional liability claim data from the Healthcare Providers Service Organization. They compared 2018 data on claims with 2013 data. The percentage of claims associated with wrong drug dispensing errors declined from 43.8% in 2013 to 36.8% in 2018. Wrong dose claims also declined, from 31.5% to 15.3%.

These researchers concluded that technology and automation have contributed to the prevention of medication errors caused by the use of the wrong drug and the wrong dose, but mistakes continue, owing to system and human errors.

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

Zolpidem (Ambien) is a well-known sedative for sleep. Letairis (Ambrisentan) is a vasodilator for the treatment of pulmonary arterial hypertension. Citalopram (Celexa) is an antidepressant; escitalopram (Lexapro) is prescribed for anxiety and depression.
 

Those are just 4 of the more than 80 pairs of drug names that the Institute for Safe Medication Practices recently added to its list of confusing drug names. The aim is to increase awareness about the potential for a serious medication mistake when the wrong drug is given because of drug names that look and sound similar.

Awareness of these drug names, however, is just the first step in preventing medication mistakes. Health care providers should take a number of other steps as well, experts said.

ISMP launched its confusing drug names list, previously called look-alike, sound-alike (LASA) drugs, in 2008. The new list is an update of the 2019 version, said Michael J. Gaunt, PharmD, senior manager of error reporting programs for the ISMP, which focuses on the prevention of medication mistakes. The new entries were chosen on the basis of a number of factors, including ISMP’s analysis of recent medication mishap reports that were submitted to it.

The ISMP list now includes about 528 drug pairs, Dr. Gaunt said. The list is long, he said, partly because each pair is listed twice, so readers can cross reference. For instance, hydralazine and hydroxyzine are listed in one entry in the list, and hydroxyzine and hydralazine are listed in another.

Brand Institute in Miami has named, among other drugs, Entresto, Rybelsus, and Lunesta. The regulatory arm of the company, the Drug Safety Institute, “considers drug names that have been confused as an important part of our comprehensive drug name assessments,” Todd Bridges, global president of the institute, said in an emailed statement. Information on the confusing drug names are incorporated into the company’s proprietary algorithm and is used when developing brand names for drugs. “We continually update this algorithm as new drug names that are often confused are identified,” Mr. Bridges said.
 

Confusing drug names: Ongoing issue

The length of the list, as well as the latest additions, are not surprising, said Mary Ann Kliethermes, PharmD, director of medication safety and quality for the American Society of Health-System Pharmacists, a membership organization of about 60,000 pharmacists who practice in inpatient and outpatient settings.

“I’ve been in practice over 45 years,” she said, “and this has been a problem ever since I have been in practice.” The sheer volume of new drugs is one reason, she said. From 2013 through 2022, the U.S. Food and Drug Administration approved an average of 43 novel drugs per year, according to a report from its Center for Drug Evaluation and Research. “Since the 90s, this [confusion about similar drug names] has happened,” Dr. Kliethermes said.

According to a 2023 report, about 7,000-9,000 people die each year in the United States as the result of a medication error. However, it’s impossible to say for sure what percentage of those errors involve name confusion, Dr. Gaunt said.

Not all the mistakes are reported. Some that are reported are dramatic and deadly. In 2022, a Tennessee nurse was convicted of gross neglect and negligent homicide. She was sentenced to 3 years’ probation after she mistakenly gave vercuronium, an anesthetic agent, instead of the sedative Versed to a patient, and the woman died.
 

Updated list: A closer look

Many of the new drug pairs that are listed in the update are cephalosporins, said Dr. Kliethermes, who reviewed the new list for this news organization. In all, 20 of the latest 82 additions are cephalosporins. These include drugs such as cefazolin, which can be confused with cefotetan, and vice versa. These drugs have been around since the 1980s, she said, but “they needed to be on there.” Even in the 1980s, it was becoming difficult to differentiate them, and there were fewer drugs in that class then, she said.

Influenza vaccines made the new list, too. Fluzone High-Dose Quadrivalent can be confused with fluzone quadrivalent. Other new additions: hydrochlorothiazide and hydroxychloroquine, Lasik and Wakix, Pitressin and Pitocin, Remeron and Rozerem.
 

Beyond the list

While it’s not possible to pinpoint how big a problem name confusion is in causing medication mistakes, “it is certainly still an issue,” Dr. Gaunt said. A variety of practices can reduce that risk substantially, Dr. Gaunt and Dr. Kliethermes agreed.

Tall-man lettering. Both the FDA and the ISMP recommend the use of so-called tall-man lettering (TML), which involves the use of uppercase letters, sometimes in boldface, to distinguish similar names on product labels and elsewhere. Examples include vinBLAStine and vinCRIStine.

Electronic prescribing. “It eliminates the risk of handwriting confusion,” Dr. Gaunt said. However, electronic prescribing can have a downside, Dr. Kliethermes said. When ordering medication, a person may type in a few letters and may then be presented with a prompt that lists several drug names, and it can be easy to click the wrong one. For that reason, ISMP and other experts recommend typing at least five letters when searching for a medication in an electronic system.

Use both brand and generic names on labels and prescriptions.

Write the indication. That can serve as a double check. If a prescription for Ambien says “For sleep,” there’s probably less risk of filling a prescription for ambrisentan, the vasodilator.

Smart formulary additions. When hospitals add medications to their formularies, “part of that formulary assessment should include looking at the potential risk for errors,” Dr. Gaunt said. This involves keeping an eye out for confusing names and similar packaging. “Do that analysis up front and put in strategies to minimize that. Maybe you look for a different drug [for the same use] that has a different name.” Or choose a different manufacturer, so the medication would at least have a different container.

Use bar code scanning. Suppose a pharmacist goes to the shelf and pulls the wrong drug. “Bar code scanning provides the opportunity to catch the error,” Dr. Gaunt said. Many community pharmacies now have bar code scanning. ISMP just issued best practices for community pharmacies, Dr. Gaunt said, and these include the use of bar code scanning and other measures.

Educate consumers. Health care providers can educate consumers on how to minimize the risk of getting the wrong drug, Dr. Gaunt said. When patients are picking up a prescription, suggest they look at the container label; if it looks different from previous prescriptions of the same medicine, ask the pharmacist for an explanation. Some patients just pass it off, Dr. Gaunt said, figuring the pharmacist or health plan switched manufacturers of their medication.

Access the list. The entire list is on the ISMP site and is accessible after free registration.
 

Goal: Preventing confusion

The FDA has provided guidance for industry on naming drugs not yet approved so that the proposed names are not too similar in sound or appearance to those already on the market. Included in the lengthy document are checklists, such as, “Across a range of dialects, are the names consistently pronounced differently?” and “Are the lengths of the names dissimilar when scripted?” (Lengths are considered different if they differ by two or more letters.)

The FDA also offers the phonetic and orthographic computer analysis (POCA) program, a software tool that employs an advanced algorithm to evaluate similarities between two drug names. The data sources are updated regularly as new drugs are approved.
 

Liability update

The problem may be decreasing. In a 2020 report, researchers used pharmacists’ professional liability claim data from the Healthcare Providers Service Organization. They compared 2018 data on claims with 2013 data. The percentage of claims associated with wrong drug dispensing errors declined from 43.8% in 2013 to 36.8% in 2018. Wrong dose claims also declined, from 31.5% to 15.3%.

These researchers concluded that technology and automation have contributed to the prevention of medication errors caused by the use of the wrong drug and the wrong dose, but mistakes continue, owing to system and human errors.

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

Zolpidem (Ambien) is a well-known sedative for sleep. Letairis (Ambrisentan) is a vasodilator for the treatment of pulmonary arterial hypertension. Citalopram (Celexa) is an antidepressant; escitalopram (Lexapro) is prescribed for anxiety and depression.
 

Those are just 4 of the more than 80 pairs of drug names that the Institute for Safe Medication Practices recently added to its list of confusing drug names. The aim is to increase awareness about the potential for a serious medication mistake when the wrong drug is given because of drug names that look and sound similar.

Awareness of these drug names, however, is just the first step in preventing medication mistakes. Health care providers should take a number of other steps as well, experts said.

ISMP launched its confusing drug names list, previously called look-alike, sound-alike (LASA) drugs, in 2008. The new list is an update of the 2019 version, said Michael J. Gaunt, PharmD, senior manager of error reporting programs for the ISMP, which focuses on the prevention of medication mistakes. The new entries were chosen on the basis of a number of factors, including ISMP’s analysis of recent medication mishap reports that were submitted to it.

The ISMP list now includes about 528 drug pairs, Dr. Gaunt said. The list is long, he said, partly because each pair is listed twice, so readers can cross reference. For instance, hydralazine and hydroxyzine are listed in one entry in the list, and hydroxyzine and hydralazine are listed in another.

Brand Institute in Miami has named, among other drugs, Entresto, Rybelsus, and Lunesta. The regulatory arm of the company, the Drug Safety Institute, “considers drug names that have been confused as an important part of our comprehensive drug name assessments,” Todd Bridges, global president of the institute, said in an emailed statement. Information on the confusing drug names are incorporated into the company’s proprietary algorithm and is used when developing brand names for drugs. “We continually update this algorithm as new drug names that are often confused are identified,” Mr. Bridges said.
 

Confusing drug names: Ongoing issue

The length of the list, as well as the latest additions, are not surprising, said Mary Ann Kliethermes, PharmD, director of medication safety and quality for the American Society of Health-System Pharmacists, a membership organization of about 60,000 pharmacists who practice in inpatient and outpatient settings.

“I’ve been in practice over 45 years,” she said, “and this has been a problem ever since I have been in practice.” The sheer volume of new drugs is one reason, she said. From 2013 through 2022, the U.S. Food and Drug Administration approved an average of 43 novel drugs per year, according to a report from its Center for Drug Evaluation and Research. “Since the 90s, this [confusion about similar drug names] has happened,” Dr. Kliethermes said.

According to a 2023 report, about 7,000-9,000 people die each year in the United States as the result of a medication error. However, it’s impossible to say for sure what percentage of those errors involve name confusion, Dr. Gaunt said.

Not all the mistakes are reported. Some that are reported are dramatic and deadly. In 2022, a Tennessee nurse was convicted of gross neglect and negligent homicide. She was sentenced to 3 years’ probation after she mistakenly gave vercuronium, an anesthetic agent, instead of the sedative Versed to a patient, and the woman died.
 

Updated list: A closer look

Many of the new drug pairs that are listed in the update are cephalosporins, said Dr. Kliethermes, who reviewed the new list for this news organization. In all, 20 of the latest 82 additions are cephalosporins. These include drugs such as cefazolin, which can be confused with cefotetan, and vice versa. These drugs have been around since the 1980s, she said, but “they needed to be on there.” Even in the 1980s, it was becoming difficult to differentiate them, and there were fewer drugs in that class then, she said.

Influenza vaccines made the new list, too. Fluzone High-Dose Quadrivalent can be confused with fluzone quadrivalent. Other new additions: hydrochlorothiazide and hydroxychloroquine, Lasik and Wakix, Pitressin and Pitocin, Remeron and Rozerem.
 

Beyond the list

While it’s not possible to pinpoint how big a problem name confusion is in causing medication mistakes, “it is certainly still an issue,” Dr. Gaunt said. A variety of practices can reduce that risk substantially, Dr. Gaunt and Dr. Kliethermes agreed.

Tall-man lettering. Both the FDA and the ISMP recommend the use of so-called tall-man lettering (TML), which involves the use of uppercase letters, sometimes in boldface, to distinguish similar names on product labels and elsewhere. Examples include vinBLAStine and vinCRIStine.

Electronic prescribing. “It eliminates the risk of handwriting confusion,” Dr. Gaunt said. However, electronic prescribing can have a downside, Dr. Kliethermes said. When ordering medication, a person may type in a few letters and may then be presented with a prompt that lists several drug names, and it can be easy to click the wrong one. For that reason, ISMP and other experts recommend typing at least five letters when searching for a medication in an electronic system.

Use both brand and generic names on labels and prescriptions.

Write the indication. That can serve as a double check. If a prescription for Ambien says “For sleep,” there’s probably less risk of filling a prescription for ambrisentan, the vasodilator.

Smart formulary additions. When hospitals add medications to their formularies, “part of that formulary assessment should include looking at the potential risk for errors,” Dr. Gaunt said. This involves keeping an eye out for confusing names and similar packaging. “Do that analysis up front and put in strategies to minimize that. Maybe you look for a different drug [for the same use] that has a different name.” Or choose a different manufacturer, so the medication would at least have a different container.

Use bar code scanning. Suppose a pharmacist goes to the shelf and pulls the wrong drug. “Bar code scanning provides the opportunity to catch the error,” Dr. Gaunt said. Many community pharmacies now have bar code scanning. ISMP just issued best practices for community pharmacies, Dr. Gaunt said, and these include the use of bar code scanning and other measures.

Educate consumers. Health care providers can educate consumers on how to minimize the risk of getting the wrong drug, Dr. Gaunt said. When patients are picking up a prescription, suggest they look at the container label; if it looks different from previous prescriptions of the same medicine, ask the pharmacist for an explanation. Some patients just pass it off, Dr. Gaunt said, figuring the pharmacist or health plan switched manufacturers of their medication.

Access the list. The entire list is on the ISMP site and is accessible after free registration.
 

Goal: Preventing confusion

The FDA has provided guidance for industry on naming drugs not yet approved so that the proposed names are not too similar in sound or appearance to those already on the market. Included in the lengthy document are checklists, such as, “Across a range of dialects, are the names consistently pronounced differently?” and “Are the lengths of the names dissimilar when scripted?” (Lengths are considered different if they differ by two or more letters.)

The FDA also offers the phonetic and orthographic computer analysis (POCA) program, a software tool that employs an advanced algorithm to evaluate similarities between two drug names. The data sources are updated regularly as new drugs are approved.
 

Liability update

The problem may be decreasing. In a 2020 report, researchers used pharmacists’ professional liability claim data from the Healthcare Providers Service Organization. They compared 2018 data on claims with 2013 data. The percentage of claims associated with wrong drug dispensing errors declined from 43.8% in 2013 to 36.8% in 2018. Wrong dose claims also declined, from 31.5% to 15.3%.

These researchers concluded that technology and automation have contributed to the prevention of medication errors caused by the use of the wrong drug and the wrong dose, but mistakes continue, owing to system and human errors.

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

THE COMPARISON

A A 51-year-old Hispanic man with a squamous cell carcinoma (SCC) of the keratoacanthoma type on the arm.

B A 75-year-old Black man with an SCC of the keratoacanthoma type on the abdomen.

C An African woman with an SCC on the lower lip decades after a large facial burn, which is known as a Marjolin ulcer.

Cutaneous squamous cell carcinoma (SCC) develops from a malignant tumor of the keratinocytes, eccrine glands, or pilosebaceous units that invades the dermis. Risk factors include lighter skin tone, higher cumulative sun exposure, human papillomavirus (HPV) infection, hidradenitis suppurativa (HS), lichen sclerosus, family history of skin cancer,1 and immunosuppression.² It typically affects sun-exposed areas of the body such as the face, scalp, neck, and extensor surfaces of the arms (Figure, A).^3,4 However, in those with darker skin tones, the most common anatomic sites are those that are not exposed to the sun (Figure, B). Squamous cell carcinoma is diagnosed via skin biopsy. Treatment options include surgical excision, destructive methods such as electrodesiccation and curettage, and Mohs micrographic surgery. Cutaneous SCC has a cure rate of more than 95% and a mortality rate of 1.5% to 2% in the United States.³

Photographs courtesy of Richard P. Usatine, MD.

Epidemiology

Squamous cell carcinoma is the most common skin cancer occurring in Black individuals, manifesting primarily in the fifth decade of life.^5-7 It is the second most common skin cancer in White, Hispanic, and Asian individuals and is more common in males.⁸ In a study of organ transplant recipients (N=413), Pritchett et al⁹ reported that HPV infection was a major risk factor in Hispanic patients because 66.7% of those with SCC had a history of HPV. However, HPV is a risk factor for SCC in all ethnic groups.¹⁰

Key clinical features in people with darker skin tones

Anatomic location

• The lower legs and anogenital areas are the most common sites for SCC in patients with skin of color.^4,11
• In Black women, SCC occurs more often on sun-exposed areas such as the arms and legs compared to Black men.^7,12-14
• The genitalia, perianal area, ocular mucosa, and oral mucosa are the least likely areas to be routinely examined, even in skin cancer clinics that see high-risk patients, despite the SCC risk in the anogenital area.^15,16
• Squamous cell carcinoma of the lips and scalp is more likely to occur in Black women vs Black men.^4,7,17 Clinical appearance
• In those with darker skin tones, SCCs may appear hyperpigmented4 or hyperkeratotic with a lack of erythema and an inconsistent appearance.^6,7,18
• A nonhealing ulceration of the skin should prompt a biopsy to rule out SCC.^3,19

Worth noting

In patients with darker skin tones, the risk for SCC increases in areas with chronic inflammation and scarring of the skin.^{4,6,7,11,18,20-22} In Black patients, 20% to 40% of cases of SCC occur in the setting of chronic inflammation and scarring.^6,7,18 Chronic inflammatory conditions include ulcers, lupus vulgaris, discoid lupus erythematosus, and HPV. In patients with discoid lupus erythematosus, there is an additive effect of sun exposure on the scars, which may play a role in the pathogenesis and metastasis risk for skin cancer in Black patients.⁴ Other scarring conditions include thermal or chemical burn scars, areas of physical trauma, and prior sites of radiation treatment.^14,23 Squamous cell carcinoma arising in a burn scar is called a Marjolin ulcer or malignant degeneration of a scar (Figure, C). It is reported more often in lower-income, underresourced countries, which may suggest the need for early detection in populations with skin of color.²⁴

Squamous cell carcinoma is more aggressive in sites that are not exposed to sun compared to sun-exposed areas.^17,25

The risk for SCC is increased in immunocompromised patients,² especially those with HPV.¹⁰

The prevalence of SCC in those with HS is approximately 4.6%. The chronic inflammation and irritation from HS in association with other risk factors such as tobacco use may contribute to the malignant transformation to SCC.²⁶

Health disparity highlight

• The risk for metastasis from SCC is 20% to 40% in Black patients vs 1% to 4% in White patients.^4,6,27
• Penile SCC was associated with a lower overall survival rate in patients of African descent.^20,21
• The increased morbidity and mortality from SCC in patients with skin of color may be attributed to delays in diagnosis and treatment as well as an incomplete understanding of tumor genetics.^4,6,18

Acknowledgment—The authors thank Elyse Gadra (Philadelphia, Pennsylvania) for assistance in the preparation of this manuscript.

THE COMPARISON

A A 51-year-old Hispanic man with a squamous cell carcinoma (SCC) of the keratoacanthoma type on the arm.

B A 75-year-old Black man with an SCC of the keratoacanthoma type on the abdomen.

C An African woman with an SCC on the lower lip decades after a large facial burn, which is known as a Marjolin ulcer.

Cutaneous squamous cell carcinoma (SCC) develops from a malignant tumor of the keratinocytes, eccrine glands, or pilosebaceous units that invades the dermis. Risk factors include lighter skin tone, higher cumulative sun exposure, human papillomavirus (HPV) infection, hidradenitis suppurativa (HS), lichen sclerosus, family history of skin cancer,1 and immunosuppression.² It typically affects sun-exposed areas of the body such as the face, scalp, neck, and extensor surfaces of the arms (Figure, A).^3,4 However, in those with darker skin tones, the most common anatomic sites are those that are not exposed to the sun (Figure, B). Squamous cell carcinoma is diagnosed via skin biopsy. Treatment options include surgical excision, destructive methods such as electrodesiccation and curettage, and Mohs micrographic surgery. Cutaneous SCC has a cure rate of more than 95% and a mortality rate of 1.5% to 2% in the United States.³

Photographs courtesy of Richard P. Usatine, MD.

Epidemiology

Squamous cell carcinoma is the most common skin cancer occurring in Black individuals, manifesting primarily in the fifth decade of life.^5-7 It is the second most common skin cancer in White, Hispanic, and Asian individuals and is more common in males.⁸ In a study of organ transplant recipients (N=413), Pritchett et al⁹ reported that HPV infection was a major risk factor in Hispanic patients because 66.7% of those with SCC had a history of HPV. However, HPV is a risk factor for SCC in all ethnic groups.¹⁰

Key clinical features in people with darker skin tones

Anatomic location

• The lower legs and anogenital areas are the most common sites for SCC in patients with skin of color.^4,11
• In Black women, SCC occurs more often on sun-exposed areas such as the arms and legs compared to Black men.^7,12-14
• The genitalia, perianal area, ocular mucosa, and oral mucosa are the least likely areas to be routinely examined, even in skin cancer clinics that see high-risk patients, despite the SCC risk in the anogenital area.^15,16
• Squamous cell carcinoma of the lips and scalp is more likely to occur in Black women vs Black men.^4,7,17 Clinical appearance
• In those with darker skin tones, SCCs may appear hyperpigmented4 or hyperkeratotic with a lack of erythema and an inconsistent appearance.^6,7,18
• A nonhealing ulceration of the skin should prompt a biopsy to rule out SCC.^3,19

Worth noting

In patients with darker skin tones, the risk for SCC increases in areas with chronic inflammation and scarring of the skin.^{4,6,7,11,18,20-22} In Black patients, 20% to 40% of cases of SCC occur in the setting of chronic inflammation and scarring.^6,7,18 Chronic inflammatory conditions include ulcers, lupus vulgaris, discoid lupus erythematosus, and HPV. In patients with discoid lupus erythematosus, there is an additive effect of sun exposure on the scars, which may play a role in the pathogenesis and metastasis risk for skin cancer in Black patients.⁴ Other scarring conditions include thermal or chemical burn scars, areas of physical trauma, and prior sites of radiation treatment.^14,23 Squamous cell carcinoma arising in a burn scar is called a Marjolin ulcer or malignant degeneration of a scar (Figure, C). It is reported more often in lower-income, underresourced countries, which may suggest the need for early detection in populations with skin of color.²⁴

Squamous cell carcinoma is more aggressive in sites that are not exposed to sun compared to sun-exposed areas.^17,25

The risk for SCC is increased in immunocompromised patients,² especially those with HPV.¹⁰

The prevalence of SCC in those with HS is approximately 4.6%. The chronic inflammation and irritation from HS in association with other risk factors such as tobacco use may contribute to the malignant transformation to SCC.²⁶

Health disparity highlight

• The risk for metastasis from SCC is 20% to 40% in Black patients vs 1% to 4% in White patients.^4,6,27
• Penile SCC was associated with a lower overall survival rate in patients of African descent.^20,21
• The increased morbidity and mortality from SCC in patients with skin of color may be attributed to delays in diagnosis and treatment as well as an incomplete understanding of tumor genetics.^4,6,18

Acknowledgment—The authors thank Elyse Gadra (Philadelphia, Pennsylvania) for assistance in the preparation of this manuscript.

THE COMPARISON

A A 51-year-old Hispanic man with a squamous cell carcinoma (SCC) of the keratoacanthoma type on the arm.

B A 75-year-old Black man with an SCC of the keratoacanthoma type on the abdomen.

C An African woman with an SCC on the lower lip decades after a large facial burn, which is known as a Marjolin ulcer.

Cutaneous squamous cell carcinoma (SCC) develops from a malignant tumor of the keratinocytes, eccrine glands, or pilosebaceous units that invades the dermis. Risk factors include lighter skin tone, higher cumulative sun exposure, human papillomavirus (HPV) infection, hidradenitis suppurativa (HS), lichen sclerosus, family history of skin cancer,1 and immunosuppression.² It typically affects sun-exposed areas of the body such as the face, scalp, neck, and extensor surfaces of the arms (Figure, A).^3,4 However, in those with darker skin tones, the most common anatomic sites are those that are not exposed to the sun (Figure, B). Squamous cell carcinoma is diagnosed via skin biopsy. Treatment options include surgical excision, destructive methods such as electrodesiccation and curettage, and Mohs micrographic surgery. Cutaneous SCC has a cure rate of more than 95% and a mortality rate of 1.5% to 2% in the United States.³

Photographs courtesy of Richard P. Usatine, MD.

Epidemiology

Squamous cell carcinoma is the most common skin cancer occurring in Black individuals, manifesting primarily in the fifth decade of life.^5-7 It is the second most common skin cancer in White, Hispanic, and Asian individuals and is more common in males.⁸ In a study of organ transplant recipients (N=413), Pritchett et al⁹ reported that HPV infection was a major risk factor in Hispanic patients because 66.7% of those with SCC had a history of HPV. However, HPV is a risk factor for SCC in all ethnic groups.¹⁰

Key clinical features in people with darker skin tones

Anatomic location

• The lower legs and anogenital areas are the most common sites for SCC in patients with skin of color.^4,11
• In Black women, SCC occurs more often on sun-exposed areas such as the arms and legs compared to Black men.^7,12-14
• The genitalia, perianal area, ocular mucosa, and oral mucosa are the least likely areas to be routinely examined, even in skin cancer clinics that see high-risk patients, despite the SCC risk in the anogenital area.^15,16
• Squamous cell carcinoma of the lips and scalp is more likely to occur in Black women vs Black men.^4,7,17 Clinical appearance
• In those with darker skin tones, SCCs may appear hyperpigmented4 or hyperkeratotic with a lack of erythema and an inconsistent appearance.^6,7,18
• A nonhealing ulceration of the skin should prompt a biopsy to rule out SCC.^3,19

Worth noting

In patients with darker skin tones, the risk for SCC increases in areas with chronic inflammation and scarring of the skin.^{4,6,7,11,18,20-22} In Black patients, 20% to 40% of cases of SCC occur in the setting of chronic inflammation and scarring.^6,7,18 Chronic inflammatory conditions include ulcers, lupus vulgaris, discoid lupus erythematosus, and HPV. In patients with discoid lupus erythematosus, there is an additive effect of sun exposure on the scars, which may play a role in the pathogenesis and metastasis risk for skin cancer in Black patients.⁴ Other scarring conditions include thermal or chemical burn scars, areas of physical trauma, and prior sites of radiation treatment.^14,23 Squamous cell carcinoma arising in a burn scar is called a Marjolin ulcer or malignant degeneration of a scar (Figure, C). It is reported more often in lower-income, underresourced countries, which may suggest the need for early detection in populations with skin of color.²⁴

Squamous cell carcinoma is more aggressive in sites that are not exposed to sun compared to sun-exposed areas.^17,25

The risk for SCC is increased in immunocompromised patients,² especially those with HPV.¹⁰

The prevalence of SCC in those with HS is approximately 4.6%. The chronic inflammation and irritation from HS in association with other risk factors such as tobacco use may contribute to the malignant transformation to SCC.²⁶

Health disparity highlight

• The risk for metastasis from SCC is 20% to 40% in Black patients vs 1% to 4% in White patients.^4,6,27
• Penile SCC was associated with a lower overall survival rate in patients of African descent.^20,21
• The increased morbidity and mortality from SCC in patients with skin of color may be attributed to delays in diagnosis and treatment as well as an incomplete understanding of tumor genetics.^4,6,18

Acknowledgment—The authors thank Elyse Gadra (Philadelphia, Pennsylvania) for assistance in the preparation of this manuscript.

Lanolin was announced as the Allergen of the Year by the American Contact Dermatitis Society in March 2023.¹ However, allergic contact dermatitis (ACD) to lanolin remains a matter of fierce debate among dermatologists. Herein, we discuss this important contact allergen, emphasizing the controversy behind its allergenicity and nuances to consider when patch testing.

What is Lanolin?

Lanolin is a greasy, yellow, fatlike substance derived from the sebaceous glands of sheep. It is extracted from wool using an intricate process of scouring with dilute alkali, centrifuging, and refining with hot alkali and bleach.² It is comprised of a complex mixture of esters, alcohols, sterols, fatty acids, lactose, and hydrocarbons.³

The hydrophobic property of lanolin helps sheep shed water from their coats.³ In humans, this hydrophobicity benefits the skin by retaining moisture already present in the epidermis. Lanolin can hold as much as twice its weight in water and may reduce transepidermal water loss by 20% to 30%.^4-6 In addition, lanolin maintains tissue breathability, which supports proper gas exchange, promoting wound healing and protecting against infection.^3,7

Many personal care products (PCPs), cosmetics, and topical medicaments contain lanolin, particularly products marketed to help restore dry cracked skin. The range of permitted concentrations of lanolin in over-the-counter products in the United States is 12.5% to 50%.³ Lanolin also may be found in industrial goods. The Table provides a comprehensive list of common items that may contain lanolin.^1,3,8,9

A Wolf in Sheep’s Clothing?

Despite its benefits, lanolin is a potential source of ACD. The first reported positive patch test (PPT) to lanolin worldwide was in the late 1920s.¹⁰ Subsequent cases of ACD to lanolin were described over the next 30 years, reaching a peak of recognition in the latter half of the 20th century with rates of PPT ranging from 0% to 7.4%, though the patient population and lanolin patch-test formulation used differed across studies.⁹ The North American Contact Dermatitis Group observed that 3.3% (1431/43,691) of patients tested from 2001 to 2018 had a PPT to either lanolin alcohol 30% in petrolatum (pet) or Amerchol L101 (10% lanolin alcohol dissolved in mineral oil) 50% pet.¹¹ Compared to patients referred for patch testing, the prevalence of contact allergy to lanolin is lower in the general population; 0.4% of the general population in Europe (N=3119) tested positive to wool alcohols 1.0 mg/cm² on the thin-layer rapid use Epicutaneous (TRUE) test.¹²

Allergic contact dermatitis to lanolin is unrelated to an allergy to wool itself, which probably does not exist, though wool is well known to cause irritant contact dermatitis, particularly in atopic individuals.¹³

Who Is at Risk for Lanolin Allergy?

In a recent comprehensive review of lanolin allergy, Jenkins and Belsito¹ summarized 4 high-risk subgroups of patients for the development of lanolin contact allergy: stasis dermatitis, chronic leg ulcers, atopic dermatitis (AD), and perianal/genital dermatitis. These chronic inflammatory skin conditions may increase the risk for ACD to lanolin via increased exposure in topical therapies and/or increased allergen penetration through an impaired epidermal barrier.^14-16 Demographically, older adults and children are at-risk groups, likely secondary to the higher prevalence of stasis dermatitis/leg ulcers in the former group and AD in the latter.¹

 

 

Lanolin Controversies

The allergenicity of lanolin is far from straightforward. In 1996, Wolf¹⁷ first described the “lanolin paradox,” modeled after the earlier “paraben paradox” described by Fisher.¹⁸ There are 4 clinical phenomena of the lanolin paradox¹⁷:

• Lanolin generally does not cause contact allergy when found in PCPs but may cause ACD when found in topical medicaments.
• Some patients can use lanolin-containing PCPs on healthy skin without issue but will develop ACD when a lanolin-containing topical medicament is applied to inflamed skin. This is because inflamed skin is more easily sensitized.
• False-negative patch test reactions to pure lanolin may occur. Since Wolf’s¹⁷ initial description of the paradox, free alcohols of lanolin have been found to be its principal allergen, though it also is possible that oxidation of lanolin could generate additional allergenic substances.¹
• Patch testing with wool alcohol 30% can generate both false-negative and false-positive results.

At one extreme, Kligman¹⁹ also was concerned about false-positive reactions to lanolin, describing lanolin allergy as a myth attributed to overzealous patch testing and a failure to appreciate the limitations of this diagnostic modality. Indeed, just having a PPT to lanolin (ie, contact allergy) does not automatically translate to a relevant ACD,¹ and determining the clinical relevance of a PPT is of utmost importance. In 2001, Wakelin et al²⁰ reported that the majority (71% [92/130]) of positive reactions to Amerchol L101 50% or 100% pet showed current clinical relevance. Data from the North American Contact Dermatitis Group in 2009 and in 2022 were similar, with 83.4% (529/634) of positive reactions to lanolin alcohol 30% pet and 86.5% (1238/1431) of positive reactions to Amerchol L101 50% pet classified as current clinical relevance.^11,21 These findings demonstrate that although lanolin may be a weak sensitizer, a PPT usually represents a highly relevant cause of dermatitis.

Considerations for Patch Testing

Considering Wolf’s¹⁷ claim that even pure lanolin is not an appropriate formulation to use for patch testing due to the risk for inaccurate results, you might now be wondering which preparation should be used. Mortensen²² popularized another compound, Amerchol L101, in 1979. In this small study of 60 patients with a PPT to lanolin and/or its derivatives, the highest proportion (37% [22/60]) were positive to Amerchol L101 but negative to wool alcohol 30%, suggesting the need to test to more than one preparation simultaneously.²² In a larger study by Miest et al,²³ 3.9% (11/268) of patients had a PPT to Amerchol L101 50% pet, whereas only 1.1% (3/268) had a PPT to lanolin alcohol 30% pet. This highlighted the importance of including Amerchol L101 when patch testing because it was thought to capture more positive results; however, some studies suggest that Amerchol L101 is not superior at predicting lanolin contact allergy vs lanolin alcohol 30% pet. The risk for an irritant reaction when patch testing with Amerchol L101 should be considered due to its mineral oil component.²⁴

Although there is no universal consensus to date, some investigators suggest patch testing both lanolin alcohol 30% pet and Amerchol L101 50% pet simultaneously.¹ The TRUE test utilizes 1000 µg/cm² of wool alcohols, while the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core 90 Series contain Amerchol L101 50% pet. Patch testing to the most allergenic component of lanolin—the free fatty alcohols (particularly alkane-α,β-diols and alkane-α,ω-diols)—has been suggested,¹ though these formulations are not yet commercially available.

When available, the patient’s own lanolin-containing PCPs should be tested.¹ Performing a repeat open application test (ROAT) to a lanolin-containing product also may be highly useful to distinguish weak-positive from irritant patch test reactions and to determine if sensitized patients can tolerate lanolin-containing products on intact skin. To complete a ROAT, a patient should apply the suspected leave-on product to a patch of unaffected skin (classically the volar forearm) twice daily for at least 10 days.²⁵ If the application site is clear after 10 days, the patient is unlikely to have ACD to the product in question. Compared to patch testing, ROAT more accurately mimics a true use situation, which is particularly important for lanolin given its tendency to preferentially impact damaged or inflamed skin while sparing healthy skin.

Alternatives to Lanolin

Patients with confirmed ACD to lanolin may use plain petrolatum, a safe and inexpensive substitute with equivalent moisturizing efficacy. It can reduce transepidermal water loss by more than 98%,⁴ with essentially no risk for ACD. Humectants such as glycerin, sorbitol, and α-hydroxy acids also have moisturizing properties akin to those of lanolin. In addition, some oils may provide benefit to patients with chronic skin conditions. Sunflower seed oil and extra virgin coconut oil have anti-inflammatory, antibacterial, and barrier repair properties.^26,27 Allergic contact dermatitis to these oils rarely, if ever, occurs.²⁸

Final Interpretation

Lanolin is a well-known yet controversial contact allergen that is widely used in PCPs, cosmetics, topical medicaments, and industrial goods. Lanolin ACD preferentially impacts patients with stasis dermatitis, chronic leg ulcers, AD, and perianal/genital dermatitis. Patch testing with more than one lanolin formulation, including lanolin alcohol 30% pet and/or Amerchol L101 50% pet, as well as testing the patient’s own products may be necessary to confirm the diagnosis. In cases of ACD to lanolin, an alternative agent, such as plain petrolatum, may be used.

Lanolin was announced as the Allergen of the Year by the American Contact Dermatitis Society in March 2023.¹ However, allergic contact dermatitis (ACD) to lanolin remains a matter of fierce debate among dermatologists. Herein, we discuss this important contact allergen, emphasizing the controversy behind its allergenicity and nuances to consider when patch testing.

What is Lanolin?

Lanolin is a greasy, yellow, fatlike substance derived from the sebaceous glands of sheep. It is extracted from wool using an intricate process of scouring with dilute alkali, centrifuging, and refining with hot alkali and bleach.² It is comprised of a complex mixture of esters, alcohols, sterols, fatty acids, lactose, and hydrocarbons.³

The hydrophobic property of lanolin helps sheep shed water from their coats.³ In humans, this hydrophobicity benefits the skin by retaining moisture already present in the epidermis. Lanolin can hold as much as twice its weight in water and may reduce transepidermal water loss by 20% to 30%.^4-6 In addition, lanolin maintains tissue breathability, which supports proper gas exchange, promoting wound healing and protecting against infection.^3,7

Many personal care products (PCPs), cosmetics, and topical medicaments contain lanolin, particularly products marketed to help restore dry cracked skin. The range of permitted concentrations of lanolin in over-the-counter products in the United States is 12.5% to 50%.³ Lanolin also may be found in industrial goods. The Table provides a comprehensive list of common items that may contain lanolin.^1,3,8,9

A Wolf in Sheep’s Clothing?

Despite its benefits, lanolin is a potential source of ACD. The first reported positive patch test (PPT) to lanolin worldwide was in the late 1920s.¹⁰ Subsequent cases of ACD to lanolin were described over the next 30 years, reaching a peak of recognition in the latter half of the 20th century with rates of PPT ranging from 0% to 7.4%, though the patient population and lanolin patch-test formulation used differed across studies.⁹ The North American Contact Dermatitis Group observed that 3.3% (1431/43,691) of patients tested from 2001 to 2018 had a PPT to either lanolin alcohol 30% in petrolatum (pet) or Amerchol L101 (10% lanolin alcohol dissolved in mineral oil) 50% pet.¹¹ Compared to patients referred for patch testing, the prevalence of contact allergy to lanolin is lower in the general population; 0.4% of the general population in Europe (N=3119) tested positive to wool alcohols 1.0 mg/cm² on the thin-layer rapid use Epicutaneous (TRUE) test.¹²

Allergic contact dermatitis to lanolin is unrelated to an allergy to wool itself, which probably does not exist, though wool is well known to cause irritant contact dermatitis, particularly in atopic individuals.¹³

Who Is at Risk for Lanolin Allergy?

In a recent comprehensive review of lanolin allergy, Jenkins and Belsito¹ summarized 4 high-risk subgroups of patients for the development of lanolin contact allergy: stasis dermatitis, chronic leg ulcers, atopic dermatitis (AD), and perianal/genital dermatitis. These chronic inflammatory skin conditions may increase the risk for ACD to lanolin via increased exposure in topical therapies and/or increased allergen penetration through an impaired epidermal barrier.^14-16 Demographically, older adults and children are at-risk groups, likely secondary to the higher prevalence of stasis dermatitis/leg ulcers in the former group and AD in the latter.¹

 

 

Lanolin Controversies

The allergenicity of lanolin is far from straightforward. In 1996, Wolf¹⁷ first described the “lanolin paradox,” modeled after the earlier “paraben paradox” described by Fisher.¹⁸ There are 4 clinical phenomena of the lanolin paradox¹⁷:

• Lanolin generally does not cause contact allergy when found in PCPs but may cause ACD when found in topical medicaments.
• Some patients can use lanolin-containing PCPs on healthy skin without issue but will develop ACD when a lanolin-containing topical medicament is applied to inflamed skin. This is because inflamed skin is more easily sensitized.
• False-negative patch test reactions to pure lanolin may occur. Since Wolf’s¹⁷ initial description of the paradox, free alcohols of lanolin have been found to be its principal allergen, though it also is possible that oxidation of lanolin could generate additional allergenic substances.¹
• Patch testing with wool alcohol 30% can generate both false-negative and false-positive results.

At one extreme, Kligman¹⁹ also was concerned about false-positive reactions to lanolin, describing lanolin allergy as a myth attributed to overzealous patch testing and a failure to appreciate the limitations of this diagnostic modality. Indeed, just having a PPT to lanolin (ie, contact allergy) does not automatically translate to a relevant ACD,¹ and determining the clinical relevance of a PPT is of utmost importance. In 2001, Wakelin et al²⁰ reported that the majority (71% [92/130]) of positive reactions to Amerchol L101 50% or 100% pet showed current clinical relevance. Data from the North American Contact Dermatitis Group in 2009 and in 2022 were similar, with 83.4% (529/634) of positive reactions to lanolin alcohol 30% pet and 86.5% (1238/1431) of positive reactions to Amerchol L101 50% pet classified as current clinical relevance.^11,21 These findings demonstrate that although lanolin may be a weak sensitizer, a PPT usually represents a highly relevant cause of dermatitis.

Considerations for Patch Testing

Considering Wolf’s¹⁷ claim that even pure lanolin is not an appropriate formulation to use for patch testing due to the risk for inaccurate results, you might now be wondering which preparation should be used. Mortensen²² popularized another compound, Amerchol L101, in 1979. In this small study of 60 patients with a PPT to lanolin and/or its derivatives, the highest proportion (37% [22/60]) were positive to Amerchol L101 but negative to wool alcohol 30%, suggesting the need to test to more than one preparation simultaneously.²² In a larger study by Miest et al,²³ 3.9% (11/268) of patients had a PPT to Amerchol L101 50% pet, whereas only 1.1% (3/268) had a PPT to lanolin alcohol 30% pet. This highlighted the importance of including Amerchol L101 when patch testing because it was thought to capture more positive results; however, some studies suggest that Amerchol L101 is not superior at predicting lanolin contact allergy vs lanolin alcohol 30% pet. The risk for an irritant reaction when patch testing with Amerchol L101 should be considered due to its mineral oil component.²⁴

Although there is no universal consensus to date, some investigators suggest patch testing both lanolin alcohol 30% pet and Amerchol L101 50% pet simultaneously.¹ The TRUE test utilizes 1000 µg/cm² of wool alcohols, while the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core 90 Series contain Amerchol L101 50% pet. Patch testing to the most allergenic component of lanolin—the free fatty alcohols (particularly alkane-α,β-diols and alkane-α,ω-diols)—has been suggested,¹ though these formulations are not yet commercially available.

When available, the patient’s own lanolin-containing PCPs should be tested.¹ Performing a repeat open application test (ROAT) to a lanolin-containing product also may be highly useful to distinguish weak-positive from irritant patch test reactions and to determine if sensitized patients can tolerate lanolin-containing products on intact skin. To complete a ROAT, a patient should apply the suspected leave-on product to a patch of unaffected skin (classically the volar forearm) twice daily for at least 10 days.²⁵ If the application site is clear after 10 days, the patient is unlikely to have ACD to the product in question. Compared to patch testing, ROAT more accurately mimics a true use situation, which is particularly important for lanolin given its tendency to preferentially impact damaged or inflamed skin while sparing healthy skin.

Alternatives to Lanolin

Patients with confirmed ACD to lanolin may use plain petrolatum, a safe and inexpensive substitute with equivalent moisturizing efficacy. It can reduce transepidermal water loss by more than 98%,⁴ with essentially no risk for ACD. Humectants such as glycerin, sorbitol, and α-hydroxy acids also have moisturizing properties akin to those of lanolin. In addition, some oils may provide benefit to patients with chronic skin conditions. Sunflower seed oil and extra virgin coconut oil have anti-inflammatory, antibacterial, and barrier repair properties.^26,27 Allergic contact dermatitis to these oils rarely, if ever, occurs.²⁸

Final Interpretation

Lanolin is a well-known yet controversial contact allergen that is widely used in PCPs, cosmetics, topical medicaments, and industrial goods. Lanolin ACD preferentially impacts patients with stasis dermatitis, chronic leg ulcers, AD, and perianal/genital dermatitis. Patch testing with more than one lanolin formulation, including lanolin alcohol 30% pet and/or Amerchol L101 50% pet, as well as testing the patient’s own products may be necessary to confirm the diagnosis. In cases of ACD to lanolin, an alternative agent, such as plain petrolatum, may be used.

Lanolin was announced as the Allergen of the Year by the American Contact Dermatitis Society in March 2023.¹ However, allergic contact dermatitis (ACD) to lanolin remains a matter of fierce debate among dermatologists. Herein, we discuss this important contact allergen, emphasizing the controversy behind its allergenicity and nuances to consider when patch testing.

What is Lanolin?

Lanolin is a greasy, yellow, fatlike substance derived from the sebaceous glands of sheep. It is extracted from wool using an intricate process of scouring with dilute alkali, centrifuging, and refining with hot alkali and bleach.² It is comprised of a complex mixture of esters, alcohols, sterols, fatty acids, lactose, and hydrocarbons.³

The hydrophobic property of lanolin helps sheep shed water from their coats.³ In humans, this hydrophobicity benefits the skin by retaining moisture already present in the epidermis. Lanolin can hold as much as twice its weight in water and may reduce transepidermal water loss by 20% to 30%.^4-6 In addition, lanolin maintains tissue breathability, which supports proper gas exchange, promoting wound healing and protecting against infection.^3,7

Many personal care products (PCPs), cosmetics, and topical medicaments contain lanolin, particularly products marketed to help restore dry cracked skin. The range of permitted concentrations of lanolin in over-the-counter products in the United States is 12.5% to 50%.³ Lanolin also may be found in industrial goods. The Table provides a comprehensive list of common items that may contain lanolin.^1,3,8,9

A Wolf in Sheep’s Clothing?

Despite its benefits, lanolin is a potential source of ACD. The first reported positive patch test (PPT) to lanolin worldwide was in the late 1920s.¹⁰ Subsequent cases of ACD to lanolin were described over the next 30 years, reaching a peak of recognition in the latter half of the 20th century with rates of PPT ranging from 0% to 7.4%, though the patient population and lanolin patch-test formulation used differed across studies.⁹ The North American Contact Dermatitis Group observed that 3.3% (1431/43,691) of patients tested from 2001 to 2018 had a PPT to either lanolin alcohol 30% in petrolatum (pet) or Amerchol L101 (10% lanolin alcohol dissolved in mineral oil) 50% pet.¹¹ Compared to patients referred for patch testing, the prevalence of contact allergy to lanolin is lower in the general population; 0.4% of the general population in Europe (N=3119) tested positive to wool alcohols 1.0 mg/cm² on the thin-layer rapid use Epicutaneous (TRUE) test.¹²

Allergic contact dermatitis to lanolin is unrelated to an allergy to wool itself, which probably does not exist, though wool is well known to cause irritant contact dermatitis, particularly in atopic individuals.¹³

Who Is at Risk for Lanolin Allergy?

In a recent comprehensive review of lanolin allergy, Jenkins and Belsito¹ summarized 4 high-risk subgroups of patients for the development of lanolin contact allergy: stasis dermatitis, chronic leg ulcers, atopic dermatitis (AD), and perianal/genital dermatitis. These chronic inflammatory skin conditions may increase the risk for ACD to lanolin via increased exposure in topical therapies and/or increased allergen penetration through an impaired epidermal barrier.^14-16 Demographically, older adults and children are at-risk groups, likely secondary to the higher prevalence of stasis dermatitis/leg ulcers in the former group and AD in the latter.¹

 

 

Lanolin Controversies

The allergenicity of lanolin is far from straightforward. In 1996, Wolf¹⁷ first described the “lanolin paradox,” modeled after the earlier “paraben paradox” described by Fisher.¹⁸ There are 4 clinical phenomena of the lanolin paradox¹⁷:

• Lanolin generally does not cause contact allergy when found in PCPs but may cause ACD when found in topical medicaments.
• Some patients can use lanolin-containing PCPs on healthy skin without issue but will develop ACD when a lanolin-containing topical medicament is applied to inflamed skin. This is because inflamed skin is more easily sensitized.
• False-negative patch test reactions to pure lanolin may occur. Since Wolf’s¹⁷ initial description of the paradox, free alcohols of lanolin have been found to be its principal allergen, though it also is possible that oxidation of lanolin could generate additional allergenic substances.¹
• Patch testing with wool alcohol 30% can generate both false-negative and false-positive results.

At one extreme, Kligman¹⁹ also was concerned about false-positive reactions to lanolin, describing lanolin allergy as a myth attributed to overzealous patch testing and a failure to appreciate the limitations of this diagnostic modality. Indeed, just having a PPT to lanolin (ie, contact allergy) does not automatically translate to a relevant ACD,¹ and determining the clinical relevance of a PPT is of utmost importance. In 2001, Wakelin et al²⁰ reported that the majority (71% [92/130]) of positive reactions to Amerchol L101 50% or 100% pet showed current clinical relevance. Data from the North American Contact Dermatitis Group in 2009 and in 2022 were similar, with 83.4% (529/634) of positive reactions to lanolin alcohol 30% pet and 86.5% (1238/1431) of positive reactions to Amerchol L101 50% pet classified as current clinical relevance.^11,21 These findings demonstrate that although lanolin may be a weak sensitizer, a PPT usually represents a highly relevant cause of dermatitis.

Considerations for Patch Testing

Considering Wolf’s¹⁷ claim that even pure lanolin is not an appropriate formulation to use for patch testing due to the risk for inaccurate results, you might now be wondering which preparation should be used. Mortensen²² popularized another compound, Amerchol L101, in 1979. In this small study of 60 patients with a PPT to lanolin and/or its derivatives, the highest proportion (37% [22/60]) were positive to Amerchol L101 but negative to wool alcohol 30%, suggesting the need to test to more than one preparation simultaneously.²² In a larger study by Miest et al,²³ 3.9% (11/268) of patients had a PPT to Amerchol L101 50% pet, whereas only 1.1% (3/268) had a PPT to lanolin alcohol 30% pet. This highlighted the importance of including Amerchol L101 when patch testing because it was thought to capture more positive results; however, some studies suggest that Amerchol L101 is not superior at predicting lanolin contact allergy vs lanolin alcohol 30% pet. The risk for an irritant reaction when patch testing with Amerchol L101 should be considered due to its mineral oil component.²⁴

Although there is no universal consensus to date, some investigators suggest patch testing both lanolin alcohol 30% pet and Amerchol L101 50% pet simultaneously.¹ The TRUE test utilizes 1000 µg/cm² of wool alcohols, while the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core 90 Series contain Amerchol L101 50% pet. Patch testing to the most allergenic component of lanolin—the free fatty alcohols (particularly alkane-α,β-diols and alkane-α,ω-diols)—has been suggested,¹ though these formulations are not yet commercially available.

When available, the patient’s own lanolin-containing PCPs should be tested.¹ Performing a repeat open application test (ROAT) to a lanolin-containing product also may be highly useful to distinguish weak-positive from irritant patch test reactions and to determine if sensitized patients can tolerate lanolin-containing products on intact skin. To complete a ROAT, a patient should apply the suspected leave-on product to a patch of unaffected skin (classically the volar forearm) twice daily for at least 10 days.²⁵ If the application site is clear after 10 days, the patient is unlikely to have ACD to the product in question. Compared to patch testing, ROAT more accurately mimics a true use situation, which is particularly important for lanolin given its tendency to preferentially impact damaged or inflamed skin while sparing healthy skin.

Alternatives to Lanolin

Patients with confirmed ACD to lanolin may use plain petrolatum, a safe and inexpensive substitute with equivalent moisturizing efficacy. It can reduce transepidermal water loss by more than 98%,⁴ with essentially no risk for ACD. Humectants such as glycerin, sorbitol, and α-hydroxy acids also have moisturizing properties akin to those of lanolin. In addition, some oils may provide benefit to patients with chronic skin conditions. Sunflower seed oil and extra virgin coconut oil have anti-inflammatory, antibacterial, and barrier repair properties.^26,27 Allergic contact dermatitis to these oils rarely, if ever, occurs.²⁸

Final Interpretation

Lanolin is a well-known yet controversial contact allergen that is widely used in PCPs, cosmetics, topical medicaments, and industrial goods. Lanolin ACD preferentially impacts patients with stasis dermatitis, chronic leg ulcers, AD, and perianal/genital dermatitis. Patch testing with more than one lanolin formulation, including lanolin alcohol 30% pet and/or Amerchol L101 50% pet, as well as testing the patient’s own products may be necessary to confirm the diagnosis. In cases of ACD to lanolin, an alternative agent, such as plain petrolatum, may be used.

The Diagnosis: Localized Cutaneous Argyria

The differential diagnosis of an enlarging pigmented lesion is broad, including various neoplasms, pigmented deep fungal infections, and cutaneous deposits secondary to systemic or topical medications or other exogenous substances. In our patient, identification of black particulate material on biopsy prompted further questioning. After the sinus tract persisted for 6 months, our patient’s infectious disease physician started applying silver nitrate at 3-week intervals to minimize drainage, exudate, and granulation tissue formation. After 3 months, marked pigmentation of the skin around the sinus tract was noted.

Argyria is a rare skin disorder that results from deposition of silver via localized exposure or systemic ingestion. Discoloration can either be reversible or irreversible, usually dependent on the length of silver exposure.¹ Affected individuals exhibit blue-gray pigmentation of the skin that may be localized or diffuse. Photoactivated reduction of silver salts leads to conversion to elemental silver in the skin.² Although argyria is most common on sun-exposed areas, the mucosae and nails may be involved in systemic cases. The etiology of argyria includes occupational exposure by ingestion of dust or traumatic cutaneous exposure in jewelry manufacturing, mining, or photographic or radiograph manufacturing. Other sources of localized argyria include prolonged contact with topical silver nitrate or silver sulfadiazine for wound care, silver-coated jewelry or piercings, acupuncture, tooth restoration procedures using dental amalgam, silver-containing surgical implants, or other silver-containing medications or wound dressings. Discontinuing contact with the source of silver minimizes further pigmentation, and excision of deposits may be helpful in some instances.³

Histopathologic findings in argyria may be subtle and diverse. Small particulate material may be apparent on careful examination at high magnification only, and the depth of deposition can depend on the etiology of absorption or implantation as well as the length of exposure. Short-term exposure may be associated with deposition of dark, brown-black, coarse granules confined to the stratum corneum.¹ Frequently, cases of argyria reveal small, extracellular, brown-black, pigmented granules in a bandlike distribution primarily around vasculature, eccrine glands, perineural tissue, hair follicles, or arrector pili muscles or free in the dermis around collagen bundles. The granules can be highlighted by dark-field microscopy that will display scattered, refractile, white particles, described as a “stars in heaven” pattern.³ Rare ochre-colored collagen bundles have been reported in some cases, described as a pseudo-ochronosis pattern of argyria.⁴

Given the clinical history in our patient, a melanocytic lesion was considered but was excluded based on the histopathologic findings. Regressed melanoma clinically may resemble cutaneous silver deposition, as tumoral melanosis can be associated with an intense blue-black presentation. Histopathology will reveal an absence of melanocytes with residual coarse melanin in melanophages (Figure 1) rather than the particulate material associated with silver deposition. Although argyria can be associated with increased melanin in the basal epidermal keratinocytes and melanophages in the papillary dermis, silver granules can be distinguished by their uniform appearance and location throughout the skin (dermis, around vasculature/adnexal structures vs melanin in melanophages and basal epidermal keratinocytes).^3,5,6

Blue nevi typically present as well-circumscribed, blue to gray or even dark brown lesions most often located on the arms, legs, head, and neck. Histopathology reveals spindle-shaped dendritic melanocytes dissecting through collagen bundles in the dermis with melanophages (Figure 2). Pigmentation may vary from extensive to little or even none. Blue nevi are demarcated and may be associated with dermal sclerosis.⁷

Drug-induced hyperpigmentation has a variable presentation both clinically and histologically depending on the type of drug implicated. Tetracyclines, particularly minocycline, are known culprits of drug-induced pigmentation, which can present as blue-gray to brown discoloration in at least 3 classically described patterns: (1) blue-black pigmentation around scars or prior inflammatory sites, (2) blue-black pigmentation on the shins or upper extremities, or (3) brown pigmentation in photosensitive areas. Histopathology reveals brown-black granules intracellularly in macrophages or fibroblasts or localized around vessels or eccrine glands (Figure 3). Special stains such as Perls Prussian blue or Fontana-Masson may highlight the pigmented granules. Widespread pigmentation in other organs, such as the thyroid, and history of long-standing tetracycline use are helpful clues to distinguish drug-induced pigmentation from other entities.⁸

Tattoo ink reaction frequently presents as an irregular pigmented lesion that can have associated features of inflammation including rash, erythema, and swelling. Histopathology reveals small clumped pigment in the dermis localized either extracellularly preferentially around vascular structures and collagen fibers or intracellularly in macrophages or fibroblasts (Figure 4). Considering the pigment is foreign material, a mixed inflammatory infiltrate can be present or more rarely the presence of pigment may induce pseudoepitheliomatous hyperplasia. The inflammatory reaction pattern on histology can vary, but granulomatous and lichenoid patterns frequently have been described. Other helpful clues to suggest tattoo pigment include refractile granules under polarized light and multiple pigmented colors.³

Dermal melanocytosis also may be considered, which consists of blue-gray irregular macules to patches on the skin that are frequently present at birth but may develop later in life. Histopathology reveals pigmented dendritic to spindle-shaped dermal melanocytes and melanophages dissecting between collagen fibers localized to the deep dermis. In addition, some hematologic or vascular disorders, including resolving hemorrhage or cyanosis, may be considered in the clinical differential. Deposition disorders such as chrysiasis and ochronosis could exhibit clinical or histopathologic similarities.^3,8

Occasionally, prolonged use of topical silver nitrate may result in a pigmented lesion that mimics a melanocytic neoplasm or other pigmented lesions. However, these conditions can be readily differentiated by their characteristic histopathologic findings along with detailed clinical history.

The Diagnosis: Localized Cutaneous Argyria

The differential diagnosis of an enlarging pigmented lesion is broad, including various neoplasms, pigmented deep fungal infections, and cutaneous deposits secondary to systemic or topical medications or other exogenous substances. In our patient, identification of black particulate material on biopsy prompted further questioning. After the sinus tract persisted for 6 months, our patient’s infectious disease physician started applying silver nitrate at 3-week intervals to minimize drainage, exudate, and granulation tissue formation. After 3 months, marked pigmentation of the skin around the sinus tract was noted.

Argyria is a rare skin disorder that results from deposition of silver via localized exposure or systemic ingestion. Discoloration can either be reversible or irreversible, usually dependent on the length of silver exposure.¹ Affected individuals exhibit blue-gray pigmentation of the skin that may be localized or diffuse. Photoactivated reduction of silver salts leads to conversion to elemental silver in the skin.² Although argyria is most common on sun-exposed areas, the mucosae and nails may be involved in systemic cases. The etiology of argyria includes occupational exposure by ingestion of dust or traumatic cutaneous exposure in jewelry manufacturing, mining, or photographic or radiograph manufacturing. Other sources of localized argyria include prolonged contact with topical silver nitrate or silver sulfadiazine for wound care, silver-coated jewelry or piercings, acupuncture, tooth restoration procedures using dental amalgam, silver-containing surgical implants, or other silver-containing medications or wound dressings. Discontinuing contact with the source of silver minimizes further pigmentation, and excision of deposits may be helpful in some instances.³

Histopathologic findings in argyria may be subtle and diverse. Small particulate material may be apparent on careful examination at high magnification only, and the depth of deposition can depend on the etiology of absorption or implantation as well as the length of exposure. Short-term exposure may be associated with deposition of dark, brown-black, coarse granules confined to the stratum corneum.¹ Frequently, cases of argyria reveal small, extracellular, brown-black, pigmented granules in a bandlike distribution primarily around vasculature, eccrine glands, perineural tissue, hair follicles, or arrector pili muscles or free in the dermis around collagen bundles. The granules can be highlighted by dark-field microscopy that will display scattered, refractile, white particles, described as a “stars in heaven” pattern.³ Rare ochre-colored collagen bundles have been reported in some cases, described as a pseudo-ochronosis pattern of argyria.⁴

Given the clinical history in our patient, a melanocytic lesion was considered but was excluded based on the histopathologic findings. Regressed melanoma clinically may resemble cutaneous silver deposition, as tumoral melanosis can be associated with an intense blue-black presentation. Histopathology will reveal an absence of melanocytes with residual coarse melanin in melanophages (Figure 1) rather than the particulate material associated with silver deposition. Although argyria can be associated with increased melanin in the basal epidermal keratinocytes and melanophages in the papillary dermis, silver granules can be distinguished by their uniform appearance and location throughout the skin (dermis, around vasculature/adnexal structures vs melanin in melanophages and basal epidermal keratinocytes).^3,5,6

Blue nevi typically present as well-circumscribed, blue to gray or even dark brown lesions most often located on the arms, legs, head, and neck. Histopathology reveals spindle-shaped dendritic melanocytes dissecting through collagen bundles in the dermis with melanophages (Figure 2). Pigmentation may vary from extensive to little or even none. Blue nevi are demarcated and may be associated with dermal sclerosis.⁷

Drug-induced hyperpigmentation has a variable presentation both clinically and histologically depending on the type of drug implicated. Tetracyclines, particularly minocycline, are known culprits of drug-induced pigmentation, which can present as blue-gray to brown discoloration in at least 3 classically described patterns: (1) blue-black pigmentation around scars or prior inflammatory sites, (2) blue-black pigmentation on the shins or upper extremities, or (3) brown pigmentation in photosensitive areas. Histopathology reveals brown-black granules intracellularly in macrophages or fibroblasts or localized around vessels or eccrine glands (Figure 3). Special stains such as Perls Prussian blue or Fontana-Masson may highlight the pigmented granules. Widespread pigmentation in other organs, such as the thyroid, and history of long-standing tetracycline use are helpful clues to distinguish drug-induced pigmentation from other entities.⁸

Tattoo ink reaction frequently presents as an irregular pigmented lesion that can have associated features of inflammation including rash, erythema, and swelling. Histopathology reveals small clumped pigment in the dermis localized either extracellularly preferentially around vascular structures and collagen fibers or intracellularly in macrophages or fibroblasts (Figure 4). Considering the pigment is foreign material, a mixed inflammatory infiltrate can be present or more rarely the presence of pigment may induce pseudoepitheliomatous hyperplasia. The inflammatory reaction pattern on histology can vary, but granulomatous and lichenoid patterns frequently have been described. Other helpful clues to suggest tattoo pigment include refractile granules under polarized light and multiple pigmented colors.³

Dermal melanocytosis also may be considered, which consists of blue-gray irregular macules to patches on the skin that are frequently present at birth but may develop later in life. Histopathology reveals pigmented dendritic to spindle-shaped dermal melanocytes and melanophages dissecting between collagen fibers localized to the deep dermis. In addition, some hematologic or vascular disorders, including resolving hemorrhage or cyanosis, may be considered in the clinical differential. Deposition disorders such as chrysiasis and ochronosis could exhibit clinical or histopathologic similarities.^3,8

Occasionally, prolonged use of topical silver nitrate may result in a pigmented lesion that mimics a melanocytic neoplasm or other pigmented lesions. However, these conditions can be readily differentiated by their characteristic histopathologic findings along with detailed clinical history.

The Diagnosis: Localized Cutaneous Argyria

The differential diagnosis of an enlarging pigmented lesion is broad, including various neoplasms, pigmented deep fungal infections, and cutaneous deposits secondary to systemic or topical medications or other exogenous substances. In our patient, identification of black particulate material on biopsy prompted further questioning. After the sinus tract persisted for 6 months, our patient’s infectious disease physician started applying silver nitrate at 3-week intervals to minimize drainage, exudate, and granulation tissue formation. After 3 months, marked pigmentation of the skin around the sinus tract was noted.

Argyria is a rare skin disorder that results from deposition of silver via localized exposure or systemic ingestion. Discoloration can either be reversible or irreversible, usually dependent on the length of silver exposure.¹ Affected individuals exhibit blue-gray pigmentation of the skin that may be localized or diffuse. Photoactivated reduction of silver salts leads to conversion to elemental silver in the skin.² Although argyria is most common on sun-exposed areas, the mucosae and nails may be involved in systemic cases. The etiology of argyria includes occupational exposure by ingestion of dust or traumatic cutaneous exposure in jewelry manufacturing, mining, or photographic or radiograph manufacturing. Other sources of localized argyria include prolonged contact with topical silver nitrate or silver sulfadiazine for wound care, silver-coated jewelry or piercings, acupuncture, tooth restoration procedures using dental amalgam, silver-containing surgical implants, or other silver-containing medications or wound dressings. Discontinuing contact with the source of silver minimizes further pigmentation, and excision of deposits may be helpful in some instances.³

Histopathologic findings in argyria may be subtle and diverse. Small particulate material may be apparent on careful examination at high magnification only, and the depth of deposition can depend on the etiology of absorption or implantation as well as the length of exposure. Short-term exposure may be associated with deposition of dark, brown-black, coarse granules confined to the stratum corneum.¹ Frequently, cases of argyria reveal small, extracellular, brown-black, pigmented granules in a bandlike distribution primarily around vasculature, eccrine glands, perineural tissue, hair follicles, or arrector pili muscles or free in the dermis around collagen bundles. The granules can be highlighted by dark-field microscopy that will display scattered, refractile, white particles, described as a “stars in heaven” pattern.³ Rare ochre-colored collagen bundles have been reported in some cases, described as a pseudo-ochronosis pattern of argyria.⁴

Given the clinical history in our patient, a melanocytic lesion was considered but was excluded based on the histopathologic findings. Regressed melanoma clinically may resemble cutaneous silver deposition, as tumoral melanosis can be associated with an intense blue-black presentation. Histopathology will reveal an absence of melanocytes with residual coarse melanin in melanophages (Figure 1) rather than the particulate material associated with silver deposition. Although argyria can be associated with increased melanin in the basal epidermal keratinocytes and melanophages in the papillary dermis, silver granules can be distinguished by their uniform appearance and location throughout the skin (dermis, around vasculature/adnexal structures vs melanin in melanophages and basal epidermal keratinocytes).^3,5,6

Blue nevi typically present as well-circumscribed, blue to gray or even dark brown lesions most often located on the arms, legs, head, and neck. Histopathology reveals spindle-shaped dendritic melanocytes dissecting through collagen bundles in the dermis with melanophages (Figure 2). Pigmentation may vary from extensive to little or even none. Blue nevi are demarcated and may be associated with dermal sclerosis.⁷

Drug-induced hyperpigmentation has a variable presentation both clinically and histologically depending on the type of drug implicated. Tetracyclines, particularly minocycline, are known culprits of drug-induced pigmentation, which can present as blue-gray to brown discoloration in at least 3 classically described patterns: (1) blue-black pigmentation around scars or prior inflammatory sites, (2) blue-black pigmentation on the shins or upper extremities, or (3) brown pigmentation in photosensitive areas. Histopathology reveals brown-black granules intracellularly in macrophages or fibroblasts or localized around vessels or eccrine glands (Figure 3). Special stains such as Perls Prussian blue or Fontana-Masson may highlight the pigmented granules. Widespread pigmentation in other organs, such as the thyroid, and history of long-standing tetracycline use are helpful clues to distinguish drug-induced pigmentation from other entities.⁸

Tattoo ink reaction frequently presents as an irregular pigmented lesion that can have associated features of inflammation including rash, erythema, and swelling. Histopathology reveals small clumped pigment in the dermis localized either extracellularly preferentially around vascular structures and collagen fibers or intracellularly in macrophages or fibroblasts (Figure 4). Considering the pigment is foreign material, a mixed inflammatory infiltrate can be present or more rarely the presence of pigment may induce pseudoepitheliomatous hyperplasia. The inflammatory reaction pattern on histology can vary, but granulomatous and lichenoid patterns frequently have been described. Other helpful clues to suggest tattoo pigment include refractile granules under polarized light and multiple pigmented colors.³

Dermal melanocytosis also may be considered, which consists of blue-gray irregular macules to patches on the skin that are frequently present at birth but may develop later in life. Histopathology reveals pigmented dendritic to spindle-shaped dermal melanocytes and melanophages dissecting between collagen fibers localized to the deep dermis. In addition, some hematologic or vascular disorders, including resolving hemorrhage or cyanosis, may be considered in the clinical differential. Deposition disorders such as chrysiasis and ochronosis could exhibit clinical or histopathologic similarities.^3,8

Occasionally, prolonged use of topical silver nitrate may result in a pigmented lesion that mimics a melanocytic neoplasm or other pigmented lesions. However, these conditions can be readily differentiated by their characteristic histopathologic findings along with detailed clinical history.

Ferritin is an iron storage protein crucial to human iron homeostasis. Because serum ferritin levels are in dynamic equilibrium with the body’s iron stores, ferritin often is measured as a reflection of iron status; however, ferritin also is an acute-phase reactant whose levels may be nonspecifically elevated in a wide range of inflammatory conditions. The various processes that alter serum ferritin levels complicate the clinical interpretation of this laboratory value. In this article, we review the structure and function of ferritin and provide a guide for clinical use.

Overview of Iron

Iron is an essential element of key biologic functions including DNA synthesis and repair, oxygen transport, and oxidative phosphorylation. The body’s iron stores are mainly derived from internal iron recycling following red blood cell breakdown, while 5% to 10% is supplied by dietary intake.^1-3 Iron metabolism is of particular importance in cells of the reticuloendothelial system (eg, spleen, liver, bone marrow), where excess iron must be appropriately sequestered and from which iron can be mobilized.⁴ Sufficient iron stores are necessary for proper cellular function and survival, as iron is a necessary component of hemoglobin for oxygen delivery, iron-sulfur clusters in electron transport, and enzyme cofactors in other cellular processes.

Although labile pools of biologically active free iron exist in limited amounts within cells, excess free iron can generate free radicals that damage cellular proteins, lipids, and nucleic acids.^5-7 As such, most intracellular iron is captured within ferritin molecules. The excretion of iron is unregulated and occurs through loss in sweat, menstruation, hair shedding, skin desquamation, and enterocyte turnover.⁸ The lack of regulated excretion highlights the need for a tightly regulated system of uptake, transportation, storage, and sequestration to maintain iron homeostasis.

Overview of Ferritin Structure and Function

Ferritin is a key regulator of iron homeostasis that also serves as an important clinical indicator of body iron status. Ferritin mainly is found as an intracellular cytosolic iron storage and detoxification protein structured as a hollow 24-subunit polymer shell that can sequester up to 4500 atoms of iron within its core.^9,10 The 24-mer is composed of both ferritin L (FTL) and ferritin H (FTH) subunits, with dynamic regulation of the H:L ratio dependent on the context and tissue in which ferritin is found.⁶

Ferritin H possesses ferroxidase, which facilitates oxidation of ferrous (Fe²⁺) iron into ferric (Fe³⁺) iron, which can then be incorporated into the mineral core of the ferritin heteropolymer.¹¹ Ferritin L is more abundant in the spleen and liver, while FTH is found predominantly in the heart and kidneys where the increased ferroxidase activity may confer an increased ability to oxidize Fe²⁺ and limit oxidative stress.⁶

Regulation of Ferritin Synthesis and Secretion

Ferritin synthesis is regulated by intracellular nonheme iron levels, governed mainly by an iron response element (IRE) and iron response protein (IRP) translational repression system. Both FTH and FTL messenger RNA (mRNA) contain an IRE that is a regulatory stem-loop structure in the 5´ untranslated region. When the IRE is bound by IRP1 or IRP2, mRNA translation of ferritin subunits is suppressed.⁶ In low iron conditions, IRPs have greater affinity for IRE, and binding suppresses ferritin translation.¹² In high iron conditions, IRPs have a decreased affinity for IRE, and ferritin mRNA synthesis is increased.¹³ Additionally, inflammatory cytokines such as tumor necrosis factor α and IL-1α transcriptionally induce FTH synthesis, resulting in an increased population of H-rich ferritins.^11,14-16 A study using cultured human primary skin fibroblasts demonstrated UV radiation–induced increases in free intracellular iron content.^17,18 Pourzand et al¹⁸ suggested that UV-mediated damage of lysosomal membranes results in leakage of lysosomal proteases into the cytosol, contributing to degradation of intracellular ferritin and subsequent release of iron within skin fibroblasts. The increased intracellular iron downregulates IRPs and increases ferritin mRNA synthesis,¹⁸ consistent with prior findings of increased ferritin synthesis in skin that is induced by UV radiation.¹⁹

Molecular analysis of serum ferritin in iron-overloaded mice revealed that extracellular ferritin found in the serum is composed of a greater fraction of FTL and has lower iron content than intracellular ferritin. The low iron content of serum ferritin compared with intracellular ferritin and transferrin suggests that serum ferritin is not a major pathway of systemic iron transport.¹⁰ However, locally secreted ferritins may play a greater role in iron transport and release in selected tissues. Additionally, in vitro studies of cell cultures from humans and mice have demonstrated the ability of macrophages to secrete ferritin, suggesting that macrophages are an important cellular source of serum ferritin.^10,20 As such, serum ferritin generally may reflect body iron status but more specifically reflects macrophage iron status.¹⁰ Although the exact pathways of ferritin release are unknown, it is hypothesized that ferritin secretion occurs through cytosolic autophagy followed by secretion of proteins from the lysosomal compartment.^10,18,21

 

 

Clinical Utility of Serum Ferritin

Low Ferritin and Iron Deficiency—Although bone marrow biopsy with iron staining remains the gold standard for diagnosis of iron deficiency, serum ferritin is a much more accessible and less invasive tool for evaluation of iron status. A serum ferritin level below 12 μg/L is highly specific for iron depletion,²² with a higher cutoff recommended in clinical practice to improve diagnostic sensitivity.^23,24 Conditions independent of iron deficiency that may reduce serum ferritin include hypothyroidism and ascorbate deficiency, though neither condition has been reported to interfere with appropriate diagnosis of iron deficiency.²⁵ Guyatt et al²⁶ conducted a systematic review of laboratory tests used in the diagnosis of iron deficiency anemia and identified 55 studies suitable for inclusion. Based on an area under the receiver operating characteristic curve (AUROC) of 0.95, serum ferritin values were superior to transferrin saturation (AUROC, 0.74), red cell protoporphyrin (AUROC, 0.77), red cell volume distribution width (AUROC, 0.62), and mean cell volume (AUROC, 0.76) for diagnosis of IDA, verified by histologic examination of aspirated bone marrow.²⁶ The likelihood ratio of iron deficiency begins to decrease for serum ferritin values of 40 μg/L or greater. For patients with inflammatory conditions—patients with concomitant chronic renal failure, inflammatory disease, infection, rheumatoid arthritis, liver disease, inflammatory bowel disease, and malignancy—the likelihood of iron deficiency begins to decrease at serum ferritin levels of 70 μg/L or greater.²⁶ Similarly, the World Health Organization recommends that in adults with infection or inflammation, serum ferritin levels lower than 70 μg/L may be used to indicate iron deficiency.²⁴ A serum ferritin level of 41 μg/L or lower was found to have a sensitivity and specificity of 98% for discriminating between iron-deficiency anemia and anemia of chronic disease (diagnosed based on bone marrow biopsy with iron staining), with an AUROC of 0.98.²⁷ As such, we recommend using a serum ferritin level of 40 μg/L or lower in patients who are otherwise healthy as an indicator of iron deficiency.

The threshold for iron supplementation may vary based on age, sex, and race. In women, ferritin levels increase during menopause and peak after menopause; ferritin levels are higher in men than in women.^28-30 A multisite longitudinal cohort study of 70 women in the United States found that the mean (SD) ferritin valuewas 69.5 (81.7) μg/L premenopause and 128.8 (125.7) μg/L postmenopause (P<.01).³¹ A separate longitudinal survey study of 8564 patients in China found that the mean (SE) ferritin value was 201.55 (3.60) μg/L for men and 80.46 (1.64) μg/L for women (P<.0001).³² Analysis of serum ferritin levels of 3554 male patients from the third National Health and Nutrition Examination Survey demonstrated that patients who self-reported as non-Hispanic Black (n=1616) had significantly higher serum ferritin levels than non-Hispanic White patients (n=1938)(serum ferritin difference of 37.1 μg/L)(P<.0001).³³ The British Society for Haematology guidelines recommend that the threshold of serum ferritin for diagnosing iron deficiency should take into account age-, sex-, and race-based differences.³⁴ Ferritin and Hair—Cutaneous manifestations of iron deficiency include koilonychia, glossitis, pruritus, angular cheilitis, and telogen effluvium (TE).¹ A case-control study of 30 females aged 15 to 45 years demonstrated that the mean (SD) ferritin level was significantly lower in patients with TE than those with no hair loss (16.3 [12.6] ng/mL vs 60.3 [50.1] ng/mL; P<.0001). Using a threshold of 30 μg/L or lower, the investigators found that the odds ratio for TE was 21.0 (95% CI, 4.2-105.0) in patients with low serum ferritin.³⁵

Another retrospective review of 54 patients with diffuse hair loss and 55 controls compared serum vitamin B₁₂, folate, thyroid-stimulating hormone, zinc, ferritin, and 25-hydroxy vitamin D levels between the 2 groups.³⁶ Exclusion criteria were clinical diagnoses of female pattern hair loss (androgenetic alopecia), pregnancy, menopause, metabolic and endocrine disorders, hormone replacement therapy, chemotherapy, immunosuppressive therapy, vitamin and mineral supplementation, scarring alopecia, eating disorders, and restrictive diets. Compared with controls, patients with diffuse nonscarring hair loss were found to have significantly lower ferritin (mean [SD], 14.72 [10.70] ng/mL vs 25.30 [14.41] ng/mL; P<.001) and 25-hydroxy vitamin D levels (mean [SD], 14.03 [8.09] ng/mL vs 17.01 [8.59] ng/mL; P=.01).³⁶

In contrast, a separate case-control study of 381 cases and 76 controls found no increase in the rate of iron deficiency—defined as ferritin ≤15 μg/L or ≤40 μg/L—among women with female pattern hair loss or chronic TE vs controls.³⁷ Taken together, these studies suggest that iron status may play a role in TE, a process that may result from nutritional deficiency, trauma, or physical or psychological stress³⁸; however, there is insufficient evidence to suggest that low iron status impacts androgenetic alopecia, in which its multifactorial pathogenesis implicates genetic and hormonal factors.³⁹ More research is needed to clarify the potential associations between iron deficiency and types of hair loss. Additionally, it is unclear whether iron supplementation improves hair growth parameters such as density and caliber.⁴⁰

Low serum ferritin (<40 μg/L) with concurrent symptoms of iron deficiency, including fatigue, pallor, dyspnea on exertion, or hair loss, should prompt treatment with supplemental iron.^41-43 Generally, ferrous (Fe2⁺) salts are preferred to ferric (Fe3⁺) salts, as the former is more readily absorbed through the duodenal mucosa⁴⁴ and is the more common formulation in commercially available supplements in the United States.⁴⁵ Oral supplementation with ferrous sulfate 325 mg (65 mg elemental iron) tablets is the first-line therapy for iron deficiency anemia.¹ Alternatively, ferrous gluconate 324 mg (38 mg elemental iron) over-the-counter and its liquid form has demonstrated superior absorption compared to ferrous sulfate tablets in a clinical study with peritoneal dialysis patients.^1,46 One study suggested that oral iron 40 to 80 mg should be taken every other day to increase absorption.⁴⁷ Due to improved bioavailability, intravenous iron may be utilized in patients with malabsorption, renal failure, or intolerance to oral iron (including those with gastric ulcers or active inflammatory bowel disease), with the formulation chosen based on underlying comorbidities and potential risks.^1,48 The theoretical risk for potentiating bacterial growth by increasing the amount of unbound iron in the blood raises concerns of iron supplementation in patients with infection or sepsis. Although far from definitive, existing data suggest that risk for infection is greater with intravenous iron supplementation and should be carefully considered prior to use.^49,50Elevated Ferritin—Elevated ferritin may be difficult to interpret given the multitude of conditions that can cause it.^23,51,52 Elevated serum ferritin can be broadly characterized by increased synthesis due to iron overload, increased synthesis due to inflammation, or increased ferritin release from cellular damage.³⁴ Further complicating interpretation is the potential diurnal fluctuations in serum iron levels dependent on dietary intake and timing of laboratory evaluation, choice of assay, differences in reference standards, and variations in calibration procedures that can lead to analytic variability in the measurement of ferritin.^23,53,54

Among healthy patients, serum ferritin is directly proportional to iron status.^9,51 A study utilizing weekly phlebotomy of 22 healthy participants to measure serum ferritin and calculate mobilizable storage iron found a strong positive correlation between the 2 variables (r=0.83, P<.001), with each 1-μg/L increase of serum ferritin corresponding to approximately an 8-mg increase of storage iron; the initial serum ferritin values ranged from 2 to 83 μg/L in females and 36 to 224 μg/L in males.⁵⁵ The correlation of ferritin with iron status also was supported by the significant correlation between the number of transfusions received in patients with transfusion-related iron overload and serum ferritin levels (r=0.89, P<.001), with an average increase of 60 μg/L per transfusion.⁵¹

Clinical guidelines on the interpretation of serum ferritin levels by Cullis et al³⁴ recommend a normal upper limit of 200 μg/L for healthy females and 300 μg/L for healthy males. Outside of clinical syndromes associated with iron overload, Lee and Means⁵⁶ found that serum ferritin of 1000 μg/L or higher was a nonspecific marker of disease, including infection and/or neoplastic disorders. We have adapted these guidelines to propose a workflow for evaluation of serum ferritin levels (Figure). In patients with inflammatory conditions or those affected by metabolic syndrome, elevated serum ferritin does not correlate with body iron status.^57,58 It is believed that inflammatory cytokines, including tumor necrosis factor α and IL-1α, can upregulate ferritin synthesis independent of cellular iron stores.^15,16 Several studies have examined the relationship between insulin resistance and/or metabolic syndrome with serum ferritin levels.^31,32 Han et al³² found that elevated serum ferritin was significantly associated with higher risk for metabolic syndrome in men (P<.0001) but not in women.

Although cutaneous manifestations of iron overload can be seen as skin hyperpigmentation due to increased iron deposits and increased melanin production,²² the effects of elevated ferritin on the skin and hair are not well known. Iron overload is a known trigger of porphyria cutanea tarda (PCT),⁵⁹ a condition in which reduced or absent enzymatic activity of uroporphyrinogen decarboxylase (UROD) leads to build up of toxic porphyrins in various organs.⁶⁰ In the skin, PCT manifests as a blistering photosensitive eruption that may resolve as dyspigmentation, scarring, and milia.⁶¹ Phlebotomy is first-line therapy in PCT to reduce serum iron and subsequent formation of UROD inhibitors, with guidelines suggesting discontinuation of phlebotomy when serum ferritin levels reach 20 ng/mL or lower.⁶⁰ Hyperferritinemia (serum ferritin >500 μg/L) is a common finding in several inflammatory disorders often accompanied by clinically apparent cutaneous symptoms such as adult-onset Still disease,⁶² hemophagocytic lymphohistiocytosis,^63,64 and anti-melanoma differentiation-associated gene 5 dermatomyositis.⁶⁵ Among these conditions, serum ferritin levels have been reported to correlate with disease activity, raising the question of whether ferritin is a bystander or a driver of the underlying pathology.^62,66,67 However, rapid decline of serum ferritin levels with treatment and control of inflammatory cytokines suggest that ferritin is unlikely to contribute to pathology.^62,67

Final Thoughts

Many clinical studies have examined the association between hair health and body iron status, the collective findings of which suggest that iron deficiency may be associated with TE. Among commonly measured serum iron parameters, low ferritin is a highly specific and sensitive marker for diagnosing iron deficiency. Serum ferritin may be a clinically useful tool for ruling out underlying iron deficiency in patients presenting with hair loss. Despite advances in our understanding of the molecular mechanisms of ferritin synthesis and regulation, whether ferritin itself contributes to cutaneous pathology is poorly understood.^35,36,68-74 For patients who are otherwise healthy with low suspicion for inflammatory disorders, chronic systemic illnesses, or malignancy, serum ferritin can be used as an indicator of body iron status. The workup for slightly elevated serum ferritin should be interpreted in the context of other laboratory findings and should be reassessed over time. Serum ferritin levels above 1000 μg/L warrant further investigation into causes such as iron overload conditions and underlying inflammatory conditions or malignancy.

Ferritin is an iron storage protein crucial to human iron homeostasis. Because serum ferritin levels are in dynamic equilibrium with the body’s iron stores, ferritin often is measured as a reflection of iron status; however, ferritin also is an acute-phase reactant whose levels may be nonspecifically elevated in a wide range of inflammatory conditions. The various processes that alter serum ferritin levels complicate the clinical interpretation of this laboratory value. In this article, we review the structure and function of ferritin and provide a guide for clinical use.

Overview of Iron

Iron is an essential element of key biologic functions including DNA synthesis and repair, oxygen transport, and oxidative phosphorylation. The body’s iron stores are mainly derived from internal iron recycling following red blood cell breakdown, while 5% to 10% is supplied by dietary intake.^1-3 Iron metabolism is of particular importance in cells of the reticuloendothelial system (eg, spleen, liver, bone marrow), where excess iron must be appropriately sequestered and from which iron can be mobilized.⁴ Sufficient iron stores are necessary for proper cellular function and survival, as iron is a necessary component of hemoglobin for oxygen delivery, iron-sulfur clusters in electron transport, and enzyme cofactors in other cellular processes.

Although labile pools of biologically active free iron exist in limited amounts within cells, excess free iron can generate free radicals that damage cellular proteins, lipids, and nucleic acids.^5-7 As such, most intracellular iron is captured within ferritin molecules. The excretion of iron is unregulated and occurs through loss in sweat, menstruation, hair shedding, skin desquamation, and enterocyte turnover.⁸ The lack of regulated excretion highlights the need for a tightly regulated system of uptake, transportation, storage, and sequestration to maintain iron homeostasis.

Overview of Ferritin Structure and Function

Ferritin is a key regulator of iron homeostasis that also serves as an important clinical indicator of body iron status. Ferritin mainly is found as an intracellular cytosolic iron storage and detoxification protein structured as a hollow 24-subunit polymer shell that can sequester up to 4500 atoms of iron within its core.^9,10 The 24-mer is composed of both ferritin L (FTL) and ferritin H (FTH) subunits, with dynamic regulation of the H:L ratio dependent on the context and tissue in which ferritin is found.⁶

Ferritin H possesses ferroxidase, which facilitates oxidation of ferrous (Fe²⁺) iron into ferric (Fe³⁺) iron, which can then be incorporated into the mineral core of the ferritin heteropolymer.¹¹ Ferritin L is more abundant in the spleen and liver, while FTH is found predominantly in the heart and kidneys where the increased ferroxidase activity may confer an increased ability to oxidize Fe²⁺ and limit oxidative stress.⁶

Regulation of Ferritin Synthesis and Secretion

Ferritin synthesis is regulated by intracellular nonheme iron levels, governed mainly by an iron response element (IRE) and iron response protein (IRP) translational repression system. Both FTH and FTL messenger RNA (mRNA) contain an IRE that is a regulatory stem-loop structure in the 5´ untranslated region. When the IRE is bound by IRP1 or IRP2, mRNA translation of ferritin subunits is suppressed.⁶ In low iron conditions, IRPs have greater affinity for IRE, and binding suppresses ferritin translation.¹² In high iron conditions, IRPs have a decreased affinity for IRE, and ferritin mRNA synthesis is increased.¹³ Additionally, inflammatory cytokines such as tumor necrosis factor α and IL-1α transcriptionally induce FTH synthesis, resulting in an increased population of H-rich ferritins.^11,14-16 A study using cultured human primary skin fibroblasts demonstrated UV radiation–induced increases in free intracellular iron content.^17,18 Pourzand et al¹⁸ suggested that UV-mediated damage of lysosomal membranes results in leakage of lysosomal proteases into the cytosol, contributing to degradation of intracellular ferritin and subsequent release of iron within skin fibroblasts. The increased intracellular iron downregulates IRPs and increases ferritin mRNA synthesis,¹⁸ consistent with prior findings of increased ferritin synthesis in skin that is induced by UV radiation.¹⁹

Molecular analysis of serum ferritin in iron-overloaded mice revealed that extracellular ferritin found in the serum is composed of a greater fraction of FTL and has lower iron content than intracellular ferritin. The low iron content of serum ferritin compared with intracellular ferritin and transferrin suggests that serum ferritin is not a major pathway of systemic iron transport.¹⁰ However, locally secreted ferritins may play a greater role in iron transport and release in selected tissues. Additionally, in vitro studies of cell cultures from humans and mice have demonstrated the ability of macrophages to secrete ferritin, suggesting that macrophages are an important cellular source of serum ferritin.^10,20 As such, serum ferritin generally may reflect body iron status but more specifically reflects macrophage iron status.¹⁰ Although the exact pathways of ferritin release are unknown, it is hypothesized that ferritin secretion occurs through cytosolic autophagy followed by secretion of proteins from the lysosomal compartment.^10,18,21

 

 

Clinical Utility of Serum Ferritin

Low Ferritin and Iron Deficiency—Although bone marrow biopsy with iron staining remains the gold standard for diagnosis of iron deficiency, serum ferritin is a much more accessible and less invasive tool for evaluation of iron status. A serum ferritin level below 12 μg/L is highly specific for iron depletion,²² with a higher cutoff recommended in clinical practice to improve diagnostic sensitivity.^23,24 Conditions independent of iron deficiency that may reduce serum ferritin include hypothyroidism and ascorbate deficiency, though neither condition has been reported to interfere with appropriate diagnosis of iron deficiency.²⁵ Guyatt et al²⁶ conducted a systematic review of laboratory tests used in the diagnosis of iron deficiency anemia and identified 55 studies suitable for inclusion. Based on an area under the receiver operating characteristic curve (AUROC) of 0.95, serum ferritin values were superior to transferrin saturation (AUROC, 0.74), red cell protoporphyrin (AUROC, 0.77), red cell volume distribution width (AUROC, 0.62), and mean cell volume (AUROC, 0.76) for diagnosis of IDA, verified by histologic examination of aspirated bone marrow.²⁶ The likelihood ratio of iron deficiency begins to decrease for serum ferritin values of 40 μg/L or greater. For patients with inflammatory conditions—patients with concomitant chronic renal failure, inflammatory disease, infection, rheumatoid arthritis, liver disease, inflammatory bowel disease, and malignancy—the likelihood of iron deficiency begins to decrease at serum ferritin levels of 70 μg/L or greater.²⁶ Similarly, the World Health Organization recommends that in adults with infection or inflammation, serum ferritin levels lower than 70 μg/L may be used to indicate iron deficiency.²⁴ A serum ferritin level of 41 μg/L or lower was found to have a sensitivity and specificity of 98% for discriminating between iron-deficiency anemia and anemia of chronic disease (diagnosed based on bone marrow biopsy with iron staining), with an AUROC of 0.98.²⁷ As such, we recommend using a serum ferritin level of 40 μg/L or lower in patients who are otherwise healthy as an indicator of iron deficiency.

The threshold for iron supplementation may vary based on age, sex, and race. In women, ferritin levels increase during menopause and peak after menopause; ferritin levels are higher in men than in women.^28-30 A multisite longitudinal cohort study of 70 women in the United States found that the mean (SD) ferritin valuewas 69.5 (81.7) μg/L premenopause and 128.8 (125.7) μg/L postmenopause (P<.01).³¹ A separate longitudinal survey study of 8564 patients in China found that the mean (SE) ferritin value was 201.55 (3.60) μg/L for men and 80.46 (1.64) μg/L for women (P<.0001).³² Analysis of serum ferritin levels of 3554 male patients from the third National Health and Nutrition Examination Survey demonstrated that patients who self-reported as non-Hispanic Black (n=1616) had significantly higher serum ferritin levels than non-Hispanic White patients (n=1938)(serum ferritin difference of 37.1 μg/L)(P<.0001).³³ The British Society for Haematology guidelines recommend that the threshold of serum ferritin for diagnosing iron deficiency should take into account age-, sex-, and race-based differences.³⁴ Ferritin and Hair—Cutaneous manifestations of iron deficiency include koilonychia, glossitis, pruritus, angular cheilitis, and telogen effluvium (TE).¹ A case-control study of 30 females aged 15 to 45 years demonstrated that the mean (SD) ferritin level was significantly lower in patients with TE than those with no hair loss (16.3 [12.6] ng/mL vs 60.3 [50.1] ng/mL; P<.0001). Using a threshold of 30 μg/L or lower, the investigators found that the odds ratio for TE was 21.0 (95% CI, 4.2-105.0) in patients with low serum ferritin.³⁵

Another retrospective review of 54 patients with diffuse hair loss and 55 controls compared serum vitamin B₁₂, folate, thyroid-stimulating hormone, zinc, ferritin, and 25-hydroxy vitamin D levels between the 2 groups.³⁶ Exclusion criteria were clinical diagnoses of female pattern hair loss (androgenetic alopecia), pregnancy, menopause, metabolic and endocrine disorders, hormone replacement therapy, chemotherapy, immunosuppressive therapy, vitamin and mineral supplementation, scarring alopecia, eating disorders, and restrictive diets. Compared with controls, patients with diffuse nonscarring hair loss were found to have significantly lower ferritin (mean [SD], 14.72 [10.70] ng/mL vs 25.30 [14.41] ng/mL; P<.001) and 25-hydroxy vitamin D levels (mean [SD], 14.03 [8.09] ng/mL vs 17.01 [8.59] ng/mL; P=.01).³⁶

In contrast, a separate case-control study of 381 cases and 76 controls found no increase in the rate of iron deficiency—defined as ferritin ≤15 μg/L or ≤40 μg/L—among women with female pattern hair loss or chronic TE vs controls.³⁷ Taken together, these studies suggest that iron status may play a role in TE, a process that may result from nutritional deficiency, trauma, or physical or psychological stress³⁸; however, there is insufficient evidence to suggest that low iron status impacts androgenetic alopecia, in which its multifactorial pathogenesis implicates genetic and hormonal factors.³⁹ More research is needed to clarify the potential associations between iron deficiency and types of hair loss. Additionally, it is unclear whether iron supplementation improves hair growth parameters such as density and caliber.⁴⁰

Low serum ferritin (<40 μg/L) with concurrent symptoms of iron deficiency, including fatigue, pallor, dyspnea on exertion, or hair loss, should prompt treatment with supplemental iron.^41-43 Generally, ferrous (Fe2⁺) salts are preferred to ferric (Fe3⁺) salts, as the former is more readily absorbed through the duodenal mucosa⁴⁴ and is the more common formulation in commercially available supplements in the United States.⁴⁵ Oral supplementation with ferrous sulfate 325 mg (65 mg elemental iron) tablets is the first-line therapy for iron deficiency anemia.¹ Alternatively, ferrous gluconate 324 mg (38 mg elemental iron) over-the-counter and its liquid form has demonstrated superior absorption compared to ferrous sulfate tablets in a clinical study with peritoneal dialysis patients.^1,46 One study suggested that oral iron 40 to 80 mg should be taken every other day to increase absorption.⁴⁷ Due to improved bioavailability, intravenous iron may be utilized in patients with malabsorption, renal failure, or intolerance to oral iron (including those with gastric ulcers or active inflammatory bowel disease), with the formulation chosen based on underlying comorbidities and potential risks.^1,48 The theoretical risk for potentiating bacterial growth by increasing the amount of unbound iron in the blood raises concerns of iron supplementation in patients with infection or sepsis. Although far from definitive, existing data suggest that risk for infection is greater with intravenous iron supplementation and should be carefully considered prior to use.^49,50Elevated Ferritin—Elevated ferritin may be difficult to interpret given the multitude of conditions that can cause it.^23,51,52 Elevated serum ferritin can be broadly characterized by increased synthesis due to iron overload, increased synthesis due to inflammation, or increased ferritin release from cellular damage.³⁴ Further complicating interpretation is the potential diurnal fluctuations in serum iron levels dependent on dietary intake and timing of laboratory evaluation, choice of assay, differences in reference standards, and variations in calibration procedures that can lead to analytic variability in the measurement of ferritin.^23,53,54

Among healthy patients, serum ferritin is directly proportional to iron status.^9,51 A study utilizing weekly phlebotomy of 22 healthy participants to measure serum ferritin and calculate mobilizable storage iron found a strong positive correlation between the 2 variables (r=0.83, P<.001), with each 1-μg/L increase of serum ferritin corresponding to approximately an 8-mg increase of storage iron; the initial serum ferritin values ranged from 2 to 83 μg/L in females and 36 to 224 μg/L in males.⁵⁵ The correlation of ferritin with iron status also was supported by the significant correlation between the number of transfusions received in patients with transfusion-related iron overload and serum ferritin levels (r=0.89, P<.001), with an average increase of 60 μg/L per transfusion.⁵¹

Clinical guidelines on the interpretation of serum ferritin levels by Cullis et al³⁴ recommend a normal upper limit of 200 μg/L for healthy females and 300 μg/L for healthy males. Outside of clinical syndromes associated with iron overload, Lee and Means⁵⁶ found that serum ferritin of 1000 μg/L or higher was a nonspecific marker of disease, including infection and/or neoplastic disorders. We have adapted these guidelines to propose a workflow for evaluation of serum ferritin levels (Figure). In patients with inflammatory conditions or those affected by metabolic syndrome, elevated serum ferritin does not correlate with body iron status.^57,58 It is believed that inflammatory cytokines, including tumor necrosis factor α and IL-1α, can upregulate ferritin synthesis independent of cellular iron stores.^15,16 Several studies have examined the relationship between insulin resistance and/or metabolic syndrome with serum ferritin levels.^31,32 Han et al³² found that elevated serum ferritin was significantly associated with higher risk for metabolic syndrome in men (P<.0001) but not in women.

Although cutaneous manifestations of iron overload can be seen as skin hyperpigmentation due to increased iron deposits and increased melanin production,²² the effects of elevated ferritin on the skin and hair are not well known. Iron overload is a known trigger of porphyria cutanea tarda (PCT),⁵⁹ a condition in which reduced or absent enzymatic activity of uroporphyrinogen decarboxylase (UROD) leads to build up of toxic porphyrins in various organs.⁶⁰ In the skin, PCT manifests as a blistering photosensitive eruption that may resolve as dyspigmentation, scarring, and milia.⁶¹ Phlebotomy is first-line therapy in PCT to reduce serum iron and subsequent formation of UROD inhibitors, with guidelines suggesting discontinuation of phlebotomy when serum ferritin levels reach 20 ng/mL or lower.⁶⁰ Hyperferritinemia (serum ferritin >500 μg/L) is a common finding in several inflammatory disorders often accompanied by clinically apparent cutaneous symptoms such as adult-onset Still disease,⁶² hemophagocytic lymphohistiocytosis,^63,64 and anti-melanoma differentiation-associated gene 5 dermatomyositis.⁶⁵ Among these conditions, serum ferritin levels have been reported to correlate with disease activity, raising the question of whether ferritin is a bystander or a driver of the underlying pathology.^62,66,67 However, rapid decline of serum ferritin levels with treatment and control of inflammatory cytokines suggest that ferritin is unlikely to contribute to pathology.^62,67

Final Thoughts

Many clinical studies have examined the association between hair health and body iron status, the collective findings of which suggest that iron deficiency may be associated with TE. Among commonly measured serum iron parameters, low ferritin is a highly specific and sensitive marker for diagnosing iron deficiency. Serum ferritin may be a clinically useful tool for ruling out underlying iron deficiency in patients presenting with hair loss. Despite advances in our understanding of the molecular mechanisms of ferritin synthesis and regulation, whether ferritin itself contributes to cutaneous pathology is poorly understood.^35,36,68-74 For patients who are otherwise healthy with low suspicion for inflammatory disorders, chronic systemic illnesses, or malignancy, serum ferritin can be used as an indicator of body iron status. The workup for slightly elevated serum ferritin should be interpreted in the context of other laboratory findings and should be reassessed over time. Serum ferritin levels above 1000 μg/L warrant further investigation into causes such as iron overload conditions and underlying inflammatory conditions or malignancy.

Ferritin is an iron storage protein crucial to human iron homeostasis. Because serum ferritin levels are in dynamic equilibrium with the body’s iron stores, ferritin often is measured as a reflection of iron status; however, ferritin also is an acute-phase reactant whose levels may be nonspecifically elevated in a wide range of inflammatory conditions. The various processes that alter serum ferritin levels complicate the clinical interpretation of this laboratory value. In this article, we review the structure and function of ferritin and provide a guide for clinical use.

Overview of Iron

Iron is an essential element of key biologic functions including DNA synthesis and repair, oxygen transport, and oxidative phosphorylation. The body’s iron stores are mainly derived from internal iron recycling following red blood cell breakdown, while 5% to 10% is supplied by dietary intake.^1-3 Iron metabolism is of particular importance in cells of the reticuloendothelial system (eg, spleen, liver, bone marrow), where excess iron must be appropriately sequestered and from which iron can be mobilized.⁴ Sufficient iron stores are necessary for proper cellular function and survival, as iron is a necessary component of hemoglobin for oxygen delivery, iron-sulfur clusters in electron transport, and enzyme cofactors in other cellular processes.

Although labile pools of biologically active free iron exist in limited amounts within cells, excess free iron can generate free radicals that damage cellular proteins, lipids, and nucleic acids.^5-7 As such, most intracellular iron is captured within ferritin molecules. The excretion of iron is unregulated and occurs through loss in sweat, menstruation, hair shedding, skin desquamation, and enterocyte turnover.⁸ The lack of regulated excretion highlights the need for a tightly regulated system of uptake, transportation, storage, and sequestration to maintain iron homeostasis.

Overview of Ferritin Structure and Function

Ferritin is a key regulator of iron homeostasis that also serves as an important clinical indicator of body iron status. Ferritin mainly is found as an intracellular cytosolic iron storage and detoxification protein structured as a hollow 24-subunit polymer shell that can sequester up to 4500 atoms of iron within its core.^9,10 The 24-mer is composed of both ferritin L (FTL) and ferritin H (FTH) subunits, with dynamic regulation of the H:L ratio dependent on the context and tissue in which ferritin is found.⁶

Ferritin H possesses ferroxidase, which facilitates oxidation of ferrous (Fe²⁺) iron into ferric (Fe³⁺) iron, which can then be incorporated into the mineral core of the ferritin heteropolymer.¹¹ Ferritin L is more abundant in the spleen and liver, while FTH is found predominantly in the heart and kidneys where the increased ferroxidase activity may confer an increased ability to oxidize Fe²⁺ and limit oxidative stress.⁶

Regulation of Ferritin Synthesis and Secretion

Ferritin synthesis is regulated by intracellular nonheme iron levels, governed mainly by an iron response element (IRE) and iron response protein (IRP) translational repression system. Both FTH and FTL messenger RNA (mRNA) contain an IRE that is a regulatory stem-loop structure in the 5´ untranslated region. When the IRE is bound by IRP1 or IRP2, mRNA translation of ferritin subunits is suppressed.⁶ In low iron conditions, IRPs have greater affinity for IRE, and binding suppresses ferritin translation.¹² In high iron conditions, IRPs have a decreased affinity for IRE, and ferritin mRNA synthesis is increased.¹³ Additionally, inflammatory cytokines such as tumor necrosis factor α and IL-1α transcriptionally induce FTH synthesis, resulting in an increased population of H-rich ferritins.^11,14-16 A study using cultured human primary skin fibroblasts demonstrated UV radiation–induced increases in free intracellular iron content.^17,18 Pourzand et al¹⁸ suggested that UV-mediated damage of lysosomal membranes results in leakage of lysosomal proteases into the cytosol, contributing to degradation of intracellular ferritin and subsequent release of iron within skin fibroblasts. The increased intracellular iron downregulates IRPs and increases ferritin mRNA synthesis,¹⁸ consistent with prior findings of increased ferritin synthesis in skin that is induced by UV radiation.¹⁹

Molecular analysis of serum ferritin in iron-overloaded mice revealed that extracellular ferritin found in the serum is composed of a greater fraction of FTL and has lower iron content than intracellular ferritin. The low iron content of serum ferritin compared with intracellular ferritin and transferrin suggests that serum ferritin is not a major pathway of systemic iron transport.¹⁰ However, locally secreted ferritins may play a greater role in iron transport and release in selected tissues. Additionally, in vitro studies of cell cultures from humans and mice have demonstrated the ability of macrophages to secrete ferritin, suggesting that macrophages are an important cellular source of serum ferritin.^10,20 As such, serum ferritin generally may reflect body iron status but more specifically reflects macrophage iron status.¹⁰ Although the exact pathways of ferritin release are unknown, it is hypothesized that ferritin secretion occurs through cytosolic autophagy followed by secretion of proteins from the lysosomal compartment.^10,18,21

 

 

Clinical Utility of Serum Ferritin

Low Ferritin and Iron Deficiency—Although bone marrow biopsy with iron staining remains the gold standard for diagnosis of iron deficiency, serum ferritin is a much more accessible and less invasive tool for evaluation of iron status. A serum ferritin level below 12 μg/L is highly specific for iron depletion,²² with a higher cutoff recommended in clinical practice to improve diagnostic sensitivity.^23,24 Conditions independent of iron deficiency that may reduce serum ferritin include hypothyroidism and ascorbate deficiency, though neither condition has been reported to interfere with appropriate diagnosis of iron deficiency.²⁵ Guyatt et al²⁶ conducted a systematic review of laboratory tests used in the diagnosis of iron deficiency anemia and identified 55 studies suitable for inclusion. Based on an area under the receiver operating characteristic curve (AUROC) of 0.95, serum ferritin values were superior to transferrin saturation (AUROC, 0.74), red cell protoporphyrin (AUROC, 0.77), red cell volume distribution width (AUROC, 0.62), and mean cell volume (AUROC, 0.76) for diagnosis of IDA, verified by histologic examination of aspirated bone marrow.²⁶ The likelihood ratio of iron deficiency begins to decrease for serum ferritin values of 40 μg/L or greater. For patients with inflammatory conditions—patients with concomitant chronic renal failure, inflammatory disease, infection, rheumatoid arthritis, liver disease, inflammatory bowel disease, and malignancy—the likelihood of iron deficiency begins to decrease at serum ferritin levels of 70 μg/L or greater.²⁶ Similarly, the World Health Organization recommends that in adults with infection or inflammation, serum ferritin levels lower than 70 μg/L may be used to indicate iron deficiency.²⁴ A serum ferritin level of 41 μg/L or lower was found to have a sensitivity and specificity of 98% for discriminating between iron-deficiency anemia and anemia of chronic disease (diagnosed based on bone marrow biopsy with iron staining), with an AUROC of 0.98.²⁷ As such, we recommend using a serum ferritin level of 40 μg/L or lower in patients who are otherwise healthy as an indicator of iron deficiency.

The threshold for iron supplementation may vary based on age, sex, and race. In women, ferritin levels increase during menopause and peak after menopause; ferritin levels are higher in men than in women.^28-30 A multisite longitudinal cohort study of 70 women in the United States found that the mean (SD) ferritin valuewas 69.5 (81.7) μg/L premenopause and 128.8 (125.7) μg/L postmenopause (P<.01).³¹ A separate longitudinal survey study of 8564 patients in China found that the mean (SE) ferritin value was 201.55 (3.60) μg/L for men and 80.46 (1.64) μg/L for women (P<.0001).³² Analysis of serum ferritin levels of 3554 male patients from the third National Health and Nutrition Examination Survey demonstrated that patients who self-reported as non-Hispanic Black (n=1616) had significantly higher serum ferritin levels than non-Hispanic White patients (n=1938)(serum ferritin difference of 37.1 μg/L)(P<.0001).³³ The British Society for Haematology guidelines recommend that the threshold of serum ferritin for diagnosing iron deficiency should take into account age-, sex-, and race-based differences.³⁴ Ferritin and Hair—Cutaneous manifestations of iron deficiency include koilonychia, glossitis, pruritus, angular cheilitis, and telogen effluvium (TE).¹ A case-control study of 30 females aged 15 to 45 years demonstrated that the mean (SD) ferritin level was significantly lower in patients with TE than those with no hair loss (16.3 [12.6] ng/mL vs 60.3 [50.1] ng/mL; P<.0001). Using a threshold of 30 μg/L or lower, the investigators found that the odds ratio for TE was 21.0 (95% CI, 4.2-105.0) in patients with low serum ferritin.³⁵

Another retrospective review of 54 patients with diffuse hair loss and 55 controls compared serum vitamin B₁₂, folate, thyroid-stimulating hormone, zinc, ferritin, and 25-hydroxy vitamin D levels between the 2 groups.³⁶ Exclusion criteria were clinical diagnoses of female pattern hair loss (androgenetic alopecia), pregnancy, menopause, metabolic and endocrine disorders, hormone replacement therapy, chemotherapy, immunosuppressive therapy, vitamin and mineral supplementation, scarring alopecia, eating disorders, and restrictive diets. Compared with controls, patients with diffuse nonscarring hair loss were found to have significantly lower ferritin (mean [SD], 14.72 [10.70] ng/mL vs 25.30 [14.41] ng/mL; P<.001) and 25-hydroxy vitamin D levels (mean [SD], 14.03 [8.09] ng/mL vs 17.01 [8.59] ng/mL; P=.01).³⁶

In contrast, a separate case-control study of 381 cases and 76 controls found no increase in the rate of iron deficiency—defined as ferritin ≤15 μg/L or ≤40 μg/L—among women with female pattern hair loss or chronic TE vs controls.³⁷ Taken together, these studies suggest that iron status may play a role in TE, a process that may result from nutritional deficiency, trauma, or physical or psychological stress³⁸; however, there is insufficient evidence to suggest that low iron status impacts androgenetic alopecia, in which its multifactorial pathogenesis implicates genetic and hormonal factors.³⁹ More research is needed to clarify the potential associations between iron deficiency and types of hair loss. Additionally, it is unclear whether iron supplementation improves hair growth parameters such as density and caliber.⁴⁰

Low serum ferritin (<40 μg/L) with concurrent symptoms of iron deficiency, including fatigue, pallor, dyspnea on exertion, or hair loss, should prompt treatment with supplemental iron.^41-43 Generally, ferrous (Fe2⁺) salts are preferred to ferric (Fe3⁺) salts, as the former is more readily absorbed through the duodenal mucosa⁴⁴ and is the more common formulation in commercially available supplements in the United States.⁴⁵ Oral supplementation with ferrous sulfate 325 mg (65 mg elemental iron) tablets is the first-line therapy for iron deficiency anemia.¹ Alternatively, ferrous gluconate 324 mg (38 mg elemental iron) over-the-counter and its liquid form has demonstrated superior absorption compared to ferrous sulfate tablets in a clinical study with peritoneal dialysis patients.^1,46 One study suggested that oral iron 40 to 80 mg should be taken every other day to increase absorption.⁴⁷ Due to improved bioavailability, intravenous iron may be utilized in patients with malabsorption, renal failure, or intolerance to oral iron (including those with gastric ulcers or active inflammatory bowel disease), with the formulation chosen based on underlying comorbidities and potential risks.^1,48 The theoretical risk for potentiating bacterial growth by increasing the amount of unbound iron in the blood raises concerns of iron supplementation in patients with infection or sepsis. Although far from definitive, existing data suggest that risk for infection is greater with intravenous iron supplementation and should be carefully considered prior to use.^49,50Elevated Ferritin—Elevated ferritin may be difficult to interpret given the multitude of conditions that can cause it.^23,51,52 Elevated serum ferritin can be broadly characterized by increased synthesis due to iron overload, increased synthesis due to inflammation, or increased ferritin release from cellular damage.³⁴ Further complicating interpretation is the potential diurnal fluctuations in serum iron levels dependent on dietary intake and timing of laboratory evaluation, choice of assay, differences in reference standards, and variations in calibration procedures that can lead to analytic variability in the measurement of ferritin.^23,53,54

Among healthy patients, serum ferritin is directly proportional to iron status.^9,51 A study utilizing weekly phlebotomy of 22 healthy participants to measure serum ferritin and calculate mobilizable storage iron found a strong positive correlation between the 2 variables (r=0.83, P<.001), with each 1-μg/L increase of serum ferritin corresponding to approximately an 8-mg increase of storage iron; the initial serum ferritin values ranged from 2 to 83 μg/L in females and 36 to 224 μg/L in males.⁵⁵ The correlation of ferritin with iron status also was supported by the significant correlation between the number of transfusions received in patients with transfusion-related iron overload and serum ferritin levels (r=0.89, P<.001), with an average increase of 60 μg/L per transfusion.⁵¹

Clinical guidelines on the interpretation of serum ferritin levels by Cullis et al³⁴ recommend a normal upper limit of 200 μg/L for healthy females and 300 μg/L for healthy males. Outside of clinical syndromes associated with iron overload, Lee and Means⁵⁶ found that serum ferritin of 1000 μg/L or higher was a nonspecific marker of disease, including infection and/or neoplastic disorders. We have adapted these guidelines to propose a workflow for evaluation of serum ferritin levels (Figure). In patients with inflammatory conditions or those affected by metabolic syndrome, elevated serum ferritin does not correlate with body iron status.^57,58 It is believed that inflammatory cytokines, including tumor necrosis factor α and IL-1α, can upregulate ferritin synthesis independent of cellular iron stores.^15,16 Several studies have examined the relationship between insulin resistance and/or metabolic syndrome with serum ferritin levels.^31,32 Han et al³² found that elevated serum ferritin was significantly associated with higher risk for metabolic syndrome in men (P<.0001) but not in women.

Although cutaneous manifestations of iron overload can be seen as skin hyperpigmentation due to increased iron deposits and increased melanin production,²² the effects of elevated ferritin on the skin and hair are not well known. Iron overload is a known trigger of porphyria cutanea tarda (PCT),⁵⁹ a condition in which reduced or absent enzymatic activity of uroporphyrinogen decarboxylase (UROD) leads to build up of toxic porphyrins in various organs.⁶⁰ In the skin, PCT manifests as a blistering photosensitive eruption that may resolve as dyspigmentation, scarring, and milia.⁶¹ Phlebotomy is first-line therapy in PCT to reduce serum iron and subsequent formation of UROD inhibitors, with guidelines suggesting discontinuation of phlebotomy when serum ferritin levels reach 20 ng/mL or lower.⁶⁰ Hyperferritinemia (serum ferritin >500 μg/L) is a common finding in several inflammatory disorders often accompanied by clinically apparent cutaneous symptoms such as adult-onset Still disease,⁶² hemophagocytic lymphohistiocytosis,^63,64 and anti-melanoma differentiation-associated gene 5 dermatomyositis.⁶⁵ Among these conditions, serum ferritin levels have been reported to correlate with disease activity, raising the question of whether ferritin is a bystander or a driver of the underlying pathology.^62,66,67 However, rapid decline of serum ferritin levels with treatment and control of inflammatory cytokines suggest that ferritin is unlikely to contribute to pathology.^62,67

Final Thoughts

Many clinical studies have examined the association between hair health and body iron status, the collective findings of which suggest that iron deficiency may be associated with TE. Among commonly measured serum iron parameters, low ferritin is a highly specific and sensitive marker for diagnosing iron deficiency. Serum ferritin may be a clinically useful tool for ruling out underlying iron deficiency in patients presenting with hair loss. Despite advances in our understanding of the molecular mechanisms of ferritin synthesis and regulation, whether ferritin itself contributes to cutaneous pathology is poorly understood.^35,36,68-74 For patients who are otherwise healthy with low suspicion for inflammatory disorders, chronic systemic illnesses, or malignancy, serum ferritin can be used as an indicator of body iron status. The workup for slightly elevated serum ferritin should be interpreted in the context of other laboratory findings and should be reassessed over time. Serum ferritin levels above 1000 μg/L warrant further investigation into causes such as iron overload conditions and underlying inflammatory conditions or malignancy.

Nail surgical procedures including biopsies, correction of onychocryptosis and other deformities, and excision of tumors are essential for diagnosing and treating nail disorders. Nail surgery often is perceived by dermatologists as a difficult-to-perform, high-risk procedure associated with patient anxiety, pain, and permanent scarring, which may limit implementation. Misconceptions about nail surgical techniques, aftercare, and patient outcomes are prevalent, and a paucity of nail surgery randomized clinical trials hinder formulation of standardized guidelines.¹ In a survey-based study of 95 dermatology residency programs (240 total respondents), 58% of residents said they performed 10 or fewer nail procedures, 10% performed more than 10 procedures, 25% only observed nail procedures, 4% were exposed by lecture only, and 1% had no exposure; 30% said they felt incompetent performing nail biopsies.² In a retrospective study of nail biopsies performed from 2012 to 2017 in the Medicare Provider Utilization and Payment Database, only 0.28% and 1.01% of all general dermatologists and Mohs surgeons, respectively, performed nail biopsies annually.³ A minimally invasive nail surgery technique is essential to alleviating dermatologist and patient apprehension, which may lead to greater adoption and improved outcomes.

Reduce Patient Anxiety During Nail Surgery

The prospect of undergoing nail surgery can be psychologically distressing to patients because the nail unit is highly sensitive, intraoperative and postoperative pain are common concerns, patient education materials generally are scarce and inaccurate,⁴ and procedures are performed under local anesthesia with the patient fully awake. In a prospective study of 48 patients undergoing nail surgery, the median preoperative Spielberger State-Trait Anxiety Inventory level was 42.00 (IQR, 6.50).⁵ Patient distress may be minimized by providing verbal and written educational materials, discussing expectations, and preoperatively using fast-acting benzodiazepines when necessary.⁶ Utilizing a sleep mask,⁷ stress ball,⁸ music,⁹ and/or virtual reality¹⁰ also may reduce patient anxiety during nail surgery.

Use Proper Anesthetic Techniques

Proper anesthetic technique is crucial to achieve the optimal patient experience during nail surgery. With a wing block, the anesthetic is injected into 3 points: (1) the proximal nail fold, (2) the medial/lateral fold, and (3) the hyponychium. The wing block is the preferred technique by many nail surgeons because the second and third injections are given in skin that is already anesthetized, reducing patient discomfort to a single pinprick¹¹; additionally, there is lower postoperative paresthesia risk with the wing block compared with other digital nerve blocks.¹² Ropivacaine, a fast-acting and long-acting anesthetic, is preferred over lidocaine to minimize immediate postoperative pain. Buffering the anesthetic solution to physiologic pH and slow infiltration can reduce pain during infiltration.¹² Distraction¹² provided by ethyl chloride refrigerant spray, an air-cooling device,¹³ or vibration also can reduce pain during anesthesia.

Punch Biopsy and Excision Tips

The punch biopsy is a minimally invasive method for diagnosing various neoplastic and inflammatory nail unit conditions, except for pigmented lesions.¹² For polydactylous nail conditions requiring biopsy, a digit on the nondominant hand should be selected if possible. The punch is applied directly to the nail plate and twisted with downward pressure until the bone is reached, with the instrument withdrawn slowly to prevent surrounding nail plate detachment. Hemostasis is easily achieved with direct pressure and/or use of epinephrine or ropivacaine during anesthesia, and a digital tourniquet generally is not required. Applying microporous polysaccharide hemospheres powder¹⁴ or kaolin-impregnated gauze¹⁵ with direct pressure is helpful in managing continued bleeding following nail surgery. Punching through the proximal nail matrix should be avoided to prevent permanent onychodystrophy.

A tangential matrix shave biopsy requires a more practiced technique and is preferred for sampling longitudinal melanonychia. A partial proximal nail plate avulsion adequately exposes the origin of pigment and avoids complete avulsion, which may cause more onychodystrophy.¹⁶ For broad erythronychia, a total nail avulsion may be necessary. For narrow, well-defined erythronychia, a less-invasive approach such as trap-door avulsion, longitudinal nail strip, or lateral nail plate curl, depending on the etiology, often is sufficient. Tissue excision should be tailored to the specific etiology, with localized excision sufficient for glomus tumors; onychopapillomas require tangential excision of the distal matrix, entire nail bed, and hyperkeratotic papule at the hyponychium. Pushing the cuticle with an elevator/spatula instead of making 2 tangential incisions on the proximal nail fold has been suggested to decrease postoperative paronychia risk.¹² A Teflon-coated blade is used to achieve a smooth cut with minimal drag, enabling collection of specimens less than 1 mm thick, which provides sufficient nail matrix epithelium and dermis for histologic examination.¹⁶ After obtaining the specimen, the avulsed nail plate may be sutured back to the nail bed using a rapidly absorbable suture such as polyglactin 910, serving as a temporary biological dressing and splint for the nail unit during healing.¹² In a retrospective study of 30 patients with longitudinal melanonychia undergoing tangential matrix excision, 27% (8/30) developed postoperative onychodystrophy.¹⁷ Although this technique carries relatively lower risk of permanent onychodystrophy compared to other methods, it still is important to acknowledge during the preoperative consent process.¹²

The lateral longitudinal excision is a valuable technique for diagnosing nail unit inflammatory conditions. Classically, a longitudinal sample including the proximal nail fold, complete matrix, lateral plate, lateral nail fold, hyponychium, and distal tip skin is obtained, with a 10% narrowing of the nail plate expected. If the lateral horn of the nail matrix is missed, permanent lateral malalignment and spicule formation are potential risks. To minimize narrowing of the nail plate and postoperative paronychia, a longitudinal nail strip—where the proximal nail fold and matrix are left intact—is an alternative technique.¹⁸

Pain Management Approaches

Appropriate postoperative pain management is crucial for optimizing patient outcomes. In a prospective study of 20 patients undergoing nail biopsy, the mean pain score 6 to 12 hours postprocedure was 5.7 on a scale of 0 to 10. Patients with presurgery pain vs those without experienced significantly higher pain levels both during anesthesia and after surgery (both P<.05).¹⁹ Therefore, a personalized approach to pain management based on presence of presurgical pain is warranted. In a randomized clinical trial of 16 patients anesthetized with lidocaine 2% and intraoperative infiltration with a combination of ropivacaine 0.5 mL and triamcinolone (10 mg/mL [0.5 mL]) vs lidocaine 2% alone, the intraoperative mixture reduced postoperative pain (mean pain score, 2 of 10 at 48 hours postprocedure vs 7.88 of 10 in the control group [P<.001]).²⁰

A Cochrane review of 4 unpublished dental and orthopedic surgery studies showed that gabapentin is superior to placebo in the treatment of acute postoperative pain. Therefore, a single dose of gabapentin (250 mg) may be considered in patients at risk for high postoperative pain.²¹ In a randomized double-blind trial of 210 Mohs micrographic surgery patients, those receiving acetaminophen and ibuprofen reported lower pain scores at 2, 4, 8, and 12 hours postprocedure compared with patients taking acetaminophen and codeine or acetaminophen alone.²² However, the role of opioids in pain management following nail surgery has not been adequately studied.

Wound Care

An efficient dressing protects the surgical wound, facilitates healing, and provides comfort. In our experience, an initial layer of petrolatum-impregnated gauze followed by a pressure-padded bandage consisting of folded dry gauze secured in place with longitudinally applied tape to avoid a tourniquet effect is effective for nail surgical wounds. As the last step, self-adherent elastic wrap is applied around the digit and extended proximally to prevent a tourniquet effect.²³

Final Thoughts

Due to the intricate anatomy of the nail unit, nail surgeries are inherently more invasive than most dermatologic surgical procedures. It is crucial to adopt a minimally invasive approach to reduce tissue damage and potential complications in both the short-term and long-term. Adopting this approach may substantially improve patient outcomes and enhance diagnostic and treatment efficacy.

Nail surgical procedures including biopsies, correction of onychocryptosis and other deformities, and excision of tumors are essential for diagnosing and treating nail disorders. Nail surgery often is perceived by dermatologists as a difficult-to-perform, high-risk procedure associated with patient anxiety, pain, and permanent scarring, which may limit implementation. Misconceptions about nail surgical techniques, aftercare, and patient outcomes are prevalent, and a paucity of nail surgery randomized clinical trials hinder formulation of standardized guidelines.¹ In a survey-based study of 95 dermatology residency programs (240 total respondents), 58% of residents said they performed 10 or fewer nail procedures, 10% performed more than 10 procedures, 25% only observed nail procedures, 4% were exposed by lecture only, and 1% had no exposure; 30% said they felt incompetent performing nail biopsies.² In a retrospective study of nail biopsies performed from 2012 to 2017 in the Medicare Provider Utilization and Payment Database, only 0.28% and 1.01% of all general dermatologists and Mohs surgeons, respectively, performed nail biopsies annually.³ A minimally invasive nail surgery technique is essential to alleviating dermatologist and patient apprehension, which may lead to greater adoption and improved outcomes.

Reduce Patient Anxiety During Nail Surgery

The prospect of undergoing nail surgery can be psychologically distressing to patients because the nail unit is highly sensitive, intraoperative and postoperative pain are common concerns, patient education materials generally are scarce and inaccurate,⁴ and procedures are performed under local anesthesia with the patient fully awake. In a prospective study of 48 patients undergoing nail surgery, the median preoperative Spielberger State-Trait Anxiety Inventory level was 42.00 (IQR, 6.50).⁵ Patient distress may be minimized by providing verbal and written educational materials, discussing expectations, and preoperatively using fast-acting benzodiazepines when necessary.⁶ Utilizing a sleep mask,⁷ stress ball,⁸ music,⁹ and/or virtual reality¹⁰ also may reduce patient anxiety during nail surgery.

Use Proper Anesthetic Techniques

Proper anesthetic technique is crucial to achieve the optimal patient experience during nail surgery. With a wing block, the anesthetic is injected into 3 points: (1) the proximal nail fold, (2) the medial/lateral fold, and (3) the hyponychium. The wing block is the preferred technique by many nail surgeons because the second and third injections are given in skin that is already anesthetized, reducing patient discomfort to a single pinprick¹¹; additionally, there is lower postoperative paresthesia risk with the wing block compared with other digital nerve blocks.¹² Ropivacaine, a fast-acting and long-acting anesthetic, is preferred over lidocaine to minimize immediate postoperative pain. Buffering the anesthetic solution to physiologic pH and slow infiltration can reduce pain during infiltration.¹² Distraction¹² provided by ethyl chloride refrigerant spray, an air-cooling device,¹³ or vibration also can reduce pain during anesthesia.

Punch Biopsy and Excision Tips

The punch biopsy is a minimally invasive method for diagnosing various neoplastic and inflammatory nail unit conditions, except for pigmented lesions.¹² For polydactylous nail conditions requiring biopsy, a digit on the nondominant hand should be selected if possible. The punch is applied directly to the nail plate and twisted with downward pressure until the bone is reached, with the instrument withdrawn slowly to prevent surrounding nail plate detachment. Hemostasis is easily achieved with direct pressure and/or use of epinephrine or ropivacaine during anesthesia, and a digital tourniquet generally is not required. Applying microporous polysaccharide hemospheres powder¹⁴ or kaolin-impregnated gauze¹⁵ with direct pressure is helpful in managing continued bleeding following nail surgery. Punching through the proximal nail matrix should be avoided to prevent permanent onychodystrophy.

A tangential matrix shave biopsy requires a more practiced technique and is preferred for sampling longitudinal melanonychia. A partial proximal nail plate avulsion adequately exposes the origin of pigment and avoids complete avulsion, which may cause more onychodystrophy.¹⁶ For broad erythronychia, a total nail avulsion may be necessary. For narrow, well-defined erythronychia, a less-invasive approach such as trap-door avulsion, longitudinal nail strip, or lateral nail plate curl, depending on the etiology, often is sufficient. Tissue excision should be tailored to the specific etiology, with localized excision sufficient for glomus tumors; onychopapillomas require tangential excision of the distal matrix, entire nail bed, and hyperkeratotic papule at the hyponychium. Pushing the cuticle with an elevator/spatula instead of making 2 tangential incisions on the proximal nail fold has been suggested to decrease postoperative paronychia risk.¹² A Teflon-coated blade is used to achieve a smooth cut with minimal drag, enabling collection of specimens less than 1 mm thick, which provides sufficient nail matrix epithelium and dermis for histologic examination.¹⁶ After obtaining the specimen, the avulsed nail plate may be sutured back to the nail bed using a rapidly absorbable suture such as polyglactin 910, serving as a temporary biological dressing and splint for the nail unit during healing.¹² In a retrospective study of 30 patients with longitudinal melanonychia undergoing tangential matrix excision, 27% (8/30) developed postoperative onychodystrophy.¹⁷ Although this technique carries relatively lower risk of permanent onychodystrophy compared to other methods, it still is important to acknowledge during the preoperative consent process.¹²

The lateral longitudinal excision is a valuable technique for diagnosing nail unit inflammatory conditions. Classically, a longitudinal sample including the proximal nail fold, complete matrix, lateral plate, lateral nail fold, hyponychium, and distal tip skin is obtained, with a 10% narrowing of the nail plate expected. If the lateral horn of the nail matrix is missed, permanent lateral malalignment and spicule formation are potential risks. To minimize narrowing of the nail plate and postoperative paronychia, a longitudinal nail strip—where the proximal nail fold and matrix are left intact—is an alternative technique.¹⁸

Pain Management Approaches

Appropriate postoperative pain management is crucial for optimizing patient outcomes. In a prospective study of 20 patients undergoing nail biopsy, the mean pain score 6 to 12 hours postprocedure was 5.7 on a scale of 0 to 10. Patients with presurgery pain vs those without experienced significantly higher pain levels both during anesthesia and after surgery (both P<.05).¹⁹ Therefore, a personalized approach to pain management based on presence of presurgical pain is warranted. In a randomized clinical trial of 16 patients anesthetized with lidocaine 2% and intraoperative infiltration with a combination of ropivacaine 0.5 mL and triamcinolone (10 mg/mL [0.5 mL]) vs lidocaine 2% alone, the intraoperative mixture reduced postoperative pain (mean pain score, 2 of 10 at 48 hours postprocedure vs 7.88 of 10 in the control group [P<.001]).²⁰

A Cochrane review of 4 unpublished dental and orthopedic surgery studies showed that gabapentin is superior to placebo in the treatment of acute postoperative pain. Therefore, a single dose of gabapentin (250 mg) may be considered in patients at risk for high postoperative pain.²¹ In a randomized double-blind trial of 210 Mohs micrographic surgery patients, those receiving acetaminophen and ibuprofen reported lower pain scores at 2, 4, 8, and 12 hours postprocedure compared with patients taking acetaminophen and codeine or acetaminophen alone.²² However, the role of opioids in pain management following nail surgery has not been adequately studied.

Wound Care

An efficient dressing protects the surgical wound, facilitates healing, and provides comfort. In our experience, an initial layer of petrolatum-impregnated gauze followed by a pressure-padded bandage consisting of folded dry gauze secured in place with longitudinally applied tape to avoid a tourniquet effect is effective for nail surgical wounds. As the last step, self-adherent elastic wrap is applied around the digit and extended proximally to prevent a tourniquet effect.²³

Final Thoughts

Due to the intricate anatomy of the nail unit, nail surgeries are inherently more invasive than most dermatologic surgical procedures. It is crucial to adopt a minimally invasive approach to reduce tissue damage and potential complications in both the short-term and long-term. Adopting this approach may substantially improve patient outcomes and enhance diagnostic and treatment efficacy.

Nail surgical procedures including biopsies, correction of onychocryptosis and other deformities, and excision of tumors are essential for diagnosing and treating nail disorders. Nail surgery often is perceived by dermatologists as a difficult-to-perform, high-risk procedure associated with patient anxiety, pain, and permanent scarring, which may limit implementation. Misconceptions about nail surgical techniques, aftercare, and patient outcomes are prevalent, and a paucity of nail surgery randomized clinical trials hinder formulation of standardized guidelines.¹ In a survey-based study of 95 dermatology residency programs (240 total respondents), 58% of residents said they performed 10 or fewer nail procedures, 10% performed more than 10 procedures, 25% only observed nail procedures, 4% were exposed by lecture only, and 1% had no exposure; 30% said they felt incompetent performing nail biopsies.² In a retrospective study of nail biopsies performed from 2012 to 2017 in the Medicare Provider Utilization and Payment Database, only 0.28% and 1.01% of all general dermatologists and Mohs surgeons, respectively, performed nail biopsies annually.³ A minimally invasive nail surgery technique is essential to alleviating dermatologist and patient apprehension, which may lead to greater adoption and improved outcomes.

Reduce Patient Anxiety During Nail Surgery

The prospect of undergoing nail surgery can be psychologically distressing to patients because the nail unit is highly sensitive, intraoperative and postoperative pain are common concerns, patient education materials generally are scarce and inaccurate,⁴ and procedures are performed under local anesthesia with the patient fully awake. In a prospective study of 48 patients undergoing nail surgery, the median preoperative Spielberger State-Trait Anxiety Inventory level was 42.00 (IQR, 6.50).⁵ Patient distress may be minimized by providing verbal and written educational materials, discussing expectations, and preoperatively using fast-acting benzodiazepines when necessary.⁶ Utilizing a sleep mask,⁷ stress ball,⁸ music,⁹ and/or virtual reality¹⁰ also may reduce patient anxiety during nail surgery.

Use Proper Anesthetic Techniques

Proper anesthetic technique is crucial to achieve the optimal patient experience during nail surgery. With a wing block, the anesthetic is injected into 3 points: (1) the proximal nail fold, (2) the medial/lateral fold, and (3) the hyponychium. The wing block is the preferred technique by many nail surgeons because the second and third injections are given in skin that is already anesthetized, reducing patient discomfort to a single pinprick¹¹; additionally, there is lower postoperative paresthesia risk with the wing block compared with other digital nerve blocks.¹² Ropivacaine, a fast-acting and long-acting anesthetic, is preferred over lidocaine to minimize immediate postoperative pain. Buffering the anesthetic solution to physiologic pH and slow infiltration can reduce pain during infiltration.¹² Distraction¹² provided by ethyl chloride refrigerant spray, an air-cooling device,¹³ or vibration also can reduce pain during anesthesia.

Punch Biopsy and Excision Tips

The punch biopsy is a minimally invasive method for diagnosing various neoplastic and inflammatory nail unit conditions, except for pigmented lesions.¹² For polydactylous nail conditions requiring biopsy, a digit on the nondominant hand should be selected if possible. The punch is applied directly to the nail plate and twisted with downward pressure until the bone is reached, with the instrument withdrawn slowly to prevent surrounding nail plate detachment. Hemostasis is easily achieved with direct pressure and/or use of epinephrine or ropivacaine during anesthesia, and a digital tourniquet generally is not required. Applying microporous polysaccharide hemospheres powder¹⁴ or kaolin-impregnated gauze¹⁵ with direct pressure is helpful in managing continued bleeding following nail surgery. Punching through the proximal nail matrix should be avoided to prevent permanent onychodystrophy.

A tangential matrix shave biopsy requires a more practiced technique and is preferred for sampling longitudinal melanonychia. A partial proximal nail plate avulsion adequately exposes the origin of pigment and avoids complete avulsion, which may cause more onychodystrophy.¹⁶ For broad erythronychia, a total nail avulsion may be necessary. For narrow, well-defined erythronychia, a less-invasive approach such as trap-door avulsion, longitudinal nail strip, or lateral nail plate curl, depending on the etiology, often is sufficient. Tissue excision should be tailored to the specific etiology, with localized excision sufficient for glomus tumors; onychopapillomas require tangential excision of the distal matrix, entire nail bed, and hyperkeratotic papule at the hyponychium. Pushing the cuticle with an elevator/spatula instead of making 2 tangential incisions on the proximal nail fold has been suggested to decrease postoperative paronychia risk.¹² A Teflon-coated blade is used to achieve a smooth cut with minimal drag, enabling collection of specimens less than 1 mm thick, which provides sufficient nail matrix epithelium and dermis for histologic examination.¹⁶ After obtaining the specimen, the avulsed nail plate may be sutured back to the nail bed using a rapidly absorbable suture such as polyglactin 910, serving as a temporary biological dressing and splint for the nail unit during healing.¹² In a retrospective study of 30 patients with longitudinal melanonychia undergoing tangential matrix excision, 27% (8/30) developed postoperative onychodystrophy.¹⁷ Although this technique carries relatively lower risk of permanent onychodystrophy compared to other methods, it still is important to acknowledge during the preoperative consent process.¹²

The lateral longitudinal excision is a valuable technique for diagnosing nail unit inflammatory conditions. Classically, a longitudinal sample including the proximal nail fold, complete matrix, lateral plate, lateral nail fold, hyponychium, and distal tip skin is obtained, with a 10% narrowing of the nail plate expected. If the lateral horn of the nail matrix is missed, permanent lateral malalignment and spicule formation are potential risks. To minimize narrowing of the nail plate and postoperative paronychia, a longitudinal nail strip—where the proximal nail fold and matrix are left intact—is an alternative technique.¹⁸

Pain Management Approaches

Appropriate postoperative pain management is crucial for optimizing patient outcomes. In a prospective study of 20 patients undergoing nail biopsy, the mean pain score 6 to 12 hours postprocedure was 5.7 on a scale of 0 to 10. Patients with presurgery pain vs those without experienced significantly higher pain levels both during anesthesia and after surgery (both P<.05).¹⁹ Therefore, a personalized approach to pain management based on presence of presurgical pain is warranted. In a randomized clinical trial of 16 patients anesthetized with lidocaine 2% and intraoperative infiltration with a combination of ropivacaine 0.5 mL and triamcinolone (10 mg/mL [0.5 mL]) vs lidocaine 2% alone, the intraoperative mixture reduced postoperative pain (mean pain score, 2 of 10 at 48 hours postprocedure vs 7.88 of 10 in the control group [P<.001]).²⁰

A Cochrane review of 4 unpublished dental and orthopedic surgery studies showed that gabapentin is superior to placebo in the treatment of acute postoperative pain. Therefore, a single dose of gabapentin (250 mg) may be considered in patients at risk for high postoperative pain.²¹ In a randomized double-blind trial of 210 Mohs micrographic surgery patients, those receiving acetaminophen and ibuprofen reported lower pain scores at 2, 4, 8, and 12 hours postprocedure compared with patients taking acetaminophen and codeine or acetaminophen alone.²² However, the role of opioids in pain management following nail surgery has not been adequately studied.

Wound Care

An efficient dressing protects the surgical wound, facilitates healing, and provides comfort. In our experience, an initial layer of petrolatum-impregnated gauze followed by a pressure-padded bandage consisting of folded dry gauze secured in place with longitudinally applied tape to avoid a tourniquet effect is effective for nail surgical wounds. As the last step, self-adherent elastic wrap is applied around the digit and extended proximally to prevent a tourniquet effect.²³

Final Thoughts

Due to the intricate anatomy of the nail unit, nail surgeries are inherently more invasive than most dermatologic surgical procedures. It is crucial to adopt a minimally invasive approach to reduce tissue damage and potential complications in both the short-term and long-term. Adopting this approach may substantially improve patient outcomes and enhance diagnostic and treatment efficacy.