Public perception of disease is everything. “Diabetics” are now referred to as “people living with diabetes,” and an “obese person” is now an “individual living with obesity.”

But what is the definition of obesity? Does it refer to a disease or a risk factor? And is the term so tainted in negativity, blame, and bias that the only solution is to scrap it and completely rename it? Society (and medicine) have changed significantly since the Latin word obesitas was adopted back in the 1600s.

Despite so much hinging on the word “obesity,” it’s remarkable that the label persists while the concepts underpinning it have evolved significantly. So perhaps it is more about finding the least-worst option rather than pursuing the impossibility of a solution that suits all?

This is precisely the challenge faced by a Lancet Diabetes & Endocrinology Commission on the Definition and Diagnosis of Clinical Obesity, which is due to publish its initial findings this coming fall. The global task force has 60 leaders in the clinical management of obesity, including representatives with lived experiences of obesity. Leading the project is Francesco Rubino, MD, chair of metabolic and bariatric surgery at King’s College London.

“Renaming ‘obesity’ is very important,” states Dr. Rubino. “The word is so stigmatized, with so much misunderstanding and misperception, some might say the only solution is to change the name.”

One possibility for a new name, introduced by the American Association of Clinical Endocrinologists (now –Endocrinology) and the American College of Endocrinology back in 2016, was based on framing the disease on the central characteristic of adiposity and was termed ABCD, for adiposity-based chronic disease.

Dr. Rubino welcomes “ABCD” but has some reservations. “It is good from a physiological point of view, but the problem is it speaks to scientists and medical professionals. I don’t know how much it would appeal to the general public. ‘ABCD’ still falls short of telling us what the illness is.”

He adds that the Lancet Commission’s approach is rather to call it “clinical obesity.” “ ‘Obesity’ itself doesn’t necessarily convey the message that you have a disease or an illness,” he observes. “It is similar to the difference in meaning between depression and clinical depression, which communicate two different things.”

But underpinning any renaming is greater clarification of the definition and diagnosis of obesity. In 1997, the World Health Organization recognized obesity as a chronic disease; in 2013, the American Medical Association did likewise, adding that it warranted medical attention; while it took until 2021 for the European Commission to define obesity as a “chronic relapsing disease, which in turn acts as a gateway to a range of other non-communicable diseases.”

Yet, 25 years after the initial recognition of obesity as a disease, the concept is still riddled with negativity, whether openly or unconsciously. Such stigma denigrates overweight people and those with obesity as “lazy, sloppy, unintelligent, and unattractive.”

Dr. Rubino explains that first, it’s important to establish and define the essential components and characteristics of the disease of obesity. This is key to improving access to clinical care, reducing personal blame, and nurturing a more supportive research environment to help inform both clinical and policy decision-making.

“This is the question that is at the core of our commission. We have a problem with the current definition of obesity, and the way we measure it does not allow us to accurately define a state of illness with obesity,” he explains.
 

Labels shape public perceptions of disease; ‘obesity’ epitomizes this

Another expert championing the need for a name that better reflects the definition – whatever that turns out to be – is Margaret Steele, PhD, School of Public Health, University College Cork (Ireland), who, according to her university webpage, has a special interest in “ ‘fatness’ as a cultural, social and political phenomenon.”

She believes that labels, including “obesity,” have a pivotal role in shaping public perceptions. In our digital, information-rich age, the boundaries of medicine and society overlap, with public perception shaping decisions of a medical nature as never before. But with this comes controversy and division – obesity management being a case in point.

Specifically, the word “obesity” is too widely associated with negative connotations, she says, and therefore she welcomes the dialogue around redefining and renaming it. Despite wide general support for a name and definition that reflects adiposity, due to its central physiologic role in the complications of obesity, Dr. Steele believes that the “effects on adipose tissue are downstream of brain issues and the food environment,” and she wants to see more attention brought to this.

Referring to most Westernized societies, she describes how people who grew up in times of food scarcity, before processed foods became widely available, have a different taste profile from those who grew up afterwards. “Growing up in 1940s and ‘50s Ireland, people recall how they remember getting an orange as a treat at Christmas, because the idea that you could have food all year-round – any fruit and veg that you want, when you want it – just wasn’t there.”

By comparison, societal changes leading to more financial and time pressure in later decades meant that fast, high-fat, high-sugar, and processed foods became more desirable, she points out. “Most young children now recognize the company name, and even the specific fast-food brand [they like], before they know their alphabet.”

The current environment has cultivated “a very different physical reaction to foods, maybe a different kind of emotional response,” she believes, highlighting the tightly woven relationship between obesity, society, mental health, and food options.

Dr. Steele wants to stimulate a conversation about the term used to describe individuals, conventionally described as ‘”obese” or using the word “obesity.” “We’re thinking in terms of maybe chronic appetite, chronic food intake, or dietary intake dysregulation.”

Changing medical terminology when it has become useless or harmful is not new, she argues, with co-author, Francis Finucane, MD, consultant endocrinologist at Galway University Hospitals, Ireland, in a recent paper on the subject.

“In the 20th century, the terms ‘feeble-minded’ and ‘moron’ had become used in a pejorative way in the wider culture and were dropped from medical usage,” Dr. Steele points out. She adds that changing the term “obesity” can facilitate pursuit of the strategic goals of clinical medicine “without causing needless controversy with those who, given their own goals and contexts, understand body mass index or body weight in a radically different way.”
 

Obesity: Disease, risk factor, or both?

Dr. Rubino stresses that prior to any renaming, there is a need to establish and define the essential components and characteristics of the disease of obesity. “This question is at the core of our Commission, and it is not an easy conversation to have.” He further explains that the struggle with the current definition of obesity, and the way it is conceived, is largely centered on it still being considered a risk factor for something else.

Disease is characterized by three things, says Dr. Rubino. These comprise the phenomenon of having a pathogenic cause, leading to pathophysiologic alterations (of the organs), causing clinical manifestations.

He adds that obesity is currently described by what it can cause – for example, type 2 diabetes, cancer, or hypertension. “Each of these things have their own clinical manifestations but obesity doesn’t. [As a disease], we don’t have a definition of the clinical manifestations of obesity other than excess adiposity.”

“If we use BMI, this does not predict excess adiposity, nor does it determine a disease here and now. There is no disease without an illness, which is the clinical manifestation, and the perception by the patient of it being an illness,” explains Dr. Rubino, pointing out that the Lancet Commission is filling this gap in knowledge by asking, “If obesity is an illness, then what does it look like?”

He adds that waist circumference probably provides a better measure than BMI in directly indicating the abnormal distribution of adiposity, known to be associated with poor cardiometabolic outcomes, “but it doesn’t tell you if you have an illness here and now – only that someone is at risk of developing cardiovascular disease in the future. Most people with some excess fat around the waist are perfectly functional and don’t feel ill.”

He also explains that confusion persists around whether obesity – or excess adiposity – is a risk factor for or a symptom of another disease. “The picture is blurred, and we do not know how to discriminate between these. We only have one name, and it applies to all those things, and we have one criterion – BMI – to diagnose it!”

Dr. Rubino adds, “So, what defines it? Is it diabetes? No, because that is another disease. You don’t define a disease by another. It has to stand on its own.”

Recently, the American Medical Association advised that BMI now be used in conjunction with other valid measures of risk such as, but not limited to, measurements of visceral fat, body adiposity index, body composition, relative fat mass, waist circumference, and genetic/metabolic factors.

Aayush Visaria, MD, an internal medicine resident at Rutgers University, New Brunswick, New Jersey, agrees that a new name might help change public perception of obesity for the better. A study he presented at the 2023 Endocrine Society Meeting found that BMI “vastly underestimates” obesity.

He agrees with Dr. Rubino that the challenge lies in the lack of precise understanding of the mechanisms driving obesity: “It’s multifactorial, so not just appetite or food intake. Putting this into one phrase is difficult.”

However, if a new term can incorporate the many facets of the disease, “overall, it’ll reduce stigma because we’ll start to think about obesity as a disease process, not a personal thing with blame attached,” says Dr. Visaria.

But simultaneously, he expresses caution around possible negative connotations associated with the classification of obesity as a disease. Dr. Steele also reflects on this risk, highlighting that medicalizing body size can be counterproductive in feeding into weight stigma and fatphobia.

“Medicalizing obesity can be discouraging rather than empowering, but by specifying more clearly that we’re talking about a specific set of interrelated metabolic conditions, it would make it much clearer, and that ... this isn’t about making people skinny, it isn’t about an aesthetic thing,” Dr. Steele observes.
 

The word ‘obesity’ hinders disease explanations

Dr. Steele explains that her goal is to overcome the ambiguity around the word “obesity” that hinders explanations of the disease of obesity to the wider public.

“Much confusion and controversy might be avoided if we were to clarify that when doctors say that obesity is a disease, they do not mean that being ‘fat’ is a disease.”

Nevertheless, adipose tissue is an active endocrine organ, producing hormones that function less well in people with obesity, she notes. “This new knowledge has led to better treatments, including drugs like semaglutide and tirzepatide. These drugs, like bariatric surgery, typically lead to significant weight loss and to improvements in overall metabolic health.”

Dr. Rubino also expresses concerns around medicalization, as determined by definition and diagnosis and the availability of drug treatment that could potentially lead to overtreatment. “Currently, when everyone with a BMI of greater than 30 gets access to every obesity treatment out there, we see drugs are running out of stock. We should prioritize that treatment.”

Ultimately, the diagnosis of obesity as a disease needs an anthropometric biomarker that provides, on an individual level, the confidence that a person has a disease today, or at least close to a 100% likelihood of developing this disease and illness, asserts Dr. Rubino.

“If we use BMI, or even waist circumference, these might diagnose the disease; but if the person lives to 90 years, what’s the point of labeling somebody as having an illness?” he points out.

“As doctors, we have to be cautious. We say this is a disease, but you must think about the implications for the person on the receiving end of that diagnosis of a chronic disease that is substantially incurable. When we say it, we need to be certain.”

Dr. Steele and Dr. Visaria have disclosed no relevant financial relationships. Dr. Rubino disclosed that he has received research grants from Novo Nordisk, Medtronic, and Johnson & Johnson. He has undertaken paid consultancy work for GI Dynamics and received honoraria for lectures from Medtronic, Novo Nordisk, and Johnson & Johnson. He is a member of the data safety monitoring board for GT Metabolic Solutions and has provided scientific advice to Keyron, Metadeq, GHP Scientific, and ViBo Health for no remuneration.

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

Public perception of disease is everything. “Diabetics” are now referred to as “people living with diabetes,” and an “obese person” is now an “individual living with obesity.”

But what is the definition of obesity? Does it refer to a disease or a risk factor? And is the term so tainted in negativity, blame, and bias that the only solution is to scrap it and completely rename it? Society (and medicine) have changed significantly since the Latin word obesitas was adopted back in the 1600s.

Despite so much hinging on the word “obesity,” it’s remarkable that the label persists while the concepts underpinning it have evolved significantly. So perhaps it is more about finding the least-worst option rather than pursuing the impossibility of a solution that suits all?

This is precisely the challenge faced by a Lancet Diabetes & Endocrinology Commission on the Definition and Diagnosis of Clinical Obesity, which is due to publish its initial findings this coming fall. The global task force has 60 leaders in the clinical management of obesity, including representatives with lived experiences of obesity. Leading the project is Francesco Rubino, MD, chair of metabolic and bariatric surgery at King’s College London.

“Renaming ‘obesity’ is very important,” states Dr. Rubino. “The word is so stigmatized, with so much misunderstanding and misperception, some might say the only solution is to change the name.”

One possibility for a new name, introduced by the American Association of Clinical Endocrinologists (now –Endocrinology) and the American College of Endocrinology back in 2016, was based on framing the disease on the central characteristic of adiposity and was termed ABCD, for adiposity-based chronic disease.

Dr. Rubino welcomes “ABCD” but has some reservations. “It is good from a physiological point of view, but the problem is it speaks to scientists and medical professionals. I don’t know how much it would appeal to the general public. ‘ABCD’ still falls short of telling us what the illness is.”

He adds that the Lancet Commission’s approach is rather to call it “clinical obesity.” “ ‘Obesity’ itself doesn’t necessarily convey the message that you have a disease or an illness,” he observes. “It is similar to the difference in meaning between depression and clinical depression, which communicate two different things.”

But underpinning any renaming is greater clarification of the definition and diagnosis of obesity. In 1997, the World Health Organization recognized obesity as a chronic disease; in 2013, the American Medical Association did likewise, adding that it warranted medical attention; while it took until 2021 for the European Commission to define obesity as a “chronic relapsing disease, which in turn acts as a gateway to a range of other non-communicable diseases.”

Yet, 25 years after the initial recognition of obesity as a disease, the concept is still riddled with negativity, whether openly or unconsciously. Such stigma denigrates overweight people and those with obesity as “lazy, sloppy, unintelligent, and unattractive.”

Dr. Rubino explains that first, it’s important to establish and define the essential components and characteristics of the disease of obesity. This is key to improving access to clinical care, reducing personal blame, and nurturing a more supportive research environment to help inform both clinical and policy decision-making.

“This is the question that is at the core of our commission. We have a problem with the current definition of obesity, and the way we measure it does not allow us to accurately define a state of illness with obesity,” he explains.
 

Labels shape public perceptions of disease; ‘obesity’ epitomizes this

Another expert championing the need for a name that better reflects the definition – whatever that turns out to be – is Margaret Steele, PhD, School of Public Health, University College Cork (Ireland), who, according to her university webpage, has a special interest in “ ‘fatness’ as a cultural, social and political phenomenon.”

She believes that labels, including “obesity,” have a pivotal role in shaping public perceptions. In our digital, information-rich age, the boundaries of medicine and society overlap, with public perception shaping decisions of a medical nature as never before. But with this comes controversy and division – obesity management being a case in point.

Specifically, the word “obesity” is too widely associated with negative connotations, she says, and therefore she welcomes the dialogue around redefining and renaming it. Despite wide general support for a name and definition that reflects adiposity, due to its central physiologic role in the complications of obesity, Dr. Steele believes that the “effects on adipose tissue are downstream of brain issues and the food environment,” and she wants to see more attention brought to this.

Referring to most Westernized societies, she describes how people who grew up in times of food scarcity, before processed foods became widely available, have a different taste profile from those who grew up afterwards. “Growing up in 1940s and ‘50s Ireland, people recall how they remember getting an orange as a treat at Christmas, because the idea that you could have food all year-round – any fruit and veg that you want, when you want it – just wasn’t there.”

By comparison, societal changes leading to more financial and time pressure in later decades meant that fast, high-fat, high-sugar, and processed foods became more desirable, she points out. “Most young children now recognize the company name, and even the specific fast-food brand [they like], before they know their alphabet.”

The current environment has cultivated “a very different physical reaction to foods, maybe a different kind of emotional response,” she believes, highlighting the tightly woven relationship between obesity, society, mental health, and food options.

Dr. Steele wants to stimulate a conversation about the term used to describe individuals, conventionally described as ‘”obese” or using the word “obesity.” “We’re thinking in terms of maybe chronic appetite, chronic food intake, or dietary intake dysregulation.”

Changing medical terminology when it has become useless or harmful is not new, she argues, with co-author, Francis Finucane, MD, consultant endocrinologist at Galway University Hospitals, Ireland, in a recent paper on the subject.

“In the 20th century, the terms ‘feeble-minded’ and ‘moron’ had become used in a pejorative way in the wider culture and were dropped from medical usage,” Dr. Steele points out. She adds that changing the term “obesity” can facilitate pursuit of the strategic goals of clinical medicine “without causing needless controversy with those who, given their own goals and contexts, understand body mass index or body weight in a radically different way.”
 

Obesity: Disease, risk factor, or both?

Dr. Rubino stresses that prior to any renaming, there is a need to establish and define the essential components and characteristics of the disease of obesity. “This question is at the core of our Commission, and it is not an easy conversation to have.” He further explains that the struggle with the current definition of obesity, and the way it is conceived, is largely centered on it still being considered a risk factor for something else.

Disease is characterized by three things, says Dr. Rubino. These comprise the phenomenon of having a pathogenic cause, leading to pathophysiologic alterations (of the organs), causing clinical manifestations.

He adds that obesity is currently described by what it can cause – for example, type 2 diabetes, cancer, or hypertension. “Each of these things have their own clinical manifestations but obesity doesn’t. [As a disease], we don’t have a definition of the clinical manifestations of obesity other than excess adiposity.”

“If we use BMI, this does not predict excess adiposity, nor does it determine a disease here and now. There is no disease without an illness, which is the clinical manifestation, and the perception by the patient of it being an illness,” explains Dr. Rubino, pointing out that the Lancet Commission is filling this gap in knowledge by asking, “If obesity is an illness, then what does it look like?”

He adds that waist circumference probably provides a better measure than BMI in directly indicating the abnormal distribution of adiposity, known to be associated with poor cardiometabolic outcomes, “but it doesn’t tell you if you have an illness here and now – only that someone is at risk of developing cardiovascular disease in the future. Most people with some excess fat around the waist are perfectly functional and don’t feel ill.”

He also explains that confusion persists around whether obesity – or excess adiposity – is a risk factor for or a symptom of another disease. “The picture is blurred, and we do not know how to discriminate between these. We only have one name, and it applies to all those things, and we have one criterion – BMI – to diagnose it!”

Dr. Rubino adds, “So, what defines it? Is it diabetes? No, because that is another disease. You don’t define a disease by another. It has to stand on its own.”

Recently, the American Medical Association advised that BMI now be used in conjunction with other valid measures of risk such as, but not limited to, measurements of visceral fat, body adiposity index, body composition, relative fat mass, waist circumference, and genetic/metabolic factors.

Aayush Visaria, MD, an internal medicine resident at Rutgers University, New Brunswick, New Jersey, agrees that a new name might help change public perception of obesity for the better. A study he presented at the 2023 Endocrine Society Meeting found that BMI “vastly underestimates” obesity.

He agrees with Dr. Rubino that the challenge lies in the lack of precise understanding of the mechanisms driving obesity: “It’s multifactorial, so not just appetite or food intake. Putting this into one phrase is difficult.”

However, if a new term can incorporate the many facets of the disease, “overall, it’ll reduce stigma because we’ll start to think about obesity as a disease process, not a personal thing with blame attached,” says Dr. Visaria.

But simultaneously, he expresses caution around possible negative connotations associated with the classification of obesity as a disease. Dr. Steele also reflects on this risk, highlighting that medicalizing body size can be counterproductive in feeding into weight stigma and fatphobia.

“Medicalizing obesity can be discouraging rather than empowering, but by specifying more clearly that we’re talking about a specific set of interrelated metabolic conditions, it would make it much clearer, and that ... this isn’t about making people skinny, it isn’t about an aesthetic thing,” Dr. Steele observes.
 

The word ‘obesity’ hinders disease explanations

Dr. Steele explains that her goal is to overcome the ambiguity around the word “obesity” that hinders explanations of the disease of obesity to the wider public.

“Much confusion and controversy might be avoided if we were to clarify that when doctors say that obesity is a disease, they do not mean that being ‘fat’ is a disease.”

Nevertheless, adipose tissue is an active endocrine organ, producing hormones that function less well in people with obesity, she notes. “This new knowledge has led to better treatments, including drugs like semaglutide and tirzepatide. These drugs, like bariatric surgery, typically lead to significant weight loss and to improvements in overall metabolic health.”

Dr. Rubino also expresses concerns around medicalization, as determined by definition and diagnosis and the availability of drug treatment that could potentially lead to overtreatment. “Currently, when everyone with a BMI of greater than 30 gets access to every obesity treatment out there, we see drugs are running out of stock. We should prioritize that treatment.”

Ultimately, the diagnosis of obesity as a disease needs an anthropometric biomarker that provides, on an individual level, the confidence that a person has a disease today, or at least close to a 100% likelihood of developing this disease and illness, asserts Dr. Rubino.

“If we use BMI, or even waist circumference, these might diagnose the disease; but if the person lives to 90 years, what’s the point of labeling somebody as having an illness?” he points out.

“As doctors, we have to be cautious. We say this is a disease, but you must think about the implications for the person on the receiving end of that diagnosis of a chronic disease that is substantially incurable. When we say it, we need to be certain.”

Dr. Steele and Dr. Visaria have disclosed no relevant financial relationships. Dr. Rubino disclosed that he has received research grants from Novo Nordisk, Medtronic, and Johnson & Johnson. He has undertaken paid consultancy work for GI Dynamics and received honoraria for lectures from Medtronic, Novo Nordisk, and Johnson & Johnson. He is a member of the data safety monitoring board for GT Metabolic Solutions and has provided scientific advice to Keyron, Metadeq, GHP Scientific, and ViBo Health for no remuneration.

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

Public perception of disease is everything. “Diabetics” are now referred to as “people living with diabetes,” and an “obese person” is now an “individual living with obesity.”

But what is the definition of obesity? Does it refer to a disease or a risk factor? And is the term so tainted in negativity, blame, and bias that the only solution is to scrap it and completely rename it? Society (and medicine) have changed significantly since the Latin word obesitas was adopted back in the 1600s.

Despite so much hinging on the word “obesity,” it’s remarkable that the label persists while the concepts underpinning it have evolved significantly. So perhaps it is more about finding the least-worst option rather than pursuing the impossibility of a solution that suits all?

This is precisely the challenge faced by a Lancet Diabetes & Endocrinology Commission on the Definition and Diagnosis of Clinical Obesity, which is due to publish its initial findings this coming fall. The global task force has 60 leaders in the clinical management of obesity, including representatives with lived experiences of obesity. Leading the project is Francesco Rubino, MD, chair of metabolic and bariatric surgery at King’s College London.

“Renaming ‘obesity’ is very important,” states Dr. Rubino. “The word is so stigmatized, with so much misunderstanding and misperception, some might say the only solution is to change the name.”

One possibility for a new name, introduced by the American Association of Clinical Endocrinologists (now –Endocrinology) and the American College of Endocrinology back in 2016, was based on framing the disease on the central characteristic of adiposity and was termed ABCD, for adiposity-based chronic disease.

Dr. Rubino welcomes “ABCD” but has some reservations. “It is good from a physiological point of view, but the problem is it speaks to scientists and medical professionals. I don’t know how much it would appeal to the general public. ‘ABCD’ still falls short of telling us what the illness is.”

He adds that the Lancet Commission’s approach is rather to call it “clinical obesity.” “ ‘Obesity’ itself doesn’t necessarily convey the message that you have a disease or an illness,” he observes. “It is similar to the difference in meaning between depression and clinical depression, which communicate two different things.”

But underpinning any renaming is greater clarification of the definition and diagnosis of obesity. In 1997, the World Health Organization recognized obesity as a chronic disease; in 2013, the American Medical Association did likewise, adding that it warranted medical attention; while it took until 2021 for the European Commission to define obesity as a “chronic relapsing disease, which in turn acts as a gateway to a range of other non-communicable diseases.”

Yet, 25 years after the initial recognition of obesity as a disease, the concept is still riddled with negativity, whether openly or unconsciously. Such stigma denigrates overweight people and those with obesity as “lazy, sloppy, unintelligent, and unattractive.”

Dr. Rubino explains that first, it’s important to establish and define the essential components and characteristics of the disease of obesity. This is key to improving access to clinical care, reducing personal blame, and nurturing a more supportive research environment to help inform both clinical and policy decision-making.

“This is the question that is at the core of our commission. We have a problem with the current definition of obesity, and the way we measure it does not allow us to accurately define a state of illness with obesity,” he explains.
 

Labels shape public perceptions of disease; ‘obesity’ epitomizes this

Another expert championing the need for a name that better reflects the definition – whatever that turns out to be – is Margaret Steele, PhD, School of Public Health, University College Cork (Ireland), who, according to her university webpage, has a special interest in “ ‘fatness’ as a cultural, social and political phenomenon.”

She believes that labels, including “obesity,” have a pivotal role in shaping public perceptions. In our digital, information-rich age, the boundaries of medicine and society overlap, with public perception shaping decisions of a medical nature as never before. But with this comes controversy and division – obesity management being a case in point.

Specifically, the word “obesity” is too widely associated with negative connotations, she says, and therefore she welcomes the dialogue around redefining and renaming it. Despite wide general support for a name and definition that reflects adiposity, due to its central physiologic role in the complications of obesity, Dr. Steele believes that the “effects on adipose tissue are downstream of brain issues and the food environment,” and she wants to see more attention brought to this.

Referring to most Westernized societies, she describes how people who grew up in times of food scarcity, before processed foods became widely available, have a different taste profile from those who grew up afterwards. “Growing up in 1940s and ‘50s Ireland, people recall how they remember getting an orange as a treat at Christmas, because the idea that you could have food all year-round – any fruit and veg that you want, when you want it – just wasn’t there.”

By comparison, societal changes leading to more financial and time pressure in later decades meant that fast, high-fat, high-sugar, and processed foods became more desirable, she points out. “Most young children now recognize the company name, and even the specific fast-food brand [they like], before they know their alphabet.”

The current environment has cultivated “a very different physical reaction to foods, maybe a different kind of emotional response,” she believes, highlighting the tightly woven relationship between obesity, society, mental health, and food options.

Dr. Steele wants to stimulate a conversation about the term used to describe individuals, conventionally described as ‘”obese” or using the word “obesity.” “We’re thinking in terms of maybe chronic appetite, chronic food intake, or dietary intake dysregulation.”

Changing medical terminology when it has become useless or harmful is not new, she argues, with co-author, Francis Finucane, MD, consultant endocrinologist at Galway University Hospitals, Ireland, in a recent paper on the subject.

“In the 20th century, the terms ‘feeble-minded’ and ‘moron’ had become used in a pejorative way in the wider culture and were dropped from medical usage,” Dr. Steele points out. She adds that changing the term “obesity” can facilitate pursuit of the strategic goals of clinical medicine “without causing needless controversy with those who, given their own goals and contexts, understand body mass index or body weight in a radically different way.”
 

Obesity: Disease, risk factor, or both?

Dr. Rubino stresses that prior to any renaming, there is a need to establish and define the essential components and characteristics of the disease of obesity. “This question is at the core of our Commission, and it is not an easy conversation to have.” He further explains that the struggle with the current definition of obesity, and the way it is conceived, is largely centered on it still being considered a risk factor for something else.

Disease is characterized by three things, says Dr. Rubino. These comprise the phenomenon of having a pathogenic cause, leading to pathophysiologic alterations (of the organs), causing clinical manifestations.

He adds that obesity is currently described by what it can cause – for example, type 2 diabetes, cancer, or hypertension. “Each of these things have their own clinical manifestations but obesity doesn’t. [As a disease], we don’t have a definition of the clinical manifestations of obesity other than excess adiposity.”

“If we use BMI, this does not predict excess adiposity, nor does it determine a disease here and now. There is no disease without an illness, which is the clinical manifestation, and the perception by the patient of it being an illness,” explains Dr. Rubino, pointing out that the Lancet Commission is filling this gap in knowledge by asking, “If obesity is an illness, then what does it look like?”

He adds that waist circumference probably provides a better measure than BMI in directly indicating the abnormal distribution of adiposity, known to be associated with poor cardiometabolic outcomes, “but it doesn’t tell you if you have an illness here and now – only that someone is at risk of developing cardiovascular disease in the future. Most people with some excess fat around the waist are perfectly functional and don’t feel ill.”

He also explains that confusion persists around whether obesity – or excess adiposity – is a risk factor for or a symptom of another disease. “The picture is blurred, and we do not know how to discriminate between these. We only have one name, and it applies to all those things, and we have one criterion – BMI – to diagnose it!”

Dr. Rubino adds, “So, what defines it? Is it diabetes? No, because that is another disease. You don’t define a disease by another. It has to stand on its own.”

Recently, the American Medical Association advised that BMI now be used in conjunction with other valid measures of risk such as, but not limited to, measurements of visceral fat, body adiposity index, body composition, relative fat mass, waist circumference, and genetic/metabolic factors.

Aayush Visaria, MD, an internal medicine resident at Rutgers University, New Brunswick, New Jersey, agrees that a new name might help change public perception of obesity for the better. A study he presented at the 2023 Endocrine Society Meeting found that BMI “vastly underestimates” obesity.

He agrees with Dr. Rubino that the challenge lies in the lack of precise understanding of the mechanisms driving obesity: “It’s multifactorial, so not just appetite or food intake. Putting this into one phrase is difficult.”

However, if a new term can incorporate the many facets of the disease, “overall, it’ll reduce stigma because we’ll start to think about obesity as a disease process, not a personal thing with blame attached,” says Dr. Visaria.

But simultaneously, he expresses caution around possible negative connotations associated with the classification of obesity as a disease. Dr. Steele also reflects on this risk, highlighting that medicalizing body size can be counterproductive in feeding into weight stigma and fatphobia.

“Medicalizing obesity can be discouraging rather than empowering, but by specifying more clearly that we’re talking about a specific set of interrelated metabolic conditions, it would make it much clearer, and that ... this isn’t about making people skinny, it isn’t about an aesthetic thing,” Dr. Steele observes.
 

The word ‘obesity’ hinders disease explanations

Dr. Steele explains that her goal is to overcome the ambiguity around the word “obesity” that hinders explanations of the disease of obesity to the wider public.

“Much confusion and controversy might be avoided if we were to clarify that when doctors say that obesity is a disease, they do not mean that being ‘fat’ is a disease.”

Nevertheless, adipose tissue is an active endocrine organ, producing hormones that function less well in people with obesity, she notes. “This new knowledge has led to better treatments, including drugs like semaglutide and tirzepatide. These drugs, like bariatric surgery, typically lead to significant weight loss and to improvements in overall metabolic health.”

Dr. Rubino also expresses concerns around medicalization, as determined by definition and diagnosis and the availability of drug treatment that could potentially lead to overtreatment. “Currently, when everyone with a BMI of greater than 30 gets access to every obesity treatment out there, we see drugs are running out of stock. We should prioritize that treatment.”

Ultimately, the diagnosis of obesity as a disease needs an anthropometric biomarker that provides, on an individual level, the confidence that a person has a disease today, or at least close to a 100% likelihood of developing this disease and illness, asserts Dr. Rubino.

“If we use BMI, or even waist circumference, these might diagnose the disease; but if the person lives to 90 years, what’s the point of labeling somebody as having an illness?” he points out.

“As doctors, we have to be cautious. We say this is a disease, but you must think about the implications for the person on the receiving end of that diagnosis of a chronic disease that is substantially incurable. When we say it, we need to be certain.”

Dr. Steele and Dr. Visaria have disclosed no relevant financial relationships. Dr. Rubino disclosed that he has received research grants from Novo Nordisk, Medtronic, and Johnson & Johnson. He has undertaken paid consultancy work for GI Dynamics and received honoraria for lectures from Medtronic, Novo Nordisk, and Johnson & Johnson. He is a member of the data safety monitoring board for GT Metabolic Solutions and has provided scientific advice to Keyron, Metadeq, GHP Scientific, and ViBo Health for no remuneration.

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

Use of dural-puncture epidural (DPE) shortened the onset time to surgical anesthesia by approximately 3 minutes, compared with standard epidural in patients undergoing cesarean delivery, based on data from 140 individuals.

DPE, while not new, has become more popular as an option for initiating labor analgesia, but data comparing DPE with standard epidural in conversion to surgical anesthesia for cesarean deliveries are limited, Nadir Sharawi, MD, of the University of Arkansas for Medical Sciences, Little Rock, and colleagues wrote.

courtesy University of Arkansas for Medical Sciences

DPE involves no injection of intrathecal drugs, and the potential advantages include easier translocation of epidural medications into the intrathecal space for improved analgesia, but the effects of DPE on the onset and reliability of surgical anesthesia remain unknown, they said.

In a study published in JAMA Network Open, the researchers randomized 70 women scheduled for cesarean delivery of singleton pregnancies to DPE and 70 to a standard epidural. The participants were aged 18 years and older, with a mean age of the 30.1 years; the study was conducted between April 2019 and October 2022 at a single center.

The primary outcome was the time to the loss of sharp sensation at T6, defined as “the start of epidural extension anesthesia (time zero on the stopwatch) to when the patient could no longer feel sharp sensation at T6 (assessed bilaterally at the midclavicular line),” the researchers wrote.

The onset time to surgical anesthesia was faster in the DPE group, compared with the standard group, with a median of 422 seconds versus 655 seconds.

A key secondary outcome was a composite measure of the quality of epidural anesthesia that included failure to achieve a T10 bilateral block preoperatively in the delivery room, failure to achieve a surgical block at T6 within 15 minutes of chloroprocaine administration, requirement for intraoperative analgesia, repeat neuraxial procedure, and conversion to general anesthesia. The composite rates of lower quality anesthesia were significantly less in the DPE group, compared with the standard group (15.7% vs. 36.3%; P = .007).

Additional secondary outcomes included maternal satisfaction and pain score during surgery, adverse events, opioid use in the first 24 hours, maternal vasopressor requirements, epidural block assessments, and neonatal outcomes. No significant differences in these outcomes were noted between the groups, and no instances of local anesthetic systemic toxicity or neurological complications were reported.

The findings were limited by several factors including the study population of women scheduled for cesarean delivery and not in labor, and the inability to detect less frequent complications such as post–dural-puncture headache and accidental dural puncture, the researchers noted.

In addition, the results may vary with the use of other combinations of local anesthetics and opioids. “Chloroprocaine was chosen in this study because of its ease of administration without the need for opioids and other additives along with the low risk of systemic toxic effects, which favors rapid administration for emergent cesarean delivery,” they wrote.

However, the results show an association between DPE within an hour of epidural extension for elective cesarean delivery and a faster onset of anesthesia, improved block quality, and a more favorable ratio of risks versus benefits, compared with the use of standard epidural, the researchers concluded.
 

No need for general anesthesia?

“There is controversy over whether the dural puncture epidural technique improves labor analgesia when compared to a standard epidural,” Dr. Shawari said in an interview. “However, there are limited data on whether the dural puncture epidural technique decreases the onset time to surgical anesthesia when compared to a standard epidural for cesarean delivery. This is important as a pre-existing epidural is commonly used to convert labor analgesia to surgical anesthesia in the setting of urgent cesarean delivery. A faster onset of epidural anesthesia could potentially avoid the need for general anesthesia in an emergency.”

The researchers were not surprised by the findings given their experience with performing dural puncture epidurals for labor analgesia, Dr. Shawari said. In those cases, DPE provided a faster onset when converting cesarean anesthesia, compared with a standard epidural.

The takeaway from the current study is that DPE also provided “a faster onset and improved quality of anesthesia when compared to standard epidural for elective cesarean delivery,” Dr. Shawari said. However, additional research is needed to confirm the findings for intrapartum cesarean delivery.
 

Progress in improving pain control

“Adequate pain control during cesarean delivery is incredibly important,” Catherine Albright, MD, a maternal-fetal medicine specialist at the University of Washington, Seattle, said in an interview. “Inadequate pain control leads to the need to provide additional intravenous medications or the need to be put under general anesthesia, which changes the birth experience and is more dangerous for the birthing person and the neonate.

courtesy University of Washington

“In my clinical experience, there are many times when patients do not have adequate pain control during a cesarean delivery,” said Dr. Albright, who was not involved in the current study. “I am pleased to see that there is research underway about how to best manage pain on labor and delivery, especially in the setting of conversion from labor anesthesia to cesarean anesthesia.”

The findings may have implications for clinical practice, said Dr. Albright. If the dural puncture epidural can improve cesarean anesthesia following an epidural during labor, rather than anesthesia provided for an elective cesarean), “then I believe it would reduce the number of patients who require additional pain medication, have a poor cesarean experience, and/or need to be put under general anesthesia.”

However, “as noted by the authors, additional research is needed to further determine possible risks and side effects from this technique, and also to ensure that it also works in the setting of labor, rather than for an elective cesarean,” Dr. Albright added.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Albright had no financial conflicts to disclose.

Use of dural-puncture epidural (DPE) shortened the onset time to surgical anesthesia by approximately 3 minutes, compared with standard epidural in patients undergoing cesarean delivery, based on data from 140 individuals.

DPE, while not new, has become more popular as an option for initiating labor analgesia, but data comparing DPE with standard epidural in conversion to surgical anesthesia for cesarean deliveries are limited, Nadir Sharawi, MD, of the University of Arkansas for Medical Sciences, Little Rock, and colleagues wrote.

courtesy University of Arkansas for Medical Sciences

DPE involves no injection of intrathecal drugs, and the potential advantages include easier translocation of epidural medications into the intrathecal space for improved analgesia, but the effects of DPE on the onset and reliability of surgical anesthesia remain unknown, they said.

In a study published in JAMA Network Open, the researchers randomized 70 women scheduled for cesarean delivery of singleton pregnancies to DPE and 70 to a standard epidural. The participants were aged 18 years and older, with a mean age of the 30.1 years; the study was conducted between April 2019 and October 2022 at a single center.

The primary outcome was the time to the loss of sharp sensation at T6, defined as “the start of epidural extension anesthesia (time zero on the stopwatch) to when the patient could no longer feel sharp sensation at T6 (assessed bilaterally at the midclavicular line),” the researchers wrote.

The onset time to surgical anesthesia was faster in the DPE group, compared with the standard group, with a median of 422 seconds versus 655 seconds.

A key secondary outcome was a composite measure of the quality of epidural anesthesia that included failure to achieve a T10 bilateral block preoperatively in the delivery room, failure to achieve a surgical block at T6 within 15 minutes of chloroprocaine administration, requirement for intraoperative analgesia, repeat neuraxial procedure, and conversion to general anesthesia. The composite rates of lower quality anesthesia were significantly less in the DPE group, compared with the standard group (15.7% vs. 36.3%; P = .007).

Additional secondary outcomes included maternal satisfaction and pain score during surgery, adverse events, opioid use in the first 24 hours, maternal vasopressor requirements, epidural block assessments, and neonatal outcomes. No significant differences in these outcomes were noted between the groups, and no instances of local anesthetic systemic toxicity or neurological complications were reported.

The findings were limited by several factors including the study population of women scheduled for cesarean delivery and not in labor, and the inability to detect less frequent complications such as post–dural-puncture headache and accidental dural puncture, the researchers noted.

In addition, the results may vary with the use of other combinations of local anesthetics and opioids. “Chloroprocaine was chosen in this study because of its ease of administration without the need for opioids and other additives along with the low risk of systemic toxic effects, which favors rapid administration for emergent cesarean delivery,” they wrote.

However, the results show an association between DPE within an hour of epidural extension for elective cesarean delivery and a faster onset of anesthesia, improved block quality, and a more favorable ratio of risks versus benefits, compared with the use of standard epidural, the researchers concluded.
 

No need for general anesthesia?

“There is controversy over whether the dural puncture epidural technique improves labor analgesia when compared to a standard epidural,” Dr. Shawari said in an interview. “However, there are limited data on whether the dural puncture epidural technique decreases the onset time to surgical anesthesia when compared to a standard epidural for cesarean delivery. This is important as a pre-existing epidural is commonly used to convert labor analgesia to surgical anesthesia in the setting of urgent cesarean delivery. A faster onset of epidural anesthesia could potentially avoid the need for general anesthesia in an emergency.”

The researchers were not surprised by the findings given their experience with performing dural puncture epidurals for labor analgesia, Dr. Shawari said. In those cases, DPE provided a faster onset when converting cesarean anesthesia, compared with a standard epidural.

The takeaway from the current study is that DPE also provided “a faster onset and improved quality of anesthesia when compared to standard epidural for elective cesarean delivery,” Dr. Shawari said. However, additional research is needed to confirm the findings for intrapartum cesarean delivery.
 

Progress in improving pain control

“Adequate pain control during cesarean delivery is incredibly important,” Catherine Albright, MD, a maternal-fetal medicine specialist at the University of Washington, Seattle, said in an interview. “Inadequate pain control leads to the need to provide additional intravenous medications or the need to be put under general anesthesia, which changes the birth experience and is more dangerous for the birthing person and the neonate.

courtesy University of Washington

“In my clinical experience, there are many times when patients do not have adequate pain control during a cesarean delivery,” said Dr. Albright, who was not involved in the current study. “I am pleased to see that there is research underway about how to best manage pain on labor and delivery, especially in the setting of conversion from labor anesthesia to cesarean anesthesia.”

The findings may have implications for clinical practice, said Dr. Albright. If the dural puncture epidural can improve cesarean anesthesia following an epidural during labor, rather than anesthesia provided for an elective cesarean), “then I believe it would reduce the number of patients who require additional pain medication, have a poor cesarean experience, and/or need to be put under general anesthesia.”

However, “as noted by the authors, additional research is needed to further determine possible risks and side effects from this technique, and also to ensure that it also works in the setting of labor, rather than for an elective cesarean,” Dr. Albright added.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Albright had no financial conflicts to disclose.

Use of dural-puncture epidural (DPE) shortened the onset time to surgical anesthesia by approximately 3 minutes, compared with standard epidural in patients undergoing cesarean delivery, based on data from 140 individuals.

DPE, while not new, has become more popular as an option for initiating labor analgesia, but data comparing DPE with standard epidural in conversion to surgical anesthesia for cesarean deliveries are limited, Nadir Sharawi, MD, of the University of Arkansas for Medical Sciences, Little Rock, and colleagues wrote.

courtesy University of Arkansas for Medical Sciences

DPE involves no injection of intrathecal drugs, and the potential advantages include easier translocation of epidural medications into the intrathecal space for improved analgesia, but the effects of DPE on the onset and reliability of surgical anesthesia remain unknown, they said.

In a study published in JAMA Network Open, the researchers randomized 70 women scheduled for cesarean delivery of singleton pregnancies to DPE and 70 to a standard epidural. The participants were aged 18 years and older, with a mean age of the 30.1 years; the study was conducted between April 2019 and October 2022 at a single center.

The primary outcome was the time to the loss of sharp sensation at T6, defined as “the start of epidural extension anesthesia (time zero on the stopwatch) to when the patient could no longer feel sharp sensation at T6 (assessed bilaterally at the midclavicular line),” the researchers wrote.

The onset time to surgical anesthesia was faster in the DPE group, compared with the standard group, with a median of 422 seconds versus 655 seconds.

A key secondary outcome was a composite measure of the quality of epidural anesthesia that included failure to achieve a T10 bilateral block preoperatively in the delivery room, failure to achieve a surgical block at T6 within 15 minutes of chloroprocaine administration, requirement for intraoperative analgesia, repeat neuraxial procedure, and conversion to general anesthesia. The composite rates of lower quality anesthesia were significantly less in the DPE group, compared with the standard group (15.7% vs. 36.3%; P = .007).

Additional secondary outcomes included maternal satisfaction and pain score during surgery, adverse events, opioid use in the first 24 hours, maternal vasopressor requirements, epidural block assessments, and neonatal outcomes. No significant differences in these outcomes were noted between the groups, and no instances of local anesthetic systemic toxicity or neurological complications were reported.

The findings were limited by several factors including the study population of women scheduled for cesarean delivery and not in labor, and the inability to detect less frequent complications such as post–dural-puncture headache and accidental dural puncture, the researchers noted.

In addition, the results may vary with the use of other combinations of local anesthetics and opioids. “Chloroprocaine was chosen in this study because of its ease of administration without the need for opioids and other additives along with the low risk of systemic toxic effects, which favors rapid administration for emergent cesarean delivery,” they wrote.

However, the results show an association between DPE within an hour of epidural extension for elective cesarean delivery and a faster onset of anesthesia, improved block quality, and a more favorable ratio of risks versus benefits, compared with the use of standard epidural, the researchers concluded.
 

No need for general anesthesia?

“There is controversy over whether the dural puncture epidural technique improves labor analgesia when compared to a standard epidural,” Dr. Shawari said in an interview. “However, there are limited data on whether the dural puncture epidural technique decreases the onset time to surgical anesthesia when compared to a standard epidural for cesarean delivery. This is important as a pre-existing epidural is commonly used to convert labor analgesia to surgical anesthesia in the setting of urgent cesarean delivery. A faster onset of epidural anesthesia could potentially avoid the need for general anesthesia in an emergency.”

The researchers were not surprised by the findings given their experience with performing dural puncture epidurals for labor analgesia, Dr. Shawari said. In those cases, DPE provided a faster onset when converting cesarean anesthesia, compared with a standard epidural.

The takeaway from the current study is that DPE also provided “a faster onset and improved quality of anesthesia when compared to standard epidural for elective cesarean delivery,” Dr. Shawari said. However, additional research is needed to confirm the findings for intrapartum cesarean delivery.
 

Progress in improving pain control

“Adequate pain control during cesarean delivery is incredibly important,” Catherine Albright, MD, a maternal-fetal medicine specialist at the University of Washington, Seattle, said in an interview. “Inadequate pain control leads to the need to provide additional intravenous medications or the need to be put under general anesthesia, which changes the birth experience and is more dangerous for the birthing person and the neonate.

courtesy University of Washington

“In my clinical experience, there are many times when patients do not have adequate pain control during a cesarean delivery,” said Dr. Albright, who was not involved in the current study. “I am pleased to see that there is research underway about how to best manage pain on labor and delivery, especially in the setting of conversion from labor anesthesia to cesarean anesthesia.”

The findings may have implications for clinical practice, said Dr. Albright. If the dural puncture epidural can improve cesarean anesthesia following an epidural during labor, rather than anesthesia provided for an elective cesarean), “then I believe it would reduce the number of patients who require additional pain medication, have a poor cesarean experience, and/or need to be put under general anesthesia.”

However, “as noted by the authors, additional research is needed to further determine possible risks and side effects from this technique, and also to ensure that it also works in the setting of labor, rather than for an elective cesarean,” Dr. Albright added.

The study received no outside funding. The researchers had no financial conflicts to disclose. Dr. Albright had no financial conflicts to disclose.

The annual probability of a person with overweight or obesity losing at least 5% of their body weight is about 1 in 10, while weight loss to a healthy category is even less common, new research finds.

On the brighter side, those with higher body mass index (BMI) had greater odds of losing at least 5% of body weight than those with lower BMI, and women were more likely to do so than men. The chances of achieving a healthy weight category – defined as BMI of 18.5-24.9 kg/m² – was less likely than losing 5% in all groups, however.

Even a modest 5% weight loss at any BMI has been associated with improved health measures, including lower systolic and diastolic blood pressure, lower fasting glucose level, lower hemoglobin A1c level, and higher HDL cholesterol level, write Lyudmyla Kompaniyets, PhD, of the National Center for Chronic Disease Prevention and Health Promotion, Atlanta, and colleagues.

The data from more than 18 million U.S. adults from a nationwide ambulatory electronic medical record database, called IQVIA, suggest that “clinicians and public health efforts can focus on messaging and referrals to interventions that support individuals with excess weight in achieving and sustaining meaningful weight loss, i.e., ≥ 5% for adults at any level of excess weight,” the authors say.

The study population was health care–seeking but not necessarily for weight loss, and their intent to lose weight was unknown. “Several studies suggest that persons who are trying to lose weight may experience greater reductions in weight,” the researchers point out in their article, which was published in JAMA Network Open.

At the initial visit, 72.5% of the participants were categorized as having either overweight (BMI, 25.0-29.9kg/m²) or obesity (BMI, ≥ 30.0 kg/m²). The median age of the patients was 54 years. A little over half (56.7%) were women, 72.3% were White, and 7.7% were Black.

During a maximum follow-up period of 14 years, the proportion with 5% or greater weight loss was 33.4% of those with initial overweight and 41.8% with initial obesity. The proportion achieving healthy weight (BMI, 18.5-24.9 kg/m²) was just 23.2% and 2.0%, respectively.

For the combined overweight/obesity groups, the adjusted annual probability of 5% or greater weight loss was 1 in 10, increasing with BMI category from 1 in 12 for those with initial overweight to 1 in 6 for those with initial BMI of 45 kg/m² or higher. The annual probability was slightly lower among Black than White women (1 in 9 vs. 1 in 8, respectively).

In contrast, the adjusted annual probability of reducing BMI to the healthy category ranged from 1 in 19 with initial overweight to 1 in 1,667 with initial BMI of 45 kg/m² or higher. This probability was higher among women than men and was highest among White women.

“These findings could, in part, be explained by barriers in availability of and access to obesity management options, including lifestyle interventions and pharmacotherapy. There is a continual need for policies and strategies that ensure community access to nutrition and physical activity opportunities,” Dr. Kompaniyets and colleague write.

Moreover, they say, “understanding patterns of weight loss could help support populations, including Hispanic or Latino and non-Hispanic Black individuals, who are disproportionately affected by obesity due to factors such as structural racism and race and ethnicity-based social and economic disadvantages.”

The authors have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

The annual probability of a person with overweight or obesity losing at least 5% of their body weight is about 1 in 10, while weight loss to a healthy category is even less common, new research finds.

On the brighter side, those with higher body mass index (BMI) had greater odds of losing at least 5% of body weight than those with lower BMI, and women were more likely to do so than men. The chances of achieving a healthy weight category – defined as BMI of 18.5-24.9 kg/m² – was less likely than losing 5% in all groups, however.

Even a modest 5% weight loss at any BMI has been associated with improved health measures, including lower systolic and diastolic blood pressure, lower fasting glucose level, lower hemoglobin A1c level, and higher HDL cholesterol level, write Lyudmyla Kompaniyets, PhD, of the National Center for Chronic Disease Prevention and Health Promotion, Atlanta, and colleagues.

The data from more than 18 million U.S. adults from a nationwide ambulatory electronic medical record database, called IQVIA, suggest that “clinicians and public health efforts can focus on messaging and referrals to interventions that support individuals with excess weight in achieving and sustaining meaningful weight loss, i.e., ≥ 5% for adults at any level of excess weight,” the authors say.

The study population was health care–seeking but not necessarily for weight loss, and their intent to lose weight was unknown. “Several studies suggest that persons who are trying to lose weight may experience greater reductions in weight,” the researchers point out in their article, which was published in JAMA Network Open.

At the initial visit, 72.5% of the participants were categorized as having either overweight (BMI, 25.0-29.9kg/m²) or obesity (BMI, ≥ 30.0 kg/m²). The median age of the patients was 54 years. A little over half (56.7%) were women, 72.3% were White, and 7.7% were Black.

During a maximum follow-up period of 14 years, the proportion with 5% or greater weight loss was 33.4% of those with initial overweight and 41.8% with initial obesity. The proportion achieving healthy weight (BMI, 18.5-24.9 kg/m²) was just 23.2% and 2.0%, respectively.

For the combined overweight/obesity groups, the adjusted annual probability of 5% or greater weight loss was 1 in 10, increasing with BMI category from 1 in 12 for those with initial overweight to 1 in 6 for those with initial BMI of 45 kg/m² or higher. The annual probability was slightly lower among Black than White women (1 in 9 vs. 1 in 8, respectively).

In contrast, the adjusted annual probability of reducing BMI to the healthy category ranged from 1 in 19 with initial overweight to 1 in 1,667 with initial BMI of 45 kg/m² or higher. This probability was higher among women than men and was highest among White women.

“These findings could, in part, be explained by barriers in availability of and access to obesity management options, including lifestyle interventions and pharmacotherapy. There is a continual need for policies and strategies that ensure community access to nutrition and physical activity opportunities,” Dr. Kompaniyets and colleague write.

Moreover, they say, “understanding patterns of weight loss could help support populations, including Hispanic or Latino and non-Hispanic Black individuals, who are disproportionately affected by obesity due to factors such as structural racism and race and ethnicity-based social and economic disadvantages.”

The authors have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

The annual probability of a person with overweight or obesity losing at least 5% of their body weight is about 1 in 10, while weight loss to a healthy category is even less common, new research finds.

On the brighter side, those with higher body mass index (BMI) had greater odds of losing at least 5% of body weight than those with lower BMI, and women were more likely to do so than men. The chances of achieving a healthy weight category – defined as BMI of 18.5-24.9 kg/m² – was less likely than losing 5% in all groups, however.

Even a modest 5% weight loss at any BMI has been associated with improved health measures, including lower systolic and diastolic blood pressure, lower fasting glucose level, lower hemoglobin A1c level, and higher HDL cholesterol level, write Lyudmyla Kompaniyets, PhD, of the National Center for Chronic Disease Prevention and Health Promotion, Atlanta, and colleagues.

The data from more than 18 million U.S. adults from a nationwide ambulatory electronic medical record database, called IQVIA, suggest that “clinicians and public health efforts can focus on messaging and referrals to interventions that support individuals with excess weight in achieving and sustaining meaningful weight loss, i.e., ≥ 5% for adults at any level of excess weight,” the authors say.

The study population was health care–seeking but not necessarily for weight loss, and their intent to lose weight was unknown. “Several studies suggest that persons who are trying to lose weight may experience greater reductions in weight,” the researchers point out in their article, which was published in JAMA Network Open.

At the initial visit, 72.5% of the participants were categorized as having either overweight (BMI, 25.0-29.9kg/m²) or obesity (BMI, ≥ 30.0 kg/m²). The median age of the patients was 54 years. A little over half (56.7%) were women, 72.3% were White, and 7.7% were Black.

During a maximum follow-up period of 14 years, the proportion with 5% or greater weight loss was 33.4% of those with initial overweight and 41.8% with initial obesity. The proportion achieving healthy weight (BMI, 18.5-24.9 kg/m²) was just 23.2% and 2.0%, respectively.

For the combined overweight/obesity groups, the adjusted annual probability of 5% or greater weight loss was 1 in 10, increasing with BMI category from 1 in 12 for those with initial overweight to 1 in 6 for those with initial BMI of 45 kg/m² or higher. The annual probability was slightly lower among Black than White women (1 in 9 vs. 1 in 8, respectively).

In contrast, the adjusted annual probability of reducing BMI to the healthy category ranged from 1 in 19 with initial overweight to 1 in 1,667 with initial BMI of 45 kg/m² or higher. This probability was higher among women than men and was highest among White women.

“These findings could, in part, be explained by barriers in availability of and access to obesity management options, including lifestyle interventions and pharmacotherapy. There is a continual need for policies and strategies that ensure community access to nutrition and physical activity opportunities,” Dr. Kompaniyets and colleague write.

Moreover, they say, “understanding patterns of weight loss could help support populations, including Hispanic or Latino and non-Hispanic Black individuals, who are disproportionately affected by obesity due to factors such as structural racism and race and ethnicity-based social and economic disadvantages.”

The authors have disclosed no relevant financial relationships.

A version of this article 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

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

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

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 latest results from the IKEMA trial, which pitted isatuximab (Sarclisa) against placebo on a background of carfilzomib and dexamethasone for relapsed/refractory multiple myeloma (MM), confirm the benefits seen in an earlier, interim analysis that won isatuximab Food and Drug Administration approval for the indication in March 2021.

Median follow up was 44 months in the new update, about 2 additional years past the earlier report.

As in the earlier analysis, adding the anti-CD38 antibody to carfilzomib and dexamethasone brought substantial benefits, including a median progression free survival (PFS) of 35.7 months versus 19.2 months with placebo, as well as a higher rates of complete response (CR, 44.1% vs. 28.5%), minimal residual disease (MRD) negativity (33.5% vs. 15.4%), and MRD negativity CR (26.3% vs. 12.2%).

Although overall survival data are not yet mature, the probability of being alive at 42 months was 66.3% with isatuximab add-on versus 54.5% with placebo.

Investigators led by Thomas G. Martin, MD, director of the University of California, San Francisco, myeloma program, noted that median PFS of nearly 3 years “is the longest PFS reported to date with a PI-based regimen in the relapsed MM [multiple myeloma] setting.” The updated results further support the combination “as a standard of care treatment for patients with relapsed MM.”

Overall, the trial adds “another effective triplet in the treatment of patients with” relapsed/refractory MM, Sergio A. Giralt, MD, head of the division of hematologic malignancies at Memorial Sloan Kettering Cancer Center, New York, said when asked for comment. The study was published May 9 in Blood Cancer Journal.
 

Safety similar to interim analysis

IKEMA randomized 179 patients to isatuximab add-on and 123 to placebo. Patients had relapsed/refractory MM with one to three prior treatment lines. Isatuximab was dosed at10 mg/kg IV in the open-label trial, weekly in the first cycle then biweekly.

The PFS benefit held across various subgroups, including the elderly and others with poor prognoses.

In their write-up, the investigators acknowledged isatuximab’s rival anti-CD38 antibody, daratumumab (Darzalex), which is also approved in the United States for use in combination with carfilzomib and dexamethasone for relapsed/refractory MM after one to three treatment lines.

“Although inter-trial evaluations should be interpreted with caution,” they noted that PFS in the latest analysis of daratumumab’s CANDOR trial in combination with carfilzomib and dexamethasone was shorter than in IKEMA, 28.6 months versus 15.2 months with placebo.

Like efficacy, safety in latest update of IKEMA was similar to that of the interim analysis. However, while there was no difference in the incidence of all-cause serious treatment-emergent adverse events (TEAEs) in the earlier report, the incidence was higher with isatuximab than placebo in the newest findings (70.1% vs. 59.8%).

The investigators said the difference was likely because patients in the isatuximab arm stayed on treatment longer, a median of 94 weeks versus 61.9 weeks in the placebo arm, making adverse events more likely.

The most common, nonhematologic TEAEs were infusion reactions (45.8% in the isatuximab arm vs. 3.3% in the placebo group), diarrhea (39.5% vs. 32%), hypertension (37.9% vs 35.2%), upper respiratory tract infection (37.3% vs 27%), and fatigue (31.6% vs 20.5%).

Grade 3 or higher pneumonia occurred in 18.6% patients in the isatuximab arm versus 12.3% in the placebo group. The incidence of skin cancer was 6.2% with isatuximab versus 3.3%. The incidence of treatment-emergent fatal events remained similar between study arms, 5.6% with isatuximab versus 4.9% with placebo.

The study was funded by Sanofi, maker of isatuximab. Investigators included two Sanofi employees. Others reported a range of ties to the company, including Dr. Martin, who reported research funding and sitting on a Sanofi steering committee.

The latest results from the IKEMA trial, which pitted isatuximab (Sarclisa) against placebo on a background of carfilzomib and dexamethasone for relapsed/refractory multiple myeloma (MM), confirm the benefits seen in an earlier, interim analysis that won isatuximab Food and Drug Administration approval for the indication in March 2021.

Median follow up was 44 months in the new update, about 2 additional years past the earlier report.

As in the earlier analysis, adding the anti-CD38 antibody to carfilzomib and dexamethasone brought substantial benefits, including a median progression free survival (PFS) of 35.7 months versus 19.2 months with placebo, as well as a higher rates of complete response (CR, 44.1% vs. 28.5%), minimal residual disease (MRD) negativity (33.5% vs. 15.4%), and MRD negativity CR (26.3% vs. 12.2%).

Although overall survival data are not yet mature, the probability of being alive at 42 months was 66.3% with isatuximab add-on versus 54.5% with placebo.

Investigators led by Thomas G. Martin, MD, director of the University of California, San Francisco, myeloma program, noted that median PFS of nearly 3 years “is the longest PFS reported to date with a PI-based regimen in the relapsed MM [multiple myeloma] setting.” The updated results further support the combination “as a standard of care treatment for patients with relapsed MM.”

Overall, the trial adds “another effective triplet in the treatment of patients with” relapsed/refractory MM, Sergio A. Giralt, MD, head of the division of hematologic malignancies at Memorial Sloan Kettering Cancer Center, New York, said when asked for comment. The study was published May 9 in Blood Cancer Journal.
 

Safety similar to interim analysis

IKEMA randomized 179 patients to isatuximab add-on and 123 to placebo. Patients had relapsed/refractory MM with one to three prior treatment lines. Isatuximab was dosed at10 mg/kg IV in the open-label trial, weekly in the first cycle then biweekly.

The PFS benefit held across various subgroups, including the elderly and others with poor prognoses.

In their write-up, the investigators acknowledged isatuximab’s rival anti-CD38 antibody, daratumumab (Darzalex), which is also approved in the United States for use in combination with carfilzomib and dexamethasone for relapsed/refractory MM after one to three treatment lines.

“Although inter-trial evaluations should be interpreted with caution,” they noted that PFS in the latest analysis of daratumumab’s CANDOR trial in combination with carfilzomib and dexamethasone was shorter than in IKEMA, 28.6 months versus 15.2 months with placebo.

Like efficacy, safety in latest update of IKEMA was similar to that of the interim analysis. However, while there was no difference in the incidence of all-cause serious treatment-emergent adverse events (TEAEs) in the earlier report, the incidence was higher with isatuximab than placebo in the newest findings (70.1% vs. 59.8%).

The investigators said the difference was likely because patients in the isatuximab arm stayed on treatment longer, a median of 94 weeks versus 61.9 weeks in the placebo arm, making adverse events more likely.

The most common, nonhematologic TEAEs were infusion reactions (45.8% in the isatuximab arm vs. 3.3% in the placebo group), diarrhea (39.5% vs. 32%), hypertension (37.9% vs 35.2%), upper respiratory tract infection (37.3% vs 27%), and fatigue (31.6% vs 20.5%).

Grade 3 or higher pneumonia occurred in 18.6% patients in the isatuximab arm versus 12.3% in the placebo group. The incidence of skin cancer was 6.2% with isatuximab versus 3.3%. The incidence of treatment-emergent fatal events remained similar between study arms, 5.6% with isatuximab versus 4.9% with placebo.

The study was funded by Sanofi, maker of isatuximab. Investigators included two Sanofi employees. Others reported a range of ties to the company, including Dr. Martin, who reported research funding and sitting on a Sanofi steering committee.

The latest results from the IKEMA trial, which pitted isatuximab (Sarclisa) against placebo on a background of carfilzomib and dexamethasone for relapsed/refractory multiple myeloma (MM), confirm the benefits seen in an earlier, interim analysis that won isatuximab Food and Drug Administration approval for the indication in March 2021.

Median follow up was 44 months in the new update, about 2 additional years past the earlier report.

As in the earlier analysis, adding the anti-CD38 antibody to carfilzomib and dexamethasone brought substantial benefits, including a median progression free survival (PFS) of 35.7 months versus 19.2 months with placebo, as well as a higher rates of complete response (CR, 44.1% vs. 28.5%), minimal residual disease (MRD) negativity (33.5% vs. 15.4%), and MRD negativity CR (26.3% vs. 12.2%).

Although overall survival data are not yet mature, the probability of being alive at 42 months was 66.3% with isatuximab add-on versus 54.5% with placebo.

Investigators led by Thomas G. Martin, MD, director of the University of California, San Francisco, myeloma program, noted that median PFS of nearly 3 years “is the longest PFS reported to date with a PI-based regimen in the relapsed MM [multiple myeloma] setting.” The updated results further support the combination “as a standard of care treatment for patients with relapsed MM.”

Overall, the trial adds “another effective triplet in the treatment of patients with” relapsed/refractory MM, Sergio A. Giralt, MD, head of the division of hematologic malignancies at Memorial Sloan Kettering Cancer Center, New York, said when asked for comment. The study was published May 9 in Blood Cancer Journal.
 

Safety similar to interim analysis

IKEMA randomized 179 patients to isatuximab add-on and 123 to placebo. Patients had relapsed/refractory MM with one to three prior treatment lines. Isatuximab was dosed at10 mg/kg IV in the open-label trial, weekly in the first cycle then biweekly.

The PFS benefit held across various subgroups, including the elderly and others with poor prognoses.

In their write-up, the investigators acknowledged isatuximab’s rival anti-CD38 antibody, daratumumab (Darzalex), which is also approved in the United States for use in combination with carfilzomib and dexamethasone for relapsed/refractory MM after one to three treatment lines.

“Although inter-trial evaluations should be interpreted with caution,” they noted that PFS in the latest analysis of daratumumab’s CANDOR trial in combination with carfilzomib and dexamethasone was shorter than in IKEMA, 28.6 months versus 15.2 months with placebo.

Like efficacy, safety in latest update of IKEMA was similar to that of the interim analysis. However, while there was no difference in the incidence of all-cause serious treatment-emergent adverse events (TEAEs) in the earlier report, the incidence was higher with isatuximab than placebo in the newest findings (70.1% vs. 59.8%).

The investigators said the difference was likely because patients in the isatuximab arm stayed on treatment longer, a median of 94 weeks versus 61.9 weeks in the placebo arm, making adverse events more likely.

The most common, nonhematologic TEAEs were infusion reactions (45.8% in the isatuximab arm vs. 3.3% in the placebo group), diarrhea (39.5% vs. 32%), hypertension (37.9% vs 35.2%), upper respiratory tract infection (37.3% vs 27%), and fatigue (31.6% vs 20.5%).

Grade 3 or higher pneumonia occurred in 18.6% patients in the isatuximab arm versus 12.3% in the placebo group. The incidence of skin cancer was 6.2% with isatuximab versus 3.3%. The incidence of treatment-emergent fatal events remained similar between study arms, 5.6% with isatuximab versus 4.9% with placebo.

The study was funded by Sanofi, maker of isatuximab. Investigators included two Sanofi employees. Others reported a range of ties to the company, including Dr. Martin, who reported research funding and sitting on a Sanofi steering committee.

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

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

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

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.

Cultures for bacteria, varicella zoster virus, herpes simplex virus, and mpox virus were all negative. A biopsy revealed suprabasilar acantholysis with follicular involvement in association with blister formation and inflammation. Direct immunofluorescence was positive for suprabasilar IgG and C₃ deposition, consistent with pemphigus vulgaris (PV).

PV is an autoimmune bullous disease in which antibodies are directed against desmoglein 1 and 3 and less commonly, plakoglobin. There is likely a genetic predisposition. Medications that may induce pemphigus include penicillamine, nifedipine, or captopril.

Clinically, flaccid blistering lesions are present that may be cutaneous and/or mucosal. Bullae can progress to erosions and crusting, which then heal with pigment alteration but not scarring. The most commonly affected sites are the mouth, intertriginous areas, face, and neck. Mucosal lesions may involve the lips, esophagus, conjunctiva, and genitals.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

Cultures for bacteria, varicella zoster virus, herpes simplex virus, and mpox virus were all negative. A biopsy revealed suprabasilar acantholysis with follicular involvement in association with blister formation and inflammation. Direct immunofluorescence was positive for suprabasilar IgG and C₃ deposition, consistent with pemphigus vulgaris (PV).

PV is an autoimmune bullous disease in which antibodies are directed against desmoglein 1 and 3 and less commonly, plakoglobin. There is likely a genetic predisposition. Medications that may induce pemphigus include penicillamine, nifedipine, or captopril.

Clinically, flaccid blistering lesions are present that may be cutaneous and/or mucosal. Bullae can progress to erosions and crusting, which then heal with pigment alteration but not scarring. The most commonly affected sites are the mouth, intertriginous areas, face, and neck. Mucosal lesions may involve the lips, esophagus, conjunctiva, and genitals.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

Cultures for bacteria, varicella zoster virus, herpes simplex virus, and mpox virus were all negative. A biopsy revealed suprabasilar acantholysis with follicular involvement in association with blister formation and inflammation. Direct immunofluorescence was positive for suprabasilar IgG and C₃ deposition, consistent with pemphigus vulgaris (PV).

PV is an autoimmune bullous disease in which antibodies are directed against desmoglein 1 and 3 and less commonly, plakoglobin. There is likely a genetic predisposition. Medications that may induce pemphigus include penicillamine, nifedipine, or captopril.

Clinically, flaccid blistering lesions are present that may be cutaneous and/or mucosal. Bullae can progress to erosions and crusting, which then heal with pigment alteration but not scarring. The most commonly affected sites are the mouth, intertriginous areas, face, and neck. Mucosal lesions may involve the lips, esophagus, conjunctiva, and genitals.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].