One in three Black men in rural America experienced suicidal or death ideation (SDI) in the past week, new research showed.

A developmental model used in the study showed a direct association between experiences pertaining to threat, deprivation, and racial discrimination during childhood and suicide risk in adulthood, suggesting that a broad range of adverse experiences in early life may affect SDI risk among Black men.

“During the past 20-30 years, young Black men have evinced increasing levels of suicidal behavior and related cognitions,” lead author Steven Kogan, PhD, professor of family and consumer sciences at the University of Georgia, Athens, Georgia, and colleagues wrote.

“By controlling for depressive symptoms in assessing increases in SDI over time, our study’s design directly informed the extent to which social adversities affect SDI independent of other depressive problems,” they added.

The findings were published online in Cultural Diversity and Ethnic Minority Psychology.
 

Second Leading Cause of Death

Suicide is the second leading cause of death for Black Americans ages 15-24, according to the Centers for Disease Control and Prevention. The outlook is worse for Black men, whose death rate from suicide is about four times greater than for Black women.

Previous research suggests Black men are disproportionately exposed to social adversity, including poverty and discrimination, which may increase the risk for SDI. In addition, racial discrimination has been shown to increase the risks for depression, anxiety, and psychological distress among Black youth and adults.

But little research exists to better understand how these negative experiences affect vulnerability to SDI. The new study tested a model linking adversity during childhood and emerging exposure to racial discrimination to increases in suicidal thoughts.

Researchers analyzed data from 504 participants in the African American Men’s Project, which included a series of surveys completed by young men in rural Georgia at three different time points over a period of about 3 years.

Composite scores for childhood threat and deprivation were developed using the Adverse Childhood Experiences Scale and Childhood Trauma Questionnaire. Everyday discrimination was measured on the Schedule of Racist Events response scale.

To assess their experience with childhood threats, the men in the study, who were about 21 years old on average when they enrolled, were asked if they experienced a series of adverse childhood experiences and deprivation through age 16. Questions explored issues such as directly experiencing physical violence or witnessing abuse in the home and whether the men felt loved and “important or special” as children.

The investigators also asked the men about their experiences of racial discrimination, the quality of their relationships, their belief that aggression is a means of gaining respect, and their cynicism regarding romantic relationships.
 

Targeted Prevention

Overall, 33.6% of participants reported SDI in the previous week. A history of childhood threats and deprivation was associated with an increased likelihood of SDI (P < .001).

Researchers also found that a history of racial discrimination was significantly associated with the development of negative relational schemas, which are characterized by beliefs that other people are untrustworthy, uncaring, and/or hostile. Negative schemas were in turn associated with an increased risk for suicidal thoughts (P = .03).

“Clinical and preventive interventions for suicidality should target the influence of racism and adverse experiences and the negative relational schemas they induce,” the investigators noted.

“Policy efforts designed to dismantle systemic racism are critically needed. Interventions that address SDI, including programming designed to support Black men through their experiences with racial discrimination and processing of childhood experiences of adversity, may help young Black men resist the psychological impacts of racism, expand their positive support networks, and decrease their risk of SDI,” they added.

The study authors reported no funding sources or relevant financial relationships.

A version of this article appeared on Medscape.com.

One in three Black men in rural America experienced suicidal or death ideation (SDI) in the past week, new research showed.

A developmental model used in the study showed a direct association between experiences pertaining to threat, deprivation, and racial discrimination during childhood and suicide risk in adulthood, suggesting that a broad range of adverse experiences in early life may affect SDI risk among Black men.

“During the past 20-30 years, young Black men have evinced increasing levels of suicidal behavior and related cognitions,” lead author Steven Kogan, PhD, professor of family and consumer sciences at the University of Georgia, Athens, Georgia, and colleagues wrote.

“By controlling for depressive symptoms in assessing increases in SDI over time, our study’s design directly informed the extent to which social adversities affect SDI independent of other depressive problems,” they added.

The findings were published online in Cultural Diversity and Ethnic Minority Psychology.
 

Second Leading Cause of Death

Suicide is the second leading cause of death for Black Americans ages 15-24, according to the Centers for Disease Control and Prevention. The outlook is worse for Black men, whose death rate from suicide is about four times greater than for Black women.

Previous research suggests Black men are disproportionately exposed to social adversity, including poverty and discrimination, which may increase the risk for SDI. In addition, racial discrimination has been shown to increase the risks for depression, anxiety, and psychological distress among Black youth and adults.

But little research exists to better understand how these negative experiences affect vulnerability to SDI. The new study tested a model linking adversity during childhood and emerging exposure to racial discrimination to increases in suicidal thoughts.

Researchers analyzed data from 504 participants in the African American Men’s Project, which included a series of surveys completed by young men in rural Georgia at three different time points over a period of about 3 years.

Composite scores for childhood threat and deprivation were developed using the Adverse Childhood Experiences Scale and Childhood Trauma Questionnaire. Everyday discrimination was measured on the Schedule of Racist Events response scale.

To assess their experience with childhood threats, the men in the study, who were about 21 years old on average when they enrolled, were asked if they experienced a series of adverse childhood experiences and deprivation through age 16. Questions explored issues such as directly experiencing physical violence or witnessing abuse in the home and whether the men felt loved and “important or special” as children.

The investigators also asked the men about their experiences of racial discrimination, the quality of their relationships, their belief that aggression is a means of gaining respect, and their cynicism regarding romantic relationships.
 

Targeted Prevention

Overall, 33.6% of participants reported SDI in the previous week. A history of childhood threats and deprivation was associated with an increased likelihood of SDI (P < .001).

Researchers also found that a history of racial discrimination was significantly associated with the development of negative relational schemas, which are characterized by beliefs that other people are untrustworthy, uncaring, and/or hostile. Negative schemas were in turn associated with an increased risk for suicidal thoughts (P = .03).

“Clinical and preventive interventions for suicidality should target the influence of racism and adverse experiences and the negative relational schemas they induce,” the investigators noted.

“Policy efforts designed to dismantle systemic racism are critically needed. Interventions that address SDI, including programming designed to support Black men through their experiences with racial discrimination and processing of childhood experiences of adversity, may help young Black men resist the psychological impacts of racism, expand their positive support networks, and decrease their risk of SDI,” they added.

The study authors reported no funding sources or relevant financial relationships.

A version of this article appeared on Medscape.com.

One in three Black men in rural America experienced suicidal or death ideation (SDI) in the past week, new research showed.

A developmental model used in the study showed a direct association between experiences pertaining to threat, deprivation, and racial discrimination during childhood and suicide risk in adulthood, suggesting that a broad range of adverse experiences in early life may affect SDI risk among Black men.

“During the past 20-30 years, young Black men have evinced increasing levels of suicidal behavior and related cognitions,” lead author Steven Kogan, PhD, professor of family and consumer sciences at the University of Georgia, Athens, Georgia, and colleagues wrote.

“By controlling for depressive symptoms in assessing increases in SDI over time, our study’s design directly informed the extent to which social adversities affect SDI independent of other depressive problems,” they added.

The findings were published online in Cultural Diversity and Ethnic Minority Psychology.
 

Second Leading Cause of Death

Suicide is the second leading cause of death for Black Americans ages 15-24, according to the Centers for Disease Control and Prevention. The outlook is worse for Black men, whose death rate from suicide is about four times greater than for Black women.

Previous research suggests Black men are disproportionately exposed to social adversity, including poverty and discrimination, which may increase the risk for SDI. In addition, racial discrimination has been shown to increase the risks for depression, anxiety, and psychological distress among Black youth and adults.

But little research exists to better understand how these negative experiences affect vulnerability to SDI. The new study tested a model linking adversity during childhood and emerging exposure to racial discrimination to increases in suicidal thoughts.

Researchers analyzed data from 504 participants in the African American Men’s Project, which included a series of surveys completed by young men in rural Georgia at three different time points over a period of about 3 years.

Composite scores for childhood threat and deprivation were developed using the Adverse Childhood Experiences Scale and Childhood Trauma Questionnaire. Everyday discrimination was measured on the Schedule of Racist Events response scale.

To assess their experience with childhood threats, the men in the study, who were about 21 years old on average when they enrolled, were asked if they experienced a series of adverse childhood experiences and deprivation through age 16. Questions explored issues such as directly experiencing physical violence or witnessing abuse in the home and whether the men felt loved and “important or special” as children.

The investigators also asked the men about their experiences of racial discrimination, the quality of their relationships, their belief that aggression is a means of gaining respect, and their cynicism regarding romantic relationships.
 

Targeted Prevention

Overall, 33.6% of participants reported SDI in the previous week. A history of childhood threats and deprivation was associated with an increased likelihood of SDI (P < .001).

Researchers also found that a history of racial discrimination was significantly associated with the development of negative relational schemas, which are characterized by beliefs that other people are untrustworthy, uncaring, and/or hostile. Negative schemas were in turn associated with an increased risk for suicidal thoughts (P = .03).

“Clinical and preventive interventions for suicidality should target the influence of racism and adverse experiences and the negative relational schemas they induce,” the investigators noted.

“Policy efforts designed to dismantle systemic racism are critically needed. Interventions that address SDI, including programming designed to support Black men through their experiences with racial discrimination and processing of childhood experiences of adversity, may help young Black men resist the psychological impacts of racism, expand their positive support networks, and decrease their risk of SDI,” they added.

The study authors reported no funding sources or relevant financial relationships.

A version of this article appeared on Medscape.com.

High levels of tumor-infiltrating lymphocytes predicted increased survival in patients with early-stage triple-negative breast cancer who did not receive chemotherapy, a new analysis finds.

The association of abundant tumor-infiltrating lymphocytes (TILs) in breast cancer tissue with outcomes in patients with early-stage triple-negative breast cancer (TNBC) who do not receive chemotherapy has not been well studied, wrote Roberto A. Leon-Ferre, MD, of the Mayo Clinic, Rochester, Minnesota, and colleagues, in JAMA.

Biomarkers to guide systemic treatment and avoid overtreatment are lacking, and such markers could help identify patients who could achieve increased survival with less intensive therapy, continued the authors of the new study of nearly 2000 individuals.

“TNBC is the most aggressive subtype of breast cancer, and for this reason, current treatment guidelines recommend chemotherapy using multiple drugs either before or after surgery,” Dr. Leon-Ferre said in an interview. “We have learned over the last several years that TNBC is not a single disease, but that there are several subtypes of TNBC that have different risks and different vulnerabilities, and treating all patients similarly may not be optimal.”

  

What is Known About Tumor-Infiltrating Lymphocytes and Cancer?

Previous studies have shown improved survival in patients with early-stage TNBC and high levels of TILs who were treated with adjuvant and neoadjuvant chemotherapy, compared with those with lower TILs. In a pooled analysis of 2148 patients from nine studies published in the Journal of Clinical Oncology in 2019, a higher percentage of TILs in the stroma surrounding a tumor was significantly associated with improved survival in TNBC patients after adjuvant chemotherapy.

Another study published in the Journal of Clinical Oncology in 2022 showed that elevated TILs were significant predictors of overall survival, but the study included fewer than 500 patients.

The potential mechanisms that drive the association between elevated TILs and improved survival include the ability of TILs to attack cancer cells, Dr. Leon-Ferre said in an interview. 

The goal of this study was to evaluate whether TILs could identify a subset of patients with TNBC who had a very low risk of cancer recurrence even if chemotherapy was not given.

“Indeed, we found that patients with stage I TNBC and high TILs had a very low risk of recurrence even when chemotherapy was not administered. These findings will pave the way for future studies aiming to reduce the need for multiple chemotherapy drugs in patients with stage I TNBC and decrease the side effects that patients face,” he said.

 

What Does the New Study Add?

The current study included 1966 individuals from 13 sites in North America, Europe, and Asia who were diagnosed with TNBC between 1979 and 2017 and were treated with surgery, with or without radiotherapy but with no adjuvant or neoadjuvant chemotherapy. The researchers examined the abundance of TILs in the breast tissue of resected primary tumors; the primary outcome was invasive disease-free survival (iDFS), with recurrence-free survival, distant recurrence-free survival, and overall survival as secondary outcomes.

The median age of the patients was 56 years, 55% had stage I TNBC, and the median TIL level was 15%.

A total of 417 patients had a TIL level of 50% or more, and the 5-year iDFS for these patients was 94%, compared with 78% for those with a TIL level less than 30%. Similarly, 5-year overall survival was 95% in patients with a TIL level of 50% or more, compared with 82% for patients with TIL levels of less than 30%.

Additionally, each 10% increase in TILs was independently associated not only with improved iDFS (hazard ratio[HR], 0.92), but also improved recurrence-free survival (HR, 0.90), distant recurrence-free survival (HR, 0.87), and overall survival (HR, 0.88) over a median follow-up of 18 years.

The current study shows that cancer stage based on tumor size and the number of lymph nodes should not be the only considerations for making treatment decisions and predicting outcomes, Dr. Leon-Ferre said in an interview.

“In fact, our study shows that for tumors of the same stage (particularly for stage I), the risk of recurrence is different depending on the number of TILs seen in the breast cancer tissue. When chemo is not given, those with high TILs have lower risk of recurrence, whereas those with low TILs have a higher risk of recurrence,” he said.
 

What are the Limitations of This Research?

The current study findings are limited by the retrospective design and use of observational data, so the researchers could not make conclusions about causality. Other limitations included lack of data on germline mutations and race or ethnicity, and the potential irrelevance of data from patients treated as long as 45 years ago.

“Because most patients with TNBC receive chemotherapy in the modern times, we needed to work with 13 hospitals around the world to find data on patients with TNBC who never received chemotherapy for various reasons,” Dr. Leon-Ferre said.

To address these limitations, Dr. Leone-Ferre and his colleagues are planning prospective studies where TILs will be used to make treatment decisions.

“Many of the patients in our cohort were treated many years ago, when chemotherapy was not routinely given. Advances in cancer detection, surgical and radiation techniques may lead to different results in patients treated today,” he added.

What Do Oncologists Need to Know?

The current study findings may provide additional information on prognosis that is important to share with patients for decision-making on the risks versus benefits of chemotherapy, Dr. Leon-Ferre said.

“Like any test, TILs should not be used in isolation to make decisions, but should be integrated with other factors including the cancer stage, the overall patient health, patient preferences, and concerns about treatment complications,” he emphasized. “The results of this study allow oncologists to offer a more refined calculation of recurrence risk if patients opt to not receive chemotherapy.”

In the current study, although younger age was associated with higher TIL levels, a finding consistent with previous studies, increased TIL, remained significantly associated with improved survival after adjusting for age, tumor size, nodal status, and histological grade.

Overall, “the findings suggest that for patients with stage I TNBC and TILs greater than 50%, chemotherapy may not be as necessary as it was previously thought,” Dr. Leon-Ferre said.

What Additional Research is Needed?

Prospective studies are needed to validate the findings, including studies in diverse populations, and additional studies may investigate whether early TBNC patients with high TIL levels could achieve high cure rates with less intensive and less toxic chemotherapy regiments than those currently recommended, the researchers wrote in their discussion.

“There are many additional research questions that we need to answer, and look forward to working on,” Dr. Leon-Ferre said, in an interview. These topics include whether TILs can be used to decide on the number of chemotherapy drugs a patient really needs and whether artificial intelligence can be used to evaluate TILs more quickly and effectively than the human eye, he said. Other research topics include identifying which particular type of TILs attack cancer cells most effectively and whether TILs could be increased in patients with low levels in order to improve their prognosis, he added.

The study was supported by the National Research Agency and General Secretariat for Investment, Clinical and Translational Science Awards, the Mayo Clinic Breast Cancer SPORE grant, the Cancer Research Society of Canada, institutional grants from the Dutch Cancer Society, The Netherlands Organization for Health Research, and several foundations. Dr. Leon-Ferre disclosed consulting honoraria to his institution for research activities from AstraZeneca, Gilead Sciences, and Lyell Immunopharma, with no personal fees outside the submitted work.

High levels of tumor-infiltrating lymphocytes predicted increased survival in patients with early-stage triple-negative breast cancer who did not receive chemotherapy, a new analysis finds.

The association of abundant tumor-infiltrating lymphocytes (TILs) in breast cancer tissue with outcomes in patients with early-stage triple-negative breast cancer (TNBC) who do not receive chemotherapy has not been well studied, wrote Roberto A. Leon-Ferre, MD, of the Mayo Clinic, Rochester, Minnesota, and colleagues, in JAMA.

Biomarkers to guide systemic treatment and avoid overtreatment are lacking, and such markers could help identify patients who could achieve increased survival with less intensive therapy, continued the authors of the new study of nearly 2000 individuals.

“TNBC is the most aggressive subtype of breast cancer, and for this reason, current treatment guidelines recommend chemotherapy using multiple drugs either before or after surgery,” Dr. Leon-Ferre said in an interview. “We have learned over the last several years that TNBC is not a single disease, but that there are several subtypes of TNBC that have different risks and different vulnerabilities, and treating all patients similarly may not be optimal.”

  

What is Known About Tumor-Infiltrating Lymphocytes and Cancer?

Previous studies have shown improved survival in patients with early-stage TNBC and high levels of TILs who were treated with adjuvant and neoadjuvant chemotherapy, compared with those with lower TILs. In a pooled analysis of 2148 patients from nine studies published in the Journal of Clinical Oncology in 2019, a higher percentage of TILs in the stroma surrounding a tumor was significantly associated with improved survival in TNBC patients after adjuvant chemotherapy.

Another study published in the Journal of Clinical Oncology in 2022 showed that elevated TILs were significant predictors of overall survival, but the study included fewer than 500 patients.

The potential mechanisms that drive the association between elevated TILs and improved survival include the ability of TILs to attack cancer cells, Dr. Leon-Ferre said in an interview. 

The goal of this study was to evaluate whether TILs could identify a subset of patients with TNBC who had a very low risk of cancer recurrence even if chemotherapy was not given.

“Indeed, we found that patients with stage I TNBC and high TILs had a very low risk of recurrence even when chemotherapy was not administered. These findings will pave the way for future studies aiming to reduce the need for multiple chemotherapy drugs in patients with stage I TNBC and decrease the side effects that patients face,” he said.

 

What Does the New Study Add?

The current study included 1966 individuals from 13 sites in North America, Europe, and Asia who were diagnosed with TNBC between 1979 and 2017 and were treated with surgery, with or without radiotherapy but with no adjuvant or neoadjuvant chemotherapy. The researchers examined the abundance of TILs in the breast tissue of resected primary tumors; the primary outcome was invasive disease-free survival (iDFS), with recurrence-free survival, distant recurrence-free survival, and overall survival as secondary outcomes.

The median age of the patients was 56 years, 55% had stage I TNBC, and the median TIL level was 15%.

A total of 417 patients had a TIL level of 50% or more, and the 5-year iDFS for these patients was 94%, compared with 78% for those with a TIL level less than 30%. Similarly, 5-year overall survival was 95% in patients with a TIL level of 50% or more, compared with 82% for patients with TIL levels of less than 30%.

Additionally, each 10% increase in TILs was independently associated not only with improved iDFS (hazard ratio[HR], 0.92), but also improved recurrence-free survival (HR, 0.90), distant recurrence-free survival (HR, 0.87), and overall survival (HR, 0.88) over a median follow-up of 18 years.

The current study shows that cancer stage based on tumor size and the number of lymph nodes should not be the only considerations for making treatment decisions and predicting outcomes, Dr. Leon-Ferre said in an interview.

“In fact, our study shows that for tumors of the same stage (particularly for stage I), the risk of recurrence is different depending on the number of TILs seen in the breast cancer tissue. When chemo is not given, those with high TILs have lower risk of recurrence, whereas those with low TILs have a higher risk of recurrence,” he said.
 

What are the Limitations of This Research?

The current study findings are limited by the retrospective design and use of observational data, so the researchers could not make conclusions about causality. Other limitations included lack of data on germline mutations and race or ethnicity, and the potential irrelevance of data from patients treated as long as 45 years ago.

“Because most patients with TNBC receive chemotherapy in the modern times, we needed to work with 13 hospitals around the world to find data on patients with TNBC who never received chemotherapy for various reasons,” Dr. Leon-Ferre said.

To address these limitations, Dr. Leone-Ferre and his colleagues are planning prospective studies where TILs will be used to make treatment decisions.

“Many of the patients in our cohort were treated many years ago, when chemotherapy was not routinely given. Advances in cancer detection, surgical and radiation techniques may lead to different results in patients treated today,” he added.

What Do Oncologists Need to Know?

The current study findings may provide additional information on prognosis that is important to share with patients for decision-making on the risks versus benefits of chemotherapy, Dr. Leon-Ferre said.

“Like any test, TILs should not be used in isolation to make decisions, but should be integrated with other factors including the cancer stage, the overall patient health, patient preferences, and concerns about treatment complications,” he emphasized. “The results of this study allow oncologists to offer a more refined calculation of recurrence risk if patients opt to not receive chemotherapy.”

In the current study, although younger age was associated with higher TIL levels, a finding consistent with previous studies, increased TIL, remained significantly associated with improved survival after adjusting for age, tumor size, nodal status, and histological grade.

Overall, “the findings suggest that for patients with stage I TNBC and TILs greater than 50%, chemotherapy may not be as necessary as it was previously thought,” Dr. Leon-Ferre said.

What Additional Research is Needed?

Prospective studies are needed to validate the findings, including studies in diverse populations, and additional studies may investigate whether early TBNC patients with high TIL levels could achieve high cure rates with less intensive and less toxic chemotherapy regiments than those currently recommended, the researchers wrote in their discussion.

“There are many additional research questions that we need to answer, and look forward to working on,” Dr. Leon-Ferre said, in an interview. These topics include whether TILs can be used to decide on the number of chemotherapy drugs a patient really needs and whether artificial intelligence can be used to evaluate TILs more quickly and effectively than the human eye, he said. Other research topics include identifying which particular type of TILs attack cancer cells most effectively and whether TILs could be increased in patients with low levels in order to improve their prognosis, he added.

The study was supported by the National Research Agency and General Secretariat for Investment, Clinical and Translational Science Awards, the Mayo Clinic Breast Cancer SPORE grant, the Cancer Research Society of Canada, institutional grants from the Dutch Cancer Society, The Netherlands Organization for Health Research, and several foundations. Dr. Leon-Ferre disclosed consulting honoraria to his institution for research activities from AstraZeneca, Gilead Sciences, and Lyell Immunopharma, with no personal fees outside the submitted work.

High levels of tumor-infiltrating lymphocytes predicted increased survival in patients with early-stage triple-negative breast cancer who did not receive chemotherapy, a new analysis finds.

The association of abundant tumor-infiltrating lymphocytes (TILs) in breast cancer tissue with outcomes in patients with early-stage triple-negative breast cancer (TNBC) who do not receive chemotherapy has not been well studied, wrote Roberto A. Leon-Ferre, MD, of the Mayo Clinic, Rochester, Minnesota, and colleagues, in JAMA.

Biomarkers to guide systemic treatment and avoid overtreatment are lacking, and such markers could help identify patients who could achieve increased survival with less intensive therapy, continued the authors of the new study of nearly 2000 individuals.

“TNBC is the most aggressive subtype of breast cancer, and for this reason, current treatment guidelines recommend chemotherapy using multiple drugs either before or after surgery,” Dr. Leon-Ferre said in an interview. “We have learned over the last several years that TNBC is not a single disease, but that there are several subtypes of TNBC that have different risks and different vulnerabilities, and treating all patients similarly may not be optimal.”

  

What is Known About Tumor-Infiltrating Lymphocytes and Cancer?

Previous studies have shown improved survival in patients with early-stage TNBC and high levels of TILs who were treated with adjuvant and neoadjuvant chemotherapy, compared with those with lower TILs. In a pooled analysis of 2148 patients from nine studies published in the Journal of Clinical Oncology in 2019, a higher percentage of TILs in the stroma surrounding a tumor was significantly associated with improved survival in TNBC patients after adjuvant chemotherapy.

Another study published in the Journal of Clinical Oncology in 2022 showed that elevated TILs were significant predictors of overall survival, but the study included fewer than 500 patients.

The potential mechanisms that drive the association between elevated TILs and improved survival include the ability of TILs to attack cancer cells, Dr. Leon-Ferre said in an interview. 

The goal of this study was to evaluate whether TILs could identify a subset of patients with TNBC who had a very low risk of cancer recurrence even if chemotherapy was not given.

“Indeed, we found that patients with stage I TNBC and high TILs had a very low risk of recurrence even when chemotherapy was not administered. These findings will pave the way for future studies aiming to reduce the need for multiple chemotherapy drugs in patients with stage I TNBC and decrease the side effects that patients face,” he said.

 

What Does the New Study Add?

The current study included 1966 individuals from 13 sites in North America, Europe, and Asia who were diagnosed with TNBC between 1979 and 2017 and were treated with surgery, with or without radiotherapy but with no adjuvant or neoadjuvant chemotherapy. The researchers examined the abundance of TILs in the breast tissue of resected primary tumors; the primary outcome was invasive disease-free survival (iDFS), with recurrence-free survival, distant recurrence-free survival, and overall survival as secondary outcomes.

The median age of the patients was 56 years, 55% had stage I TNBC, and the median TIL level was 15%.

A total of 417 patients had a TIL level of 50% or more, and the 5-year iDFS for these patients was 94%, compared with 78% for those with a TIL level less than 30%. Similarly, 5-year overall survival was 95% in patients with a TIL level of 50% or more, compared with 82% for patients with TIL levels of less than 30%.

Additionally, each 10% increase in TILs was independently associated not only with improved iDFS (hazard ratio[HR], 0.92), but also improved recurrence-free survival (HR, 0.90), distant recurrence-free survival (HR, 0.87), and overall survival (HR, 0.88) over a median follow-up of 18 years.

The current study shows that cancer stage based on tumor size and the number of lymph nodes should not be the only considerations for making treatment decisions and predicting outcomes, Dr. Leon-Ferre said in an interview.

“In fact, our study shows that for tumors of the same stage (particularly for stage I), the risk of recurrence is different depending on the number of TILs seen in the breast cancer tissue. When chemo is not given, those with high TILs have lower risk of recurrence, whereas those with low TILs have a higher risk of recurrence,” he said.
 

What are the Limitations of This Research?

The current study findings are limited by the retrospective design and use of observational data, so the researchers could not make conclusions about causality. Other limitations included lack of data on germline mutations and race or ethnicity, and the potential irrelevance of data from patients treated as long as 45 years ago.

“Because most patients with TNBC receive chemotherapy in the modern times, we needed to work with 13 hospitals around the world to find data on patients with TNBC who never received chemotherapy for various reasons,” Dr. Leon-Ferre said.

To address these limitations, Dr. Leone-Ferre and his colleagues are planning prospective studies where TILs will be used to make treatment decisions.

“Many of the patients in our cohort were treated many years ago, when chemotherapy was not routinely given. Advances in cancer detection, surgical and radiation techniques may lead to different results in patients treated today,” he added.

What Do Oncologists Need to Know?

The current study findings may provide additional information on prognosis that is important to share with patients for decision-making on the risks versus benefits of chemotherapy, Dr. Leon-Ferre said.

“Like any test, TILs should not be used in isolation to make decisions, but should be integrated with other factors including the cancer stage, the overall patient health, patient preferences, and concerns about treatment complications,” he emphasized. “The results of this study allow oncologists to offer a more refined calculation of recurrence risk if patients opt to not receive chemotherapy.”

In the current study, although younger age was associated with higher TIL levels, a finding consistent with previous studies, increased TIL, remained significantly associated with improved survival after adjusting for age, tumor size, nodal status, and histological grade.

Overall, “the findings suggest that for patients with stage I TNBC and TILs greater than 50%, chemotherapy may not be as necessary as it was previously thought,” Dr. Leon-Ferre said.

What Additional Research is Needed?

Prospective studies are needed to validate the findings, including studies in diverse populations, and additional studies may investigate whether early TBNC patients with high TIL levels could achieve high cure rates with less intensive and less toxic chemotherapy regiments than those currently recommended, the researchers wrote in their discussion.

“There are many additional research questions that we need to answer, and look forward to working on,” Dr. Leon-Ferre said, in an interview. These topics include whether TILs can be used to decide on the number of chemotherapy drugs a patient really needs and whether artificial intelligence can be used to evaluate TILs more quickly and effectively than the human eye, he said. Other research topics include identifying which particular type of TILs attack cancer cells most effectively and whether TILs could be increased in patients with low levels in order to improve their prognosis, he added.

The study was supported by the National Research Agency and General Secretariat for Investment, Clinical and Translational Science Awards, the Mayo Clinic Breast Cancer SPORE grant, the Cancer Research Society of Canada, institutional grants from the Dutch Cancer Society, The Netherlands Organization for Health Research, and several foundations. Dr. Leon-Ferre disclosed consulting honoraria to his institution for research activities from AstraZeneca, Gilead Sciences, and Lyell Immunopharma, with no personal fees outside the submitted work.

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

The Diagnosis: Lymphoepithelioma-like Carcinoma

Lymphoepithelioma-like carcinoma (LELC) is a rare, poorly differentiated, primary cutaneous neoplasm that occurs on sun-exposed skin, particularly on the head and neck of elderly individuals. It often manifests as an asymptomatic, slow-growing, flesh-colored or erythematous dermal nodule, though ulceration and tenderness have been reported.¹ Histopathologically, these neoplasms often are poorly circumscribed and can infiltrate surrounding subcutaneous and soft tissue. As a biphasic tumor, LELC is characterized by islands, nests, or trabeculae of epithelioid cells within the mid dermis surrounded by a dense lymphocytic infiltrate with plasma cells (Figure 1).¹ The epithelial component rarely communicates with the overlying epidermis and is composed of atypical polygonal cells with eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and frequent mitosis.² These epithelial nests can be highlighted by pancytokeratin AE1/AE3 or other epithelial differentiation markers (eg, CAM 5.2, CK5/6, epithelial membrane antigen, high-molecular-weight cytokeratin), while the surrounding lymphocytic infiltrate consists of an admixture of T cells and B cells. Lymphoepithelioma-like carcinomas also can demonstrate sebaceous, eccrine, or follicular differentiations.³ The epithelial nests of LELC also are positive for p63 and epithelial membrane antigen.²

The usual treatment of LELC is wide local excision or Mohs micrographic surgery.¹ Despite the poorly differentiated morphology of the tumor, LELC has a generally good prognosis with low metastatic potential and few reports of local recurrence after incomplete excision.³ Patients who are not candidates for surgery as well as recalcitrant cases are managed with radiotherapy.¹

Cutaneous lymphadenoma (CL) is a benign adnexal neoplasm that manifests as a small, solitary, fleshcolored nodule usually in the head and neck region.⁴ Histologically, CL consists of well-circumscribed epithelial nests within the dermis that are peripherally outlined by palisading basaloid cells and filled with clear to eosinophilic epithelioid cells (Figure 2).5 The fibrotic tumor stroma often is infiltrated by numerous intralobular dendritic cells and lymphocytes that occasionally can be arranged in germinal center–like nodules.⁴ The lymphoepithelial nature of CL can be challenging to distinguish morphologically from LELC, and immunohistochemistry stains may be required. In CL, both the basaloid and epithelioid cells stain positive for pancytokeratin AE1/ AE3, but the peripheral palisaded basaloid cells also stain positive for BerEP4. Additionally, the fibrotic stroma can be highlighted by CD34 and the intralobular dendritic cells by S-100.⁴

Nasopharyngeal carcinoma (NPC), formerly known as lymphoepithelioma, refers to carcinoma arising within the epithelium of the nasopharynx.⁶ Endemic to China, NPC manifests as an enlarging nasopharyngeal mass, causing clinical symptoms such as nasal obstruction and epistaxis.⁷ Histologically, nonkeratinizing NPC exhibits a biphasic morphology consisting of epithelioid neoplastic cells and background lymphocytic infiltrates (Figure 3). The epithelial component consists of round to oval neoplastic cells with amphophilic to eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli.⁶ Nasopharyngeal carcinoma is associated strongly with the Epstein-Barr virus while LELC is not; thus, Epstein- Barr encoding region in situ hybridization can reliably distinguish these entities. Metastatic NPC is rare but has been reported; therefore, it is highly recommended to perform an otolaryngologic examination in addition to testing for Epstein-Barr virus reactivity as part of a complete evaluation.⁸

Cutaneous squamous cell carcinoma (SCC) is a common epidermal malignancy with multiple subtypes and variable morphology. The clinical presentation of SCC is similar to LELC—an enlarging hyperkeratotic papule or nodule on sun-exposed skin that often is ulcerated and tender.⁹ Histologically, poorly differentiated nonkeratinizing SCC can form nests and trabeculae of epithelioid cells that are stained by epithelial differentiation markers, resembling the epithelioid nests of LELC. Distinguishing between LELC and poorly differentiated SCC with robust inflammatory infiltrate can be challenging (Figure 4). In fact, some experts support LELC as an SCC variant rather than a separate entity.9 However, in contrast to LELC, the dermal nests of SCC usually maintain an epidermal connection and often are associated with an overlying area of SCC in situ or welldifferentiated SCC.³

Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma. It is the most common type of cutaneous lymphoma, accounting for almost 50% of all reported cases.¹⁰ Classic MF has an indolent course and progresses through several clinical stages. Patches and plaques characterize early stages; lymphadenopathy indicates progression to later stages in which erythroderma may develop with coalescence of patches, plaques, and tumors; and MF present in blood or lymph nodes characterizes the late stage. Each stage of MF is different histologically—from a superficial lichenoid infiltrate with exocytosis of malignant T cells in the patch stage, to more robust epidermotropism and dermal infiltrate in the plaque stage, and finally a dense dermal infiltrate in the late stage.¹¹ The rare syringotropic variant of MF clinically manifests as solitary or multiple erythematous lesions, often with overlying alopecia. Syringotropic MF uniquely exhibits folliculotropism and syringotropism along with syringometaplasia on histologic evaluation (Figure 5).¹² The syringometaplasia can be difficult to distinguish from the epithelial nests of LELC, particularly with the lymphocytic background. Immunohistochemical panels for T-cell markers can highlight aberrant T cells in syringotropic MF through their usual loss of CD5 and CD7, in comparison to normal T cells in LELC.¹¹ An elevated CD4:CD8 ratio of 4:1 and molecular analysis for T-cell receptor gene clonal rearrangements also can support the diagnosis of MF.¹²

Patients hurl verbal abuse at Michelle Ravera every day in the emergency room. Physical violence is less common, she said, but has become a growing threat.

Ravera, an ER nurse at Sutter Medical Center in Sacramento, recalled an incident in which an agitated patient wanted to leave. “Without any warning he just reached up, grabbed my glasses, and punched me in the face,” said Ravera, 54. “And then he was getting ready to attack another patient in the room.” Ravera and hospital security guards subdued the patient so he couldn’t hurt anyone else.

Violence against health care workers is on the rise, including in the ER, where tensions can run high as staff juggle multiple urgent tasks. Covid-19 only made things worse: With routine care harder to come by, many patients ended up in the ER with serious diseases — and brimming with frustrations.

In California, simple assault against workers inside an ER is considered the same as simple assault against almost anyone else, and carries a maximum punishment of a $1,000 fine and six months in jail. In contrast, simple assault against emergency medical workers in the field, such as an EMT responding to a 911 call, carries maximum penalties of a $2,000 fine and a year in jail. Simple assault does not involve the use of a deadly weapon or the intention to inflict serious bodily injury.

State Assembly member Freddie Rodriguez, who worked as an EMT, has authored a bill to make the punishments consistent: a $2,000 fine and one year in jail for simple assault on any on-the-job emergency health care worker, whether in the field or an ER. The measure would also eliminate the discrepancy for simple battery.

Patients and family members are assaulting staff and “doing things they shouldn’t be doing to the people that are there to take care of your loved ones,” said Rodriguez, a Democrat from Pomona. The bill passed the state Assembly unanimously in January and awaits consideration in the Senate.

Rodriguez has introduced similar measures twice before. Then-Gov. Jerry Brown vetoed one in 2015, saying he doubted a longer jail sentence would deter violence. “We need to find more creative ways to protect the safety of these critical workers,” he wrote in his veto message. The 2019 bill died in the state Senate.

Rodriguez said ERs have become more dangerous for health care workers since then and that “there has to be accountability” for violent behavior. Opponents fear stiffer penalties would be levied disproportionately on patients of color or those with developmental disabilities. They also point out that violent patients can already face penalties under existing assault and battery laws.

Data from the California Division of Occupational Safety and Health shows that reported attacks on ER workers by patients, visitors, and strangers jumped about 25% from 2018 to 2023, from 2,587 to 3,238. The rate of attacks per 100,000 ER visits also increased.

Punching, kicking, pushing, and similar aggression accounted for most of the attacks. Only a small number included weapons.

These numbers are likely an undercount, said Al’ai Alvarez, an ER doctor and clinical associate professor at Stanford University’s Department of Emergency Medicine. Many hospital staffers don’t fill out workplace violence reports because they don’t have time or feel nothing will come of it, he said.

Ravera remembers when her community rallied around health care workers at the start of the pandemic, acting respectfully and bringing food and extra N95 masks to workers.

“Then something just switched,” she said. “The patients became angrier and more aggressive.”

Violence can contribute to burnout and drive workers to quit — or worse, said Alvarez, who has lost colleagues to suicide, and thinks burnout was a key factor. “The cost of burnout is more than just loss of productivity,” he said. “It’s loss of human beings that also had the potential to take care of many more people.”

The National Center for Health Workforce Analysis projects California will experience an 18% shortage of all types of nurses in 2035, the third worst in the country.

Federal legislation called the Safety From Violence for Healthcare Employees Act would set sentences of up to 10 years for assault against a health care worker, not limited to emergency workers, and up to 20 years in cases involving dangerous weapons or bodily injury. Though it was introduced in 2023, it has not yet had a committee hearing.

Opponents of the California bill, which include ACLU California Action, the California Public Defenders Association, and advocates for people with autism, argue it wouldn’t deter attacks — and would unfairly target certain patients.

“There’s no evidence to suggest that increased penalties are going to meaningfully address this conduct,” said Eric Henderson, a legislative advocate for ACLU California Action. “Most importantly, there are already laws on the books to address assaultive conduct.”

Beth Burt, executive director of the Autism Society Inland Empire, said the measure doesn’t take into account the special needs of people with autism and other developmental disorders.

The smells, lights, textures, and crowds in the ER can overstimulate a person with autism, she said. When that happens, they can struggle to articulate their feelings, which can result in a violent outburst, “whether it’s a 9-year-old or a 29-year-old,” Burt said.

She worries that hospital staff may misunderstand these reactions, and involve law enforcement when it’s not necessary. As “a parent, it is still my worst fear” that she’ll get a phone call to inform her that her adult son with autism has been arrested, she said.

Burt would rather the state prioritize de-escalation programs over penalties, such as the training programs for first responders she helped create through the Autism Society Inland Empire. After implementing the training, hospital administrators asked Burt to share some strategies with them, she said. Hospital security staffers who do not want to use physical restraints on autistic patients have also sought her advice, she said.

Supporters of the bill, including health care and law enforcement groups, counter that people with mental health conditions or autism who are charged with assault in an ER may be eligible for existing programs that provide mental health treatment in lieu of a criminal sentence.

Stephanie Jensen, an ER nurse and head of governmental affairs for the Emergency Nurses Association, California State Council, said her organization is simply arguing for equity. “If you punch me in the hospital, it’s the same as if you punch me on the street,” she said.

If lawmakers don’t act, she warned, there won’t be enough workers for the patients who need them.

“It’s hard to keep those human resources accessible when it just seems like you’re showing up to get beat up every day,” Jensen said. “The emergency department is taking it on the chin, literally and figuratively.”

This article was produced by KFF Health News, which publishes California Healthline, an editorially independent service of the California Health Care Foundation. KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

Patients hurl verbal abuse at Michelle Ravera every day in the emergency room. Physical violence is less common, she said, but has become a growing threat.

Ravera, an ER nurse at Sutter Medical Center in Sacramento, recalled an incident in which an agitated patient wanted to leave. “Without any warning he just reached up, grabbed my glasses, and punched me in the face,” said Ravera, 54. “And then he was getting ready to attack another patient in the room.” Ravera and hospital security guards subdued the patient so he couldn’t hurt anyone else.

Violence against health care workers is on the rise, including in the ER, where tensions can run high as staff juggle multiple urgent tasks. Covid-19 only made things worse: With routine care harder to come by, many patients ended up in the ER with serious diseases — and brimming with frustrations.

In California, simple assault against workers inside an ER is considered the same as simple assault against almost anyone else, and carries a maximum punishment of a $1,000 fine and six months in jail. In contrast, simple assault against emergency medical workers in the field, such as an EMT responding to a 911 call, carries maximum penalties of a $2,000 fine and a year in jail. Simple assault does not involve the use of a deadly weapon or the intention to inflict serious bodily injury.

State Assembly member Freddie Rodriguez, who worked as an EMT, has authored a bill to make the punishments consistent: a $2,000 fine and one year in jail for simple assault on any on-the-job emergency health care worker, whether in the field or an ER. The measure would also eliminate the discrepancy for simple battery.

Patients and family members are assaulting staff and “doing things they shouldn’t be doing to the people that are there to take care of your loved ones,” said Rodriguez, a Democrat from Pomona. The bill passed the state Assembly unanimously in January and awaits consideration in the Senate.

Rodriguez has introduced similar measures twice before. Then-Gov. Jerry Brown vetoed one in 2015, saying he doubted a longer jail sentence would deter violence. “We need to find more creative ways to protect the safety of these critical workers,” he wrote in his veto message. The 2019 bill died in the state Senate.

Rodriguez said ERs have become more dangerous for health care workers since then and that “there has to be accountability” for violent behavior. Opponents fear stiffer penalties would be levied disproportionately on patients of color or those with developmental disabilities. They also point out that violent patients can already face penalties under existing assault and battery laws.

Data from the California Division of Occupational Safety and Health shows that reported attacks on ER workers by patients, visitors, and strangers jumped about 25% from 2018 to 2023, from 2,587 to 3,238. The rate of attacks per 100,000 ER visits also increased.

Punching, kicking, pushing, and similar aggression accounted for most of the attacks. Only a small number included weapons.

These numbers are likely an undercount, said Al’ai Alvarez, an ER doctor and clinical associate professor at Stanford University’s Department of Emergency Medicine. Many hospital staffers don’t fill out workplace violence reports because they don’t have time or feel nothing will come of it, he said.

Ravera remembers when her community rallied around health care workers at the start of the pandemic, acting respectfully and bringing food and extra N95 masks to workers.

“Then something just switched,” she said. “The patients became angrier and more aggressive.”

Violence can contribute to burnout and drive workers to quit — or worse, said Alvarez, who has lost colleagues to suicide, and thinks burnout was a key factor. “The cost of burnout is more than just loss of productivity,” he said. “It’s loss of human beings that also had the potential to take care of many more people.”

The National Center for Health Workforce Analysis projects California will experience an 18% shortage of all types of nurses in 2035, the third worst in the country.

Federal legislation called the Safety From Violence for Healthcare Employees Act would set sentences of up to 10 years for assault against a health care worker, not limited to emergency workers, and up to 20 years in cases involving dangerous weapons or bodily injury. Though it was introduced in 2023, it has not yet had a committee hearing.

Opponents of the California bill, which include ACLU California Action, the California Public Defenders Association, and advocates for people with autism, argue it wouldn’t deter attacks — and would unfairly target certain patients.

“There’s no evidence to suggest that increased penalties are going to meaningfully address this conduct,” said Eric Henderson, a legislative advocate for ACLU California Action. “Most importantly, there are already laws on the books to address assaultive conduct.”

Beth Burt, executive director of the Autism Society Inland Empire, said the measure doesn’t take into account the special needs of people with autism and other developmental disorders.

The smells, lights, textures, and crowds in the ER can overstimulate a person with autism, she said. When that happens, they can struggle to articulate their feelings, which can result in a violent outburst, “whether it’s a 9-year-old or a 29-year-old,” Burt said.

She worries that hospital staff may misunderstand these reactions, and involve law enforcement when it’s not necessary. As “a parent, it is still my worst fear” that she’ll get a phone call to inform her that her adult son with autism has been arrested, she said.

Burt would rather the state prioritize de-escalation programs over penalties, such as the training programs for first responders she helped create through the Autism Society Inland Empire. After implementing the training, hospital administrators asked Burt to share some strategies with them, she said. Hospital security staffers who do not want to use physical restraints on autistic patients have also sought her advice, she said.

Supporters of the bill, including health care and law enforcement groups, counter that people with mental health conditions or autism who are charged with assault in an ER may be eligible for existing programs that provide mental health treatment in lieu of a criminal sentence.

Stephanie Jensen, an ER nurse and head of governmental affairs for the Emergency Nurses Association, California State Council, said her organization is simply arguing for equity. “If you punch me in the hospital, it’s the same as if you punch me on the street,” she said.

If lawmakers don’t act, she warned, there won’t be enough workers for the patients who need them.

“It’s hard to keep those human resources accessible when it just seems like you’re showing up to get beat up every day,” Jensen said. “The emergency department is taking it on the chin, literally and figuratively.”

This article was produced by KFF Health News, which publishes California Healthline, an editorially independent service of the California Health Care Foundation. KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

Patients hurl verbal abuse at Michelle Ravera every day in the emergency room. Physical violence is less common, she said, but has become a growing threat.

Ravera, an ER nurse at Sutter Medical Center in Sacramento, recalled an incident in which an agitated patient wanted to leave. “Without any warning he just reached up, grabbed my glasses, and punched me in the face,” said Ravera, 54. “And then he was getting ready to attack another patient in the room.” Ravera and hospital security guards subdued the patient so he couldn’t hurt anyone else.

Violence against health care workers is on the rise, including in the ER, where tensions can run high as staff juggle multiple urgent tasks. Covid-19 only made things worse: With routine care harder to come by, many patients ended up in the ER with serious diseases — and brimming with frustrations.

In California, simple assault against workers inside an ER is considered the same as simple assault against almost anyone else, and carries a maximum punishment of a $1,000 fine and six months in jail. In contrast, simple assault against emergency medical workers in the field, such as an EMT responding to a 911 call, carries maximum penalties of a $2,000 fine and a year in jail. Simple assault does not involve the use of a deadly weapon or the intention to inflict serious bodily injury.

State Assembly member Freddie Rodriguez, who worked as an EMT, has authored a bill to make the punishments consistent: a $2,000 fine and one year in jail for simple assault on any on-the-job emergency health care worker, whether in the field or an ER. The measure would also eliminate the discrepancy for simple battery.

Patients and family members are assaulting staff and “doing things they shouldn’t be doing to the people that are there to take care of your loved ones,” said Rodriguez, a Democrat from Pomona. The bill passed the state Assembly unanimously in January and awaits consideration in the Senate.

Rodriguez has introduced similar measures twice before. Then-Gov. Jerry Brown vetoed one in 2015, saying he doubted a longer jail sentence would deter violence. “We need to find more creative ways to protect the safety of these critical workers,” he wrote in his veto message. The 2019 bill died in the state Senate.

Rodriguez said ERs have become more dangerous for health care workers since then and that “there has to be accountability” for violent behavior. Opponents fear stiffer penalties would be levied disproportionately on patients of color or those with developmental disabilities. They also point out that violent patients can already face penalties under existing assault and battery laws.

Data from the California Division of Occupational Safety and Health shows that reported attacks on ER workers by patients, visitors, and strangers jumped about 25% from 2018 to 2023, from 2,587 to 3,238. The rate of attacks per 100,000 ER visits also increased.

Punching, kicking, pushing, and similar aggression accounted for most of the attacks. Only a small number included weapons.

These numbers are likely an undercount, said Al’ai Alvarez, an ER doctor and clinical associate professor at Stanford University’s Department of Emergency Medicine. Many hospital staffers don’t fill out workplace violence reports because they don’t have time or feel nothing will come of it, he said.

Ravera remembers when her community rallied around health care workers at the start of the pandemic, acting respectfully and bringing food and extra N95 masks to workers.

“Then something just switched,” she said. “The patients became angrier and more aggressive.”

Violence can contribute to burnout and drive workers to quit — or worse, said Alvarez, who has lost colleagues to suicide, and thinks burnout was a key factor. “The cost of burnout is more than just loss of productivity,” he said. “It’s loss of human beings that also had the potential to take care of many more people.”

The National Center for Health Workforce Analysis projects California will experience an 18% shortage of all types of nurses in 2035, the third worst in the country.

Federal legislation called the Safety From Violence for Healthcare Employees Act would set sentences of up to 10 years for assault against a health care worker, not limited to emergency workers, and up to 20 years in cases involving dangerous weapons or bodily injury. Though it was introduced in 2023, it has not yet had a committee hearing.

Opponents of the California bill, which include ACLU California Action, the California Public Defenders Association, and advocates for people with autism, argue it wouldn’t deter attacks — and would unfairly target certain patients.

“There’s no evidence to suggest that increased penalties are going to meaningfully address this conduct,” said Eric Henderson, a legislative advocate for ACLU California Action. “Most importantly, there are already laws on the books to address assaultive conduct.”

Beth Burt, executive director of the Autism Society Inland Empire, said the measure doesn’t take into account the special needs of people with autism and other developmental disorders.

The smells, lights, textures, and crowds in the ER can overstimulate a person with autism, she said. When that happens, they can struggle to articulate their feelings, which can result in a violent outburst, “whether it’s a 9-year-old or a 29-year-old,” Burt said.

She worries that hospital staff may misunderstand these reactions, and involve law enforcement when it’s not necessary. As “a parent, it is still my worst fear” that she’ll get a phone call to inform her that her adult son with autism has been arrested, she said.

Burt would rather the state prioritize de-escalation programs over penalties, such as the training programs for first responders she helped create through the Autism Society Inland Empire. After implementing the training, hospital administrators asked Burt to share some strategies with them, she said. Hospital security staffers who do not want to use physical restraints on autistic patients have also sought her advice, she said.

Supporters of the bill, including health care and law enforcement groups, counter that people with mental health conditions or autism who are charged with assault in an ER may be eligible for existing programs that provide mental health treatment in lieu of a criminal sentence.

Stephanie Jensen, an ER nurse and head of governmental affairs for the Emergency Nurses Association, California State Council, said her organization is simply arguing for equity. “If you punch me in the hospital, it’s the same as if you punch me on the street,” she said.

If lawmakers don’t act, she warned, there won’t be enough workers for the patients who need them.

“It’s hard to keep those human resources accessible when it just seems like you’re showing up to get beat up every day,” Jensen said. “The emergency department is taking it on the chin, literally and figuratively.”

This article was produced by KFF Health News, which publishes California Healthline, an editorially independent service of the California Health Care Foundation. KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

Experts say pediatricians and primary care clinicians should do more to prevent the toxic effects of lead in their young patients following a 2023 outbreak of elevated levels of lead in children associated with consumption of contaminated applesauce.

Federal legislation in the 1970s eliminated lead from gasoline, paints, and other consumer products, and resulted in significantly reduced blood lead levels (BLLs) in children throughout the United States.

But recently published studies highlight persistent issues with lead in drinking water and consumer products, suggesting that the fight is not over.
 

It’s in the Water

In 2014 the city of Flint, Michigan, changed its water supply and high levels of lead were later found in the municipal water supply.

Effects of that crisis still plague the city today. An initial study found that elevated BLLs had doubled among children between 2013 and 2015.

Lead exposure in young children is associated with several negative outcomes, including decreased cognitive ability, brain volume, and social mobility, and increased anxiety/depression and impulsivity, and higher rates of criminal offenses later in life. 

Many other water systems still contain lead pipes, despite a 1986 ban by the US Environmental Protection Agency on using them for installing or repairing public water systems. The mayor of Chicago announced a plan to start replacing lead service lines in 2020; however, 400,000 households are still served by these pipes, the most in the nation.

Benjamin Huynh, a native of Chicago, was curious about the impact of all those lead service lines. Now an assistant professor in the Department of Environmental Health and Engineering at Johns Hopkins University in Baltimore, Maryland, he and his colleagues researched how many children under the age of 6 years were exposed to contaminated water.

The results showed that lead contamination of water is widespread. 

“We’re estimating that 68% of kids under the age of 6 in Chicago were exposed to lead-contaminated drinking water,” Mr. Huynh said. 

He added that residents in predominantly Black and Latino neighborhoods had the highest risk for lead contamination in their water, but children living on these blocks were less likely to get tested, suggesting a need for more outreach to raise awareness.

Meanwhile, a little over one third of Chicago residents reported drinking bottled water as their main source of drinking water.

But even bottled water could contain lead. The US Food and Drug Administration (FDA) has set a limit for lead in bottled water to five parts per billion. The FDA threshold for taking action in public drinking water systems is 15 parts per billion. But the American Academy of Pediatrics states that no amount of lead in drinking water is considered safe for drinking. 

Mr. Huynh also pointed out that not all home water filters remove lead. Only devices that meet National Sanitation Foundation 53 standards are certified for lead removal. Consumers should verify that the filter package specifically lists the device as certified for removing contaminant lead.
 

Lead-tainted Cinnamon 

Last fall, the North Carolina Department of Health and Human Services identified several children with elevated levels of lead who had consumed WanaBana Apple Cinnamon Fruit Puree pouches.

An investigation by the FDA identified additional brands containing lead and issued a recall of applesauce pouches sold by retailers like Dollar Tree and Amazon.

According to the US Centers for Disease Control and Prevention, nearly 500 children were affected by the tainted applesauce. The FDA traced the source of the lead to cinnamon from a supplier in Ecuador.

An FDA spokesperson told this news organization the episode appears to have resulted from “economically motivated adulteration,” which occurs when a manufacturer leaves out or substitutes a valuable ingredient or part of a food. In the case of spices, lead may be added as a coloring agent or to increase the product weight.

“When we look at domestically made products from large, reputable companies, in general, they do a pretty good job of following safe product guidelines and regulations,” said Kevin Osterhoudt, MD, professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “But when we use third-party sellers and we import things from other countries that aren’t regulated as closely, we certainly take a lot more risk in the products that we receive.”

While the Food Safety Modernization Act of 2011 aimed to improve agency’s capacity to manage the ever-rising volume of food produced domestically and imported from overseas, the funding has stayed flat while the volume of inspections has increased. In the early 1990s, the number of shipments screened by the agency numbered in the thousands annually. Last year the FDA screened 15 million shipments from more than 200 countries, according to the agency.

Prompted by the finding of lead in applesauce, the FDA began a wider investigation into ground cinnamon by sampling the product from discount retail stores. It recalled an additional six brands of cinnamon sold in the United States containing lead.

Dr. Osterhoudt’s message to families who think their child might have been exposed to a contaminated product is to dispose of it as directed by FDA and CDC guidelines. 

In Philadelphia, where Dr. Osterhoudt practices as an emergency room physician, baseline rates of childhood lead poisoning are already high, so he advises families to “do a larger inventory of all the source potential sources of lead in their life and to reduce all the exposures as low as possible.” 

He also advises parents that a nutritious diet high in calcium and iron can protect their children from the deleterious effects of lead.
 

Current Standards for Lead Screening and Testing

Lead is ubiquitous. The common routes of exposure to humans include use of fossil fuels such as leaded gasoline, some types of industrial facilities, and past use of lead-based paint in homes. In addition to spices, lead has been found in a wide variety of products such as toys, jewelry, antiques, cosmetics, and dietary supplements imported from other countries.

Noah Buncher, DO, is a primary care pediatrician in South Philadelphia at Children’s Hospital of Pennsylvania and the former director of a lead clinic in Boston that provides care for children with lead poisoning. He follows guidelines from the American Academy of Pediatrics that define an elevated BLL as ≥ 3.5 µg/dL. The guidelines recommend screening children for lead exposures during well child visits starting at age 6 months up to 6 years and obtaining a BLL if risks for lead exposure are present. 

Dr. Buncher starts with a basic environmental history that covers items like the age, condition, zip code of home, parental occupations, or hobbies that might result in exposing family members to lead, and if another child in the home has a history of elevated BLLs. 

But a careful history for potential lead exposures can be time-consuming. 

“There’s a lot to cover in a routine well child visit,” Dr. Buncher said. “We have maybe 15-20 minutes to cover a lot.” 

Clinics also vary on whether lead screening questions are put into workflows in the electronic medical record. Although parents can complete a written questionnaire about possible lead exposures, they may have difficulty answering questions about the age of their home or not know whether their occupation is high risk.

Transportation to a clinic is often a barrier for families, and sometimes patients must travel to a separate lab to be tested for lead. 

Dr. Buncher also pointed to the patchwork of local and state requirements that can lead to confusion among providers. Massachusetts, where he formerly practiced, has a universal requirement to test all children at ages 1, 2, and 3 years. But in Pennsylvania, screening laws vary from county to county. 

“Pennsylvania should implement universal screening recommendations for all kids under 6 regardless of what county you live in,” Dr. Buncher said.
 

Protective Measures 

Alan Woolf, MD, a professor of pediatrics at Harvard Medical School, Boston, Massachusetts, and director of the Pediatric Environmental Health Center at Boston Children’s Hospital, has a few ideas about how providers can step up their lead game, including partnering with their local health department. 

The CDC funds Childhood Lead Poisoning Prevention Programs based in state and local health departments to work with clinicians to improve rates of blood lead testing, monitor the prevalence of lead in their jurisdictions, and ensure that a system of referral is available for treatment and lead remediation services in the home.

Dr. Woolf also suggested that clinicians refer patients under age 3 years with high BLLs to their local Early Intervention Program. 

“They’ll assess their child’s development, their speech, their motor skills, their social skills, and if they qualify, it’s free,” Dr. Woolf said. 

He cited research showing children with elevated lead levels who received early intervention services performed better in grade school than equally exposed children who did not access similar services.

Another key strategy for pediatric clinicians is to learn local or state regulations for testing children for lead and how to access lead surveillance data in their practice area. Children who reside in high-risk areas are automatic candidates for screening. 

Dr. Woolf pointed out that big cities are not the only localities with lead in the drinking water. If families are drawing water from their own well, they should collect that water annually to have it tested for lead and microbes.

At the clinic-wide level, Dr. Woolf recommends the use of blood lead testing as a quality improvement measure. For example, Akron Children’s Hospital developed a quality improvement initiative using a clinical decision support tool to raise screening rates in their network of 30 clinics. One year after beginning the project, lead screenings during 12-month well visits increased from 71% to 96%. 

“What we’re interested in as pediatric health professionals is eliminating all background sources of lead in a child’s environment,” Dr. Woolf said. “Whether that’s applesauce pouches, whether that’s lead-containing paint, lead in water, lead in spices, or lead in imported pottery or cookware — there are just a tremendous number of sources of lead that we can do something about.”

None of the subjects reported financial conflicts of interest.

A former pediatrician, Dr. Thomas is a freelance science writer living in Portland, Oregon.

A version of this article appeared on Medscape.com.

Experts say pediatricians and primary care clinicians should do more to prevent the toxic effects of lead in their young patients following a 2023 outbreak of elevated levels of lead in children associated with consumption of contaminated applesauce.

Federal legislation in the 1970s eliminated lead from gasoline, paints, and other consumer products, and resulted in significantly reduced blood lead levels (BLLs) in children throughout the United States.

But recently published studies highlight persistent issues with lead in drinking water and consumer products, suggesting that the fight is not over.
 

It’s in the Water

In 2014 the city of Flint, Michigan, changed its water supply and high levels of lead were later found in the municipal water supply.

Effects of that crisis still plague the city today. An initial study found that elevated BLLs had doubled among children between 2013 and 2015.

Lead exposure in young children is associated with several negative outcomes, including decreased cognitive ability, brain volume, and social mobility, and increased anxiety/depression and impulsivity, and higher rates of criminal offenses later in life. 

Many other water systems still contain lead pipes, despite a 1986 ban by the US Environmental Protection Agency on using them for installing or repairing public water systems. The mayor of Chicago announced a plan to start replacing lead service lines in 2020; however, 400,000 households are still served by these pipes, the most in the nation.

Benjamin Huynh, a native of Chicago, was curious about the impact of all those lead service lines. Now an assistant professor in the Department of Environmental Health and Engineering at Johns Hopkins University in Baltimore, Maryland, he and his colleagues researched how many children under the age of 6 years were exposed to contaminated water.

The results showed that lead contamination of water is widespread. 

“We’re estimating that 68% of kids under the age of 6 in Chicago were exposed to lead-contaminated drinking water,” Mr. Huynh said. 

He added that residents in predominantly Black and Latino neighborhoods had the highest risk for lead contamination in their water, but children living on these blocks were less likely to get tested, suggesting a need for more outreach to raise awareness.

Meanwhile, a little over one third of Chicago residents reported drinking bottled water as their main source of drinking water.

But even bottled water could contain lead. The US Food and Drug Administration (FDA) has set a limit for lead in bottled water to five parts per billion. The FDA threshold for taking action in public drinking water systems is 15 parts per billion. But the American Academy of Pediatrics states that no amount of lead in drinking water is considered safe for drinking. 

Mr. Huynh also pointed out that not all home water filters remove lead. Only devices that meet National Sanitation Foundation 53 standards are certified for lead removal. Consumers should verify that the filter package specifically lists the device as certified for removing contaminant lead.
 

Lead-tainted Cinnamon 

Last fall, the North Carolina Department of Health and Human Services identified several children with elevated levels of lead who had consumed WanaBana Apple Cinnamon Fruit Puree pouches.

An investigation by the FDA identified additional brands containing lead and issued a recall of applesauce pouches sold by retailers like Dollar Tree and Amazon.

According to the US Centers for Disease Control and Prevention, nearly 500 children were affected by the tainted applesauce. The FDA traced the source of the lead to cinnamon from a supplier in Ecuador.

An FDA spokesperson told this news organization the episode appears to have resulted from “economically motivated adulteration,” which occurs when a manufacturer leaves out or substitutes a valuable ingredient or part of a food. In the case of spices, lead may be added as a coloring agent or to increase the product weight.

“When we look at domestically made products from large, reputable companies, in general, they do a pretty good job of following safe product guidelines and regulations,” said Kevin Osterhoudt, MD, professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “But when we use third-party sellers and we import things from other countries that aren’t regulated as closely, we certainly take a lot more risk in the products that we receive.”

While the Food Safety Modernization Act of 2011 aimed to improve agency’s capacity to manage the ever-rising volume of food produced domestically and imported from overseas, the funding has stayed flat while the volume of inspections has increased. In the early 1990s, the number of shipments screened by the agency numbered in the thousands annually. Last year the FDA screened 15 million shipments from more than 200 countries, according to the agency.

Prompted by the finding of lead in applesauce, the FDA began a wider investigation into ground cinnamon by sampling the product from discount retail stores. It recalled an additional six brands of cinnamon sold in the United States containing lead.

Dr. Osterhoudt’s message to families who think their child might have been exposed to a contaminated product is to dispose of it as directed by FDA and CDC guidelines. 

In Philadelphia, where Dr. Osterhoudt practices as an emergency room physician, baseline rates of childhood lead poisoning are already high, so he advises families to “do a larger inventory of all the source potential sources of lead in their life and to reduce all the exposures as low as possible.” 

He also advises parents that a nutritious diet high in calcium and iron can protect their children from the deleterious effects of lead.
 

Current Standards for Lead Screening and Testing

Lead is ubiquitous. The common routes of exposure to humans include use of fossil fuels such as leaded gasoline, some types of industrial facilities, and past use of lead-based paint in homes. In addition to spices, lead has been found in a wide variety of products such as toys, jewelry, antiques, cosmetics, and dietary supplements imported from other countries.

Noah Buncher, DO, is a primary care pediatrician in South Philadelphia at Children’s Hospital of Pennsylvania and the former director of a lead clinic in Boston that provides care for children with lead poisoning. He follows guidelines from the American Academy of Pediatrics that define an elevated BLL as ≥ 3.5 µg/dL. The guidelines recommend screening children for lead exposures during well child visits starting at age 6 months up to 6 years and obtaining a BLL if risks for lead exposure are present. 

Dr. Buncher starts with a basic environmental history that covers items like the age, condition, zip code of home, parental occupations, or hobbies that might result in exposing family members to lead, and if another child in the home has a history of elevated BLLs. 

But a careful history for potential lead exposures can be time-consuming. 

“There’s a lot to cover in a routine well child visit,” Dr. Buncher said. “We have maybe 15-20 minutes to cover a lot.” 

Clinics also vary on whether lead screening questions are put into workflows in the electronic medical record. Although parents can complete a written questionnaire about possible lead exposures, they may have difficulty answering questions about the age of their home or not know whether their occupation is high risk.

Transportation to a clinic is often a barrier for families, and sometimes patients must travel to a separate lab to be tested for lead. 

Dr. Buncher also pointed to the patchwork of local and state requirements that can lead to confusion among providers. Massachusetts, where he formerly practiced, has a universal requirement to test all children at ages 1, 2, and 3 years. But in Pennsylvania, screening laws vary from county to county. 

“Pennsylvania should implement universal screening recommendations for all kids under 6 regardless of what county you live in,” Dr. Buncher said.
 

Protective Measures 

Alan Woolf, MD, a professor of pediatrics at Harvard Medical School, Boston, Massachusetts, and director of the Pediatric Environmental Health Center at Boston Children’s Hospital, has a few ideas about how providers can step up their lead game, including partnering with their local health department. 

The CDC funds Childhood Lead Poisoning Prevention Programs based in state and local health departments to work with clinicians to improve rates of blood lead testing, monitor the prevalence of lead in their jurisdictions, and ensure that a system of referral is available for treatment and lead remediation services in the home.

Dr. Woolf also suggested that clinicians refer patients under age 3 years with high BLLs to their local Early Intervention Program. 

“They’ll assess their child’s development, their speech, their motor skills, their social skills, and if they qualify, it’s free,” Dr. Woolf said. 

He cited research showing children with elevated lead levels who received early intervention services performed better in grade school than equally exposed children who did not access similar services.

Another key strategy for pediatric clinicians is to learn local or state regulations for testing children for lead and how to access lead surveillance data in their practice area. Children who reside in high-risk areas are automatic candidates for screening. 

Dr. Woolf pointed out that big cities are not the only localities with lead in the drinking water. If families are drawing water from their own well, they should collect that water annually to have it tested for lead and microbes.

At the clinic-wide level, Dr. Woolf recommends the use of blood lead testing as a quality improvement measure. For example, Akron Children’s Hospital developed a quality improvement initiative using a clinical decision support tool to raise screening rates in their network of 30 clinics. One year after beginning the project, lead screenings during 12-month well visits increased from 71% to 96%. 

“What we’re interested in as pediatric health professionals is eliminating all background sources of lead in a child’s environment,” Dr. Woolf said. “Whether that’s applesauce pouches, whether that’s lead-containing paint, lead in water, lead in spices, or lead in imported pottery or cookware — there are just a tremendous number of sources of lead that we can do something about.”

None of the subjects reported financial conflicts of interest.

A former pediatrician, Dr. Thomas is a freelance science writer living in Portland, Oregon.

A version of this article appeared on Medscape.com.

Experts say pediatricians and primary care clinicians should do more to prevent the toxic effects of lead in their young patients following a 2023 outbreak of elevated levels of lead in children associated with consumption of contaminated applesauce.

Federal legislation in the 1970s eliminated lead from gasoline, paints, and other consumer products, and resulted in significantly reduced blood lead levels (BLLs) in children throughout the United States.

But recently published studies highlight persistent issues with lead in drinking water and consumer products, suggesting that the fight is not over.
 

It’s in the Water

In 2014 the city of Flint, Michigan, changed its water supply and high levels of lead were later found in the municipal water supply.

Effects of that crisis still plague the city today. An initial study found that elevated BLLs had doubled among children between 2013 and 2015.

Lead exposure in young children is associated with several negative outcomes, including decreased cognitive ability, brain volume, and social mobility, and increased anxiety/depression and impulsivity, and higher rates of criminal offenses later in life. 

Many other water systems still contain lead pipes, despite a 1986 ban by the US Environmental Protection Agency on using them for installing or repairing public water systems. The mayor of Chicago announced a plan to start replacing lead service lines in 2020; however, 400,000 households are still served by these pipes, the most in the nation.

Benjamin Huynh, a native of Chicago, was curious about the impact of all those lead service lines. Now an assistant professor in the Department of Environmental Health and Engineering at Johns Hopkins University in Baltimore, Maryland, he and his colleagues researched how many children under the age of 6 years were exposed to contaminated water.

The results showed that lead contamination of water is widespread. 

“We’re estimating that 68% of kids under the age of 6 in Chicago were exposed to lead-contaminated drinking water,” Mr. Huynh said. 

He added that residents in predominantly Black and Latino neighborhoods had the highest risk for lead contamination in their water, but children living on these blocks were less likely to get tested, suggesting a need for more outreach to raise awareness.

Meanwhile, a little over one third of Chicago residents reported drinking bottled water as their main source of drinking water.

But even bottled water could contain lead. The US Food and Drug Administration (FDA) has set a limit for lead in bottled water to five parts per billion. The FDA threshold for taking action in public drinking water systems is 15 parts per billion. But the American Academy of Pediatrics states that no amount of lead in drinking water is considered safe for drinking. 

Mr. Huynh also pointed out that not all home water filters remove lead. Only devices that meet National Sanitation Foundation 53 standards are certified for lead removal. Consumers should verify that the filter package specifically lists the device as certified for removing contaminant lead.
 

Lead-tainted Cinnamon 

Last fall, the North Carolina Department of Health and Human Services identified several children with elevated levels of lead who had consumed WanaBana Apple Cinnamon Fruit Puree pouches.

An investigation by the FDA identified additional brands containing lead and issued a recall of applesauce pouches sold by retailers like Dollar Tree and Amazon.

According to the US Centers for Disease Control and Prevention, nearly 500 children were affected by the tainted applesauce. The FDA traced the source of the lead to cinnamon from a supplier in Ecuador.

An FDA spokesperson told this news organization the episode appears to have resulted from “economically motivated adulteration,” which occurs when a manufacturer leaves out or substitutes a valuable ingredient or part of a food. In the case of spices, lead may be added as a coloring agent or to increase the product weight.

“When we look at domestically made products from large, reputable companies, in general, they do a pretty good job of following safe product guidelines and regulations,” said Kevin Osterhoudt, MD, professor of pediatrics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. “But when we use third-party sellers and we import things from other countries that aren’t regulated as closely, we certainly take a lot more risk in the products that we receive.”

While the Food Safety Modernization Act of 2011 aimed to improve agency’s capacity to manage the ever-rising volume of food produced domestically and imported from overseas, the funding has stayed flat while the volume of inspections has increased. In the early 1990s, the number of shipments screened by the agency numbered in the thousands annually. Last year the FDA screened 15 million shipments from more than 200 countries, according to the agency.

Prompted by the finding of lead in applesauce, the FDA began a wider investigation into ground cinnamon by sampling the product from discount retail stores. It recalled an additional six brands of cinnamon sold in the United States containing lead.

Dr. Osterhoudt’s message to families who think their child might have been exposed to a contaminated product is to dispose of it as directed by FDA and CDC guidelines. 

In Philadelphia, where Dr. Osterhoudt practices as an emergency room physician, baseline rates of childhood lead poisoning are already high, so he advises families to “do a larger inventory of all the source potential sources of lead in their life and to reduce all the exposures as low as possible.” 

He also advises parents that a nutritious diet high in calcium and iron can protect their children from the deleterious effects of lead.
 

Current Standards for Lead Screening and Testing

Lead is ubiquitous. The common routes of exposure to humans include use of fossil fuels such as leaded gasoline, some types of industrial facilities, and past use of lead-based paint in homes. In addition to spices, lead has been found in a wide variety of products such as toys, jewelry, antiques, cosmetics, and dietary supplements imported from other countries.

Noah Buncher, DO, is a primary care pediatrician in South Philadelphia at Children’s Hospital of Pennsylvania and the former director of a lead clinic in Boston that provides care for children with lead poisoning. He follows guidelines from the American Academy of Pediatrics that define an elevated BLL as ≥ 3.5 µg/dL. The guidelines recommend screening children for lead exposures during well child visits starting at age 6 months up to 6 years and obtaining a BLL if risks for lead exposure are present. 

Dr. Buncher starts with a basic environmental history that covers items like the age, condition, zip code of home, parental occupations, or hobbies that might result in exposing family members to lead, and if another child in the home has a history of elevated BLLs. 

But a careful history for potential lead exposures can be time-consuming. 

“There’s a lot to cover in a routine well child visit,” Dr. Buncher said. “We have maybe 15-20 minutes to cover a lot.” 

Clinics also vary on whether lead screening questions are put into workflows in the electronic medical record. Although parents can complete a written questionnaire about possible lead exposures, they may have difficulty answering questions about the age of their home or not know whether their occupation is high risk.

Transportation to a clinic is often a barrier for families, and sometimes patients must travel to a separate lab to be tested for lead. 

Dr. Buncher also pointed to the patchwork of local and state requirements that can lead to confusion among providers. Massachusetts, where he formerly practiced, has a universal requirement to test all children at ages 1, 2, and 3 years. But in Pennsylvania, screening laws vary from county to county. 

“Pennsylvania should implement universal screening recommendations for all kids under 6 regardless of what county you live in,” Dr. Buncher said.
 

Protective Measures 

Alan Woolf, MD, a professor of pediatrics at Harvard Medical School, Boston, Massachusetts, and director of the Pediatric Environmental Health Center at Boston Children’s Hospital, has a few ideas about how providers can step up their lead game, including partnering with their local health department. 

The CDC funds Childhood Lead Poisoning Prevention Programs based in state and local health departments to work with clinicians to improve rates of blood lead testing, monitor the prevalence of lead in their jurisdictions, and ensure that a system of referral is available for treatment and lead remediation services in the home.

Dr. Woolf also suggested that clinicians refer patients under age 3 years with high BLLs to their local Early Intervention Program. 

“They’ll assess their child’s development, their speech, their motor skills, their social skills, and if they qualify, it’s free,” Dr. Woolf said. 

He cited research showing children with elevated lead levels who received early intervention services performed better in grade school than equally exposed children who did not access similar services.

Another key strategy for pediatric clinicians is to learn local or state regulations for testing children for lead and how to access lead surveillance data in their practice area. Children who reside in high-risk areas are automatic candidates for screening. 

Dr. Woolf pointed out that big cities are not the only localities with lead in the drinking water. If families are drawing water from their own well, they should collect that water annually to have it tested for lead and microbes.

At the clinic-wide level, Dr. Woolf recommends the use of blood lead testing as a quality improvement measure. For example, Akron Children’s Hospital developed a quality improvement initiative using a clinical decision support tool to raise screening rates in their network of 30 clinics. One year after beginning the project, lead screenings during 12-month well visits increased from 71% to 96%. 

“What we’re interested in as pediatric health professionals is eliminating all background sources of lead in a child’s environment,” Dr. Woolf said. “Whether that’s applesauce pouches, whether that’s lead-containing paint, lead in water, lead in spices, or lead in imported pottery or cookware — there are just a tremendous number of sources of lead that we can do something about.”

None of the subjects reported financial conflicts of interest.

A former pediatrician, Dr. Thomas is a freelance science writer living in Portland, Oregon.

A version of this article appeared on Medscape.com.

A San Antonio oncology practice and diagnostic reference laboratory have agreed to settle a federal lawsuit, which alleged the two entities had entered an unlawful kickback arrangement.

The US Department of Justice (DOJ) announced on April 2 that Oncology San Antonio, PA, and its physicians have agreed to pay $1.3 million, and CorePath Laboratories, PA, has agreed to pay nearly $2.75 million plus accrued interest in civil settlements with the United States and Texas for alleged violations of the False Claims Act.

According to the DOJ, the diagnostic reference laboratory, CorePath Laboratories, conducted in-office bone marrow biopsies at Oncology San Antonio practice locations and performed diagnostic testing on the samples. CorePath Laboratories agreed to pay $115 for each biopsy referred by Oncology San Antonio physicians, and these biopsy payments were allegedly paid to the private practices of three physicians at Oncology San Antonio. This arrangement allegedly began in August 2016.

The DOJ claimed that the payments for referring biopsies constituted illegal kickbacks under the Anti-Kickback Statute, which prohibits offering or receiving payments to encourage referrals of services covered by federal healthcare programs like Medicare and Medicaid.

“Violations of the Anti-Kickback Statute involving oncology services can waste scarce federal healthcare program funds and corrupt the medical decision-making process,” Special Agent in Charge Jason E. Meadows with the US Department of Health and Human Services Office of Inspector General said in a statement.

Oncology San Antonio told this news organization that the cost and distraction of prolonged litigation were the primary factors in its decision to settle. “The decision to settle was an extremely difficult one because Oncology San Antonio was confident that it would have prevailed in any action,” the practice said via email.

This civil settlement with Oncology San Antonio also resolved allegations that a physician affiliated with the practice, Jayasree Rao, MD, provided unnecessary tests, services, and treatments to patients covered by Medicare, TRICARE, and Texas Medicaid in the San Antonio Metro Area and billed these federal healthcare programs for the unnecessary services.

The DOJ identified Slavisa Gasic, MD, a physician formerly employed by Dr. Rao, as a whistleblower in the investigation. When asked for comment, Oncology San Antonio alleged Dr. Gasic was “disgruntled for not being promoted.”

According to Oncology San Antonio, the contract for bone marrow biopsies was negotiated and signed by a former nonphysician officer of the company without the input of Oncology San Antonio physicians. The contract permitted bone marrow biopsies at Oncology San Antonio clinics instead of requiring older adult and sick patients to go to a different facility for these services.

“Oncology San Antonio and Rao vehemently denied Gasic’s allegations as wholly unfounded,” the company told this news organization.

Dr. Rao retired in March and is no longer practicing. CorePath Laboratories, PA, did not respond to this news organization’s request for comment.

According to the DOJ press release, the “investigation and resolution of this matter illustrate the government’s emphasis on combating healthcare fraud.”
 

A version of this article appeared on Medscape.com.

A San Antonio oncology practice and diagnostic reference laboratory have agreed to settle a federal lawsuit, which alleged the two entities had entered an unlawful kickback arrangement.

The US Department of Justice (DOJ) announced on April 2 that Oncology San Antonio, PA, and its physicians have agreed to pay $1.3 million, and CorePath Laboratories, PA, has agreed to pay nearly $2.75 million plus accrued interest in civil settlements with the United States and Texas for alleged violations of the False Claims Act.

According to the DOJ, the diagnostic reference laboratory, CorePath Laboratories, conducted in-office bone marrow biopsies at Oncology San Antonio practice locations and performed diagnostic testing on the samples. CorePath Laboratories agreed to pay $115 for each biopsy referred by Oncology San Antonio physicians, and these biopsy payments were allegedly paid to the private practices of three physicians at Oncology San Antonio. This arrangement allegedly began in August 2016.

The DOJ claimed that the payments for referring biopsies constituted illegal kickbacks under the Anti-Kickback Statute, which prohibits offering or receiving payments to encourage referrals of services covered by federal healthcare programs like Medicare and Medicaid.

“Violations of the Anti-Kickback Statute involving oncology services can waste scarce federal healthcare program funds and corrupt the medical decision-making process,” Special Agent in Charge Jason E. Meadows with the US Department of Health and Human Services Office of Inspector General said in a statement.

Oncology San Antonio told this news organization that the cost and distraction of prolonged litigation were the primary factors in its decision to settle. “The decision to settle was an extremely difficult one because Oncology San Antonio was confident that it would have prevailed in any action,” the practice said via email.

This civil settlement with Oncology San Antonio also resolved allegations that a physician affiliated with the practice, Jayasree Rao, MD, provided unnecessary tests, services, and treatments to patients covered by Medicare, TRICARE, and Texas Medicaid in the San Antonio Metro Area and billed these federal healthcare programs for the unnecessary services.

The DOJ identified Slavisa Gasic, MD, a physician formerly employed by Dr. Rao, as a whistleblower in the investigation. When asked for comment, Oncology San Antonio alleged Dr. Gasic was “disgruntled for not being promoted.”

According to Oncology San Antonio, the contract for bone marrow biopsies was negotiated and signed by a former nonphysician officer of the company without the input of Oncology San Antonio physicians. The contract permitted bone marrow biopsies at Oncology San Antonio clinics instead of requiring older adult and sick patients to go to a different facility for these services.

“Oncology San Antonio and Rao vehemently denied Gasic’s allegations as wholly unfounded,” the company told this news organization.

Dr. Rao retired in March and is no longer practicing. CorePath Laboratories, PA, did not respond to this news organization’s request for comment.

According to the DOJ press release, the “investigation and resolution of this matter illustrate the government’s emphasis on combating healthcare fraud.”
 

A version of this article appeared on Medscape.com.

A San Antonio oncology practice and diagnostic reference laboratory have agreed to settle a federal lawsuit, which alleged the two entities had entered an unlawful kickback arrangement.

The US Department of Justice (DOJ) announced on April 2 that Oncology San Antonio, PA, and its physicians have agreed to pay $1.3 million, and CorePath Laboratories, PA, has agreed to pay nearly $2.75 million plus accrued interest in civil settlements with the United States and Texas for alleged violations of the False Claims Act.

According to the DOJ, the diagnostic reference laboratory, CorePath Laboratories, conducted in-office bone marrow biopsies at Oncology San Antonio practice locations and performed diagnostic testing on the samples. CorePath Laboratories agreed to pay $115 for each biopsy referred by Oncology San Antonio physicians, and these biopsy payments were allegedly paid to the private practices of three physicians at Oncology San Antonio. This arrangement allegedly began in August 2016.

The DOJ claimed that the payments for referring biopsies constituted illegal kickbacks under the Anti-Kickback Statute, which prohibits offering or receiving payments to encourage referrals of services covered by federal healthcare programs like Medicare and Medicaid.

“Violations of the Anti-Kickback Statute involving oncology services can waste scarce federal healthcare program funds and corrupt the medical decision-making process,” Special Agent in Charge Jason E. Meadows with the US Department of Health and Human Services Office of Inspector General said in a statement.

Oncology San Antonio told this news organization that the cost and distraction of prolonged litigation were the primary factors in its decision to settle. “The decision to settle was an extremely difficult one because Oncology San Antonio was confident that it would have prevailed in any action,” the practice said via email.

This civil settlement with Oncology San Antonio also resolved allegations that a physician affiliated with the practice, Jayasree Rao, MD, provided unnecessary tests, services, and treatments to patients covered by Medicare, TRICARE, and Texas Medicaid in the San Antonio Metro Area and billed these federal healthcare programs for the unnecessary services.

The DOJ identified Slavisa Gasic, MD, a physician formerly employed by Dr. Rao, as a whistleblower in the investigation. When asked for comment, Oncology San Antonio alleged Dr. Gasic was “disgruntled for not being promoted.”

According to Oncology San Antonio, the contract for bone marrow biopsies was negotiated and signed by a former nonphysician officer of the company without the input of Oncology San Antonio physicians. The contract permitted bone marrow biopsies at Oncology San Antonio clinics instead of requiring older adult and sick patients to go to a different facility for these services.

“Oncology San Antonio and Rao vehemently denied Gasic’s allegations as wholly unfounded,” the company told this news organization.

Dr. Rao retired in March and is no longer practicing. CorePath Laboratories, PA, did not respond to this news organization’s request for comment.

According to the DOJ press release, the “investigation and resolution of this matter illustrate the government’s emphasis on combating healthcare fraud.”
 

A version of this article appeared on Medscape.com.

Plant Parts and Nomenclature

Ficus carica (common fig) is a deciduous shrub or small tree with smooth gray bark that can grow up to 10 m in height (Figure 1). It is characterized by many spreading branches, but the trunk rarely grows beyond a diameter of 7 in. Its hairy leaves are coarse on the upper side and soft underneath with 3 to 7 deep lobes that can extend up to 25 cm in length or width; the leaves grow individually, alternating along the sides of the branches. Fig trees often can be seen adorning yards, gardens, and parks, especially in tropical and subtropical climates. Ficus carica should not be confused with Ficus benjamina (weeping fig), a common ornamental tree that also is used to provide shade in hot climates, though both can cause phototoxic skin eruptions.

The common fig tree originated in the Mediterranean and western Asia¹ and has been cultivated by humans since the second and third millennia bc for its fruit, which commonly is used to sweeten cookies, cakes, and jams.² Figs are the most commonly mentioned food plant in the Bible, with at least 56 references in the Old and New Testaments.³ The “fruit” technically is a syconium—a hollow fleshy receptacle with a small opening at the apex partly closed by small scales. It can be obovoid, turbinate, or pear shaped; can be 1 to 4 inches long; and can vary in color from yellowish green to coppery, bronze, or dark purple (Figure 2).

Ficus carica is a member of the Moraceae family (derived from the Latin name for the mulberry tree), which includes 53 genera and approximately 1400 species, of which about 850 belong to the genus Ficus (the Latin name for a fig tree). The term carica likely comes from the Latin word carricare (to load) to describe a tree loaded with figs. Family members include trees, shrubs, lianas, and herbs that usually contain laticifers with a milky latex.

Traditional Uses

For centuries, components of the fig tree have been used in herbal teas and pastes to treat ailments ranging from sore throats to diarrhea, though there is no evidence to support their efficacy.⁴ Ancient Indians and Egyptians used plants such as the common fig tree containing furocoumarins to induce hyperpigmentation in vitiligo.⁵

Phototoxic Components

The leaves and sap of the common fig tree contain psoralens, which are members of the furocoumarin group of chemical compounds and are the source of its phototoxicity. The fruit does not contain psoralens.^6-9 The tree also produces proteolytic enzymes such as protease, amylase, ficin, triterpenoids, and lipodiastase that enhance its phototoxic effects.⁸ Exposure to UV light between 320 and 400 nm following contact with these phototoxic components triggers a reaction in the skin over the course of 1 to 3 days.⁵ The psoralens bind in epidermal cells, cross-link the DNA, and cause cell-membrane destruction, leading to edema and necrosis.¹⁰ The delay in symptoms may be attributed to the time needed to synthesize acute-phase reaction proteins such as tumor necrosis factor α and IL-1.¹¹ In spring and summer months, an increased concentration of psoralens in the leaves and sap contribute to an increased incidence of phytophotodermatitis.⁹ Humidity and sweat also increase the percutaneous absorption of psoralens.^12,13

Allergens

Fig trees produce a latex protein that can cause cross-reactive hypersensitivity reactions in those allergic to F benjamina latex and rubber latex.⁶ The latex proteins in fig trees can act as airborne respiratory allergens. Ingestion of figs can produce anaphylactic reactions in those sensitized to rubber latex and F benjamina latex.⁷ Other plant families associated with phototoxic reactions include Rutaceae (lemon, lime, bitter orange), Apiaceae (formerly Umbelliferae)(carrot, parsnip, parsley, dill, celery, hogweed), and Fabaceae (prairie turnip).

Most cases of fig phytophotodermatitis begin with burning, pain, and/or itching within hours of sunlight exposure in areas of the skin that encountered components of the fig tree, often in a linear pattern. The affected areas become erythematous and edematous with formation of bullae and unilocular vesicles over the course of 1 to 3 days.^12,14,15 Lesions may extend beyond the region of contact with the fig tree as they spread across the skin due to sweat or friction, and pain may linger even after the lesions resolve.^12,13,16 Adults who handle fig trees (eg, pruning) are susceptible to phototoxic reactions, especially those using chain saws or other mechanisms that result in spray exposure, as the photosensitizing sap permeates the wood and bark of the entire tree.¹⁷ Similarly, children who handle fig leaves or sap during outdoor play can develop bullous eruptions. Severe cases have resulted in hospital admission after prolonged exposure.¹⁶ Additionally, irritant dermatitis may arise from contact with the trichomes or “hairs” on various parts of the plant.

Image provided with permission by Scott Norton, MD, MPH, MSc (Washington, DC).

Patients who use natural remedies containing components of the fig tree without the supervision of a medical provider put themselves at risk for unsafe or unwanted adverse effects, such as phytophotodermatitis.^12,15,16,18 An entire family presented with burns after they applied fig leaf extract to the skin prior to tanning outside in the sun.¹⁹ A 42-year-old woman acquired a severe burn covering 81% of the body surface after topically applying fig leaf tea to the skin as a tanning agent.²⁰ A subset of patients ingesting or applying fig tree components for conditions such as vitiligo, dermatitis, onychomycosis, and motor retardation developed similar cutaneous reactions.^13,14,21,22 Lesions resembling finger marks can raise concerns for potential abuse or neglect in children.²²

The differential diagnosis for fig phytophotodermatitis includes sunburn, chemical burns, drug-related photosensitivity, infectious lesions (eg, herpes simplex, bullous impetigo, Lyme disease, superficial lymphangitis), connective tissue disease (eg, systemic lupus erythematosus), contact dermatitis, and nonaccidental trauma.^12,15,18 Compared to sunburn, phytophotodermatitis tends to increase in severity over days following exposure and heals with dramatic hyperpigmentation, which also prompts visits to dermatology.¹²

Treatment

Treatment of fig phytophotodermatitis chiefly is symptomatic, including analgesia, appropriate wound care, and infection prophylaxis. Topical and systemic corticosteroids may aid in the resolution of moderate to severe reactions.^15,23,24 Even severe injuries over small areas or mild injuries to a high percentage of the total body surface area may require treatment in a burn unit. Patients should be encouraged to use mineral-based sunscreens on the affected areas to reduce the risk for hyperpigmentation. Individuals who regularly handle fig trees should use contact barriers including gloves and protective clothing (eg, long-sleeved shirts, long pants).

Plant Parts and Nomenclature

Ficus carica (common fig) is a deciduous shrub or small tree with smooth gray bark that can grow up to 10 m in height (Figure 1). It is characterized by many spreading branches, but the trunk rarely grows beyond a diameter of 7 in. Its hairy leaves are coarse on the upper side and soft underneath with 3 to 7 deep lobes that can extend up to 25 cm in length or width; the leaves grow individually, alternating along the sides of the branches. Fig trees often can be seen adorning yards, gardens, and parks, especially in tropical and subtropical climates. Ficus carica should not be confused with Ficus benjamina (weeping fig), a common ornamental tree that also is used to provide shade in hot climates, though both can cause phototoxic skin eruptions.

The common fig tree originated in the Mediterranean and western Asia¹ and has been cultivated by humans since the second and third millennia bc for its fruit, which commonly is used to sweeten cookies, cakes, and jams.² Figs are the most commonly mentioned food plant in the Bible, with at least 56 references in the Old and New Testaments.³ The “fruit” technically is a syconium—a hollow fleshy receptacle with a small opening at the apex partly closed by small scales. It can be obovoid, turbinate, or pear shaped; can be 1 to 4 inches long; and can vary in color from yellowish green to coppery, bronze, or dark purple (Figure 2).

Ficus carica is a member of the Moraceae family (derived from the Latin name for the mulberry tree), which includes 53 genera and approximately 1400 species, of which about 850 belong to the genus Ficus (the Latin name for a fig tree). The term carica likely comes from the Latin word carricare (to load) to describe a tree loaded with figs. Family members include trees, shrubs, lianas, and herbs that usually contain laticifers with a milky latex.

Traditional Uses

For centuries, components of the fig tree have been used in herbal teas and pastes to treat ailments ranging from sore throats to diarrhea, though there is no evidence to support their efficacy.⁴ Ancient Indians and Egyptians used plants such as the common fig tree containing furocoumarins to induce hyperpigmentation in vitiligo.⁵

Phototoxic Components

The leaves and sap of the common fig tree contain psoralens, which are members of the furocoumarin group of chemical compounds and are the source of its phototoxicity. The fruit does not contain psoralens.^6-9 The tree also produces proteolytic enzymes such as protease, amylase, ficin, triterpenoids, and lipodiastase that enhance its phototoxic effects.⁸ Exposure to UV light between 320 and 400 nm following contact with these phototoxic components triggers a reaction in the skin over the course of 1 to 3 days.⁵ The psoralens bind in epidermal cells, cross-link the DNA, and cause cell-membrane destruction, leading to edema and necrosis.¹⁰ The delay in symptoms may be attributed to the time needed to synthesize acute-phase reaction proteins such as tumor necrosis factor α and IL-1.¹¹ In spring and summer months, an increased concentration of psoralens in the leaves and sap contribute to an increased incidence of phytophotodermatitis.⁹ Humidity and sweat also increase the percutaneous absorption of psoralens.^12,13

Allergens

Fig trees produce a latex protein that can cause cross-reactive hypersensitivity reactions in those allergic to F benjamina latex and rubber latex.⁶ The latex proteins in fig trees can act as airborne respiratory allergens. Ingestion of figs can produce anaphylactic reactions in those sensitized to rubber latex and F benjamina latex.⁷ Other plant families associated with phototoxic reactions include Rutaceae (lemon, lime, bitter orange), Apiaceae (formerly Umbelliferae)(carrot, parsnip, parsley, dill, celery, hogweed), and Fabaceae (prairie turnip).

Most cases of fig phytophotodermatitis begin with burning, pain, and/or itching within hours of sunlight exposure in areas of the skin that encountered components of the fig tree, often in a linear pattern. The affected areas become erythematous and edematous with formation of bullae and unilocular vesicles over the course of 1 to 3 days.^12,14,15 Lesions may extend beyond the region of contact with the fig tree as they spread across the skin due to sweat or friction, and pain may linger even after the lesions resolve.^12,13,16 Adults who handle fig trees (eg, pruning) are susceptible to phototoxic reactions, especially those using chain saws or other mechanisms that result in spray exposure, as the photosensitizing sap permeates the wood and bark of the entire tree.¹⁷ Similarly, children who handle fig leaves or sap during outdoor play can develop bullous eruptions. Severe cases have resulted in hospital admission after prolonged exposure.¹⁶ Additionally, irritant dermatitis may arise from contact with the trichomes or “hairs” on various parts of the plant.

Image provided with permission by Scott Norton, MD, MPH, MSc (Washington, DC).

Patients who use natural remedies containing components of the fig tree without the supervision of a medical provider put themselves at risk for unsafe or unwanted adverse effects, such as phytophotodermatitis.^12,15,16,18 An entire family presented with burns after they applied fig leaf extract to the skin prior to tanning outside in the sun.¹⁹ A 42-year-old woman acquired a severe burn covering 81% of the body surface after topically applying fig leaf tea to the skin as a tanning agent.²⁰ A subset of patients ingesting or applying fig tree components for conditions such as vitiligo, dermatitis, onychomycosis, and motor retardation developed similar cutaneous reactions.^13,14,21,22 Lesions resembling finger marks can raise concerns for potential abuse or neglect in children.²²

The differential diagnosis for fig phytophotodermatitis includes sunburn, chemical burns, drug-related photosensitivity, infectious lesions (eg, herpes simplex, bullous impetigo, Lyme disease, superficial lymphangitis), connective tissue disease (eg, systemic lupus erythematosus), contact dermatitis, and nonaccidental trauma.^12,15,18 Compared to sunburn, phytophotodermatitis tends to increase in severity over days following exposure and heals with dramatic hyperpigmentation, which also prompts visits to dermatology.¹²

Treatment

Treatment of fig phytophotodermatitis chiefly is symptomatic, including analgesia, appropriate wound care, and infection prophylaxis. Topical and systemic corticosteroids may aid in the resolution of moderate to severe reactions.^15,23,24 Even severe injuries over small areas or mild injuries to a high percentage of the total body surface area may require treatment in a burn unit. Patients should be encouraged to use mineral-based sunscreens on the affected areas to reduce the risk for hyperpigmentation. Individuals who regularly handle fig trees should use contact barriers including gloves and protective clothing (eg, long-sleeved shirts, long pants).

Plant Parts and Nomenclature

Ficus carica (common fig) is a deciduous shrub or small tree with smooth gray bark that can grow up to 10 m in height (Figure 1). It is characterized by many spreading branches, but the trunk rarely grows beyond a diameter of 7 in. Its hairy leaves are coarse on the upper side and soft underneath with 3 to 7 deep lobes that can extend up to 25 cm in length or width; the leaves grow individually, alternating along the sides of the branches. Fig trees often can be seen adorning yards, gardens, and parks, especially in tropical and subtropical climates. Ficus carica should not be confused with Ficus benjamina (weeping fig), a common ornamental tree that also is used to provide shade in hot climates, though both can cause phototoxic skin eruptions.

The common fig tree originated in the Mediterranean and western Asia¹ and has been cultivated by humans since the second and third millennia bc for its fruit, which commonly is used to sweeten cookies, cakes, and jams.² Figs are the most commonly mentioned food plant in the Bible, with at least 56 references in the Old and New Testaments.³ The “fruit” technically is a syconium—a hollow fleshy receptacle with a small opening at the apex partly closed by small scales. It can be obovoid, turbinate, or pear shaped; can be 1 to 4 inches long; and can vary in color from yellowish green to coppery, bronze, or dark purple (Figure 2).

Ficus carica is a member of the Moraceae family (derived from the Latin name for the mulberry tree), which includes 53 genera and approximately 1400 species, of which about 850 belong to the genus Ficus (the Latin name for a fig tree). The term carica likely comes from the Latin word carricare (to load) to describe a tree loaded with figs. Family members include trees, shrubs, lianas, and herbs that usually contain laticifers with a milky latex.

Traditional Uses

For centuries, components of the fig tree have been used in herbal teas and pastes to treat ailments ranging from sore throats to diarrhea, though there is no evidence to support their efficacy.⁴ Ancient Indians and Egyptians used plants such as the common fig tree containing furocoumarins to induce hyperpigmentation in vitiligo.⁵

Phototoxic Components

The leaves and sap of the common fig tree contain psoralens, which are members of the furocoumarin group of chemical compounds and are the source of its phototoxicity. The fruit does not contain psoralens.^6-9 The tree also produces proteolytic enzymes such as protease, amylase, ficin, triterpenoids, and lipodiastase that enhance its phototoxic effects.⁸ Exposure to UV light between 320 and 400 nm following contact with these phototoxic components triggers a reaction in the skin over the course of 1 to 3 days.⁵ The psoralens bind in epidermal cells, cross-link the DNA, and cause cell-membrane destruction, leading to edema and necrosis.¹⁰ The delay in symptoms may be attributed to the time needed to synthesize acute-phase reaction proteins such as tumor necrosis factor α and IL-1.¹¹ In spring and summer months, an increased concentration of psoralens in the leaves and sap contribute to an increased incidence of phytophotodermatitis.⁹ Humidity and sweat also increase the percutaneous absorption of psoralens.^12,13

Allergens

Fig trees produce a latex protein that can cause cross-reactive hypersensitivity reactions in those allergic to F benjamina latex and rubber latex.⁶ The latex proteins in fig trees can act as airborne respiratory allergens. Ingestion of figs can produce anaphylactic reactions in those sensitized to rubber latex and F benjamina latex.⁷ Other plant families associated with phototoxic reactions include Rutaceae (lemon, lime, bitter orange), Apiaceae (formerly Umbelliferae)(carrot, parsnip, parsley, dill, celery, hogweed), and Fabaceae (prairie turnip).

Most cases of fig phytophotodermatitis begin with burning, pain, and/or itching within hours of sunlight exposure in areas of the skin that encountered components of the fig tree, often in a linear pattern. The affected areas become erythematous and edematous with formation of bullae and unilocular vesicles over the course of 1 to 3 days.^12,14,15 Lesions may extend beyond the region of contact with the fig tree as they spread across the skin due to sweat or friction, and pain may linger even after the lesions resolve.^12,13,16 Adults who handle fig trees (eg, pruning) are susceptible to phototoxic reactions, especially those using chain saws or other mechanisms that result in spray exposure, as the photosensitizing sap permeates the wood and bark of the entire tree.¹⁷ Similarly, children who handle fig leaves or sap during outdoor play can develop bullous eruptions. Severe cases have resulted in hospital admission after prolonged exposure.¹⁶ Additionally, irritant dermatitis may arise from contact with the trichomes or “hairs” on various parts of the plant.

Image provided with permission by Scott Norton, MD, MPH, MSc (Washington, DC).

Patients who use natural remedies containing components of the fig tree without the supervision of a medical provider put themselves at risk for unsafe or unwanted adverse effects, such as phytophotodermatitis.^12,15,16,18 An entire family presented with burns after they applied fig leaf extract to the skin prior to tanning outside in the sun.¹⁹ A 42-year-old woman acquired a severe burn covering 81% of the body surface after topically applying fig leaf tea to the skin as a tanning agent.²⁰ A subset of patients ingesting or applying fig tree components for conditions such as vitiligo, dermatitis, onychomycosis, and motor retardation developed similar cutaneous reactions.^13,14,21,22 Lesions resembling finger marks can raise concerns for potential abuse or neglect in children.²²

The differential diagnosis for fig phytophotodermatitis includes sunburn, chemical burns, drug-related photosensitivity, infectious lesions (eg, herpes simplex, bullous impetigo, Lyme disease, superficial lymphangitis), connective tissue disease (eg, systemic lupus erythematosus), contact dermatitis, and nonaccidental trauma.^12,15,18 Compared to sunburn, phytophotodermatitis tends to increase in severity over days following exposure and heals with dramatic hyperpigmentation, which also prompts visits to dermatology.¹²

Treatment

Treatment of fig phytophotodermatitis chiefly is symptomatic, including analgesia, appropriate wound care, and infection prophylaxis. Topical and systemic corticosteroids may aid in the resolution of moderate to severe reactions.^15,23,24 Even severe injuries over small areas or mild injuries to a high percentage of the total body surface area may require treatment in a burn unit. Patients should be encouraged to use mineral-based sunscreens on the affected areas to reduce the risk for hyperpigmentation. Individuals who regularly handle fig trees should use contact barriers including gloves and protective clothing (eg, long-sleeved shirts, long pants).

In 2023, ESPEN (the European Society for Clinical Nutrition and Metabolism) published consensus recommendations highlighting the importance of regular monitoring and treatment of nutrient deficiencies in patients with inflammatory bowel disease (IBD) for improved prognosis, mortality, and quality of life.¹ Suboptimal nutrition in patients with IBD predominantly results from inflammation of the gastrointestinal (GI) tract leading to malabsorption; however, medications commonly used to manage IBD also can contribute to malnutrition.^2,3 Additionally, patients may develop nausea and food avoidance due to medication or the disease itself, leading to nutritional withdrawal and eventual deficiency.⁴ Even with the development of diets focused on balancing nutritional needs and decreasing inflammation,⁵ offsetting this aversion to food can be difficult to overcome.²

Cutaneous manifestations of IBD are multifaceted and can be secondary to the disease, reactive to or associated with IBD, or effects from nutritional deficiencies. The most common vitamin and nutrient deficiencies in patients with IBD include iron; zinc; calcium; vitamin D; and vitamins B₆ (pyridoxine), B₉ (folic acid), and B₁₂.⁶ Malnutrition may manifest with cutaneous disease, and dermatologists can be the first to identify and assess for nutritional deficiencies. In this article, we review the mechanisms of these micronutrient depletions in the context of IBD, their subsequent dermatologic manifestations (Table), and treatment and monitoring guidelines for each deficiency.

Iron

A systematic review conducted from 2007 to 2012 in European patients with IBD (N=2192) found the overall prevalence of anemia in this population to be 24% (95% CI, 18%-31%), with 57% of patients with anemia experiencing iron deficiency.⁷ Anemia is observed more commonly in patients hospitalized with IBD and is common in patients with both Crohn disease and ulcerative colitis.⁸

Pathophysiology—Iron is critically important in oxygen transportation throughout the body as a major component of hemoglobin. Physiologically, the low pH of the duodenum and proximal jejunum allows divalent metal transporter 1 to transfer dietary Fe³⁺ into enterocytes, where it is reduced to the transportable Fe²⁺.^9,10 Distribution of Fe²⁺ ions from enterocytes relies on ferroportin, an iron-transporting protein, which is heavily regulated by the protein hepcidin.¹¹ Hepcidin, a known acute phase reactant, will increase in the setting of active IBD, causing a depletion of ferroportin and an inability of the body to utilize the stored iron in enterocytes.¹² This poor utilization of iron stores combined with blood loss caused by inflammation in the GI tract is the proposed primary mechanism of iron-deficiency anemia observed in patients with IBD.¹³

Cutaneous Manifestations—From a dermatologic perspective, iron-deficiency anemia can manifest with a wide range of symptoms including glossitis, koilonychia, xerosis and/or pruritus, and brittle hair or hair loss.^14,15 Although the underlying pathophysiology of these cutaneous manifestations is not fully understood, there are several theories assessing the mechanisms behind the skin findings of iron deficiency.

Atrophic glossitis has been observed in many patients with iron deficiency and is thought to manifest due to low iron concentrations in the blood, thereby decreasing oxygen delivery to the papillae of the dorsal tongue with resultant atrophy.^16,17 Similarly, decreased oxygen delivery to the nail bed capillaries may cause deformities in the nail called koilonychia (or “spoon nails”).¹⁸ Iron is a key co-factor in collagen lysyl hydroxylase that promotes collagen binding; iron deficiency may lead to disruptions in the epidermal barrier that can cause pruritus and xerosis.¹⁹ An observational study of 200 healthy patients with a primary concern of pruritus found a correlation between low serum ferritin and a higher degree of pruritus (r=−0.768; P<.00001).²⁰

Evidence for iron’s role in hair growth comes from a mouse model study with a mutation in the serine protease TMPRSS6—a protein that regulates hepcidin and iron absorption—which caused an increase in hepcidin production and subsequent systemic iron deficiency. Mice at 4 weeks of age were devoid of all body hair but had substantial regrowth after initiation of a 2-week iron-rich diet, which suggests a connection between iron repletion and hair growth in mice with iron deficiency.²¹ Additionally, a meta-analysis analyzing the comorbidities of patients with alopecia areata found them to have higher odds (odds ratio [OR]=2.78; 95% CI, 1.23-6.29) of iron-deficiency anemia but no association with IBD (OR=1.48; 95% CI, 0.32-6.82).²²

Diagnosis and Monitoring—The American Gastroenterological Association recommends a complete blood cell count (CBC), serum ferritin, transferrin saturation (TfS), and C-reactive protein (CRP) as standard evaluations for iron deficiency in patients with IBD. Patients with active IBD should be screened every 3 months,and patients with inactive disease should be screened every 6 to 12 months.²³

Although ferritin and TfS often are used as markers for iron status in healthy individuals, they are positive and negative acute phase reactants, respectively. Using them to assess iron status in patients with IBD may inaccurately represent iron status in the setting of inflammation from the disease.²⁴ The European Crohn’s and Colitis Organisation (ECCO) produced guidelines to define iron deficiency as a TfS less than 20% or a ferritin level less than 30 µg/L in patients without evidence of active IBD and a ferritin level less than 100 µg/L for patients with active inflammation.²⁵

A 2020 multicenter observational study of 202 patients with diagnosed IBD found that the ECCO guideline of ferritin less than 30 µg/L had an area under the receiver operating characteristic (AUROC) curve of 0.69, a sensitivity of 0.43, and a specificity of 0.95 in their population.²⁶ In a sensitivity analysis stratifying patients by CRP level (<10 or ≥10 mg/L), the authors found that for patients with ulcerative colitis and a CRP less than 10 mg/L, a cut-off value of ferritin less than 65 µg/L (AUROC=0.78) had a sensitivity of 0.78 and specificity of 0.76, and a TfS value of less than 16% (AUROC=0.88) had a sensitivity of 0.79 and a specificity of 0.9. In patients with a CRP of 10 mg/L or greater, a cut-off value of ferritin 80 µg/L (AUROC=0.76) had a sensitivity of 0.75 and a specificity of 0.82, and a TfS value of less than 11% (AUROC=0.69) had a sensitivity of 0.79 and a specificity of 0.88. There were no ferritin cut-off values associated with good diagnostic performance (defined as both sensitivity and specificity >0.70) for iron deficiency in patients with Crohn disease.²⁶

The authors recommended using an alternative iron measurement such as soluble transferrin receptor (sTfR)/log ferritin ratio (TfR-F) that is not influenced by active inflammation and has a good correlation with ferritin values (TfR-F: r=0.66; P<.001).²⁶ However, both sTfR and TfR-F have high costs and intermethod variability as well as differences in their reference ranges depending on which laboratory performs the analysis, limiting the accessibility and practicality of easily obtaining these tests.²⁷ Although there may be inaccuracies for standard ferritin or TfS under ECCO guidelines, proposed alternatives have their own limitations, which may make ferritin and TfS the most reasonable evaluations of iron status as long as disease activity status at the time of testing is taken into consideration.

Treatment—Treatment of underlying iron deficiency in patients with IBD requires reversing the cause of the deficiency and supplementing iron. In patients with IBD, the options to supplement iron may be limited by active disease, making oral intake less effective. Oral iron supplementation also is associated with notable GI adverse effects that may be exacerbated in patients with IBD. A systematic review of 43 randomized controlled trials (RCTs) evaluating GI adverse effects (eg, nausea, abdominal pain, diarrhea, constipation, and black or tarry stools) of oral ferrous sulfate compared with placebo or intravenous (IV) iron supplementation in healthy nonanemic individuals found a significant increase in GI adverse effects with oral supplementation (placebo: OR=2.32; P<.0001; IV: OR=3.05; P<.0001).²⁸

Therefore, IV iron repletion may be necessary in patients with IBD and may require numerous infusions depending on the formulation of iron. In an RCT conducted in 2011, patients with iron-deficiency anemia with quiescent or mild to moderate IBD were treated with either IV iron sulfate or ferric carboxymaltose.²⁹ With a primary end point of hemoglobin response greater than 2 g/dL, the authors found that 150 of 240 patients responded to ferric carboxymaltose vs 118 of 235 treated with iron sulfate (P=.004). The dosing for ferric carboxymaltose was 1 to 3 infusions of 500 to 1000 mg of iron and for iron sulfate up to 11 infusions of 200 mg of iron.²⁹

Zinc

A systematic review of zinc deficiency in patients with IBD identified 7 studies including 2413 patients and revealed those with Crohn disease had a higher prevalence of zinc deficiency compared with patients with ulcerative colitis (54% vs 41%).³⁰

Pathophysiology—Zinc serves as a catalytic cofactor for enzymatic activity within proteins and immune cells.³¹ The homeostasis of zinc is tightly regulated within the brush border of the small intestine by zinc transporters ZIP4 and ZIP1 from the lumen of enterocytes into the bloodstream.³² Inflammation in the small intestine due to Crohn disease can result in zinc malabsorption.

Ranaldi et al³³ exposed intestinal cells and zinc-depleted intestinal cells to tumor necrosis factor α media to simulate an inflammatory environment. They measured transepithelial electrical resistance as a surrogate for transmembrane permeability and found that zinc-depleted cells had a statistically significantly higher transepithelial electrical resistance percentage (60% reduction after 4 hours; P<1.10^–6) when exposed to tumor necrosis factor α signaling compared with normal intestinal cells. They concluded that zinc deficiency can increase intestinal permeability in the presence of inflammation, creating a cycle of further nutrient malabsorption and inflammation exacerbating IBD symptoms.³³

Cutaneous Manifestations—After absorption in the small intestine, approximately 5% of zinc resides in the skin, with the highest concentration in the stratum spinosum.³⁴ A cell study found that keratinocytes in zinc-deficient environments had higher rates of apoptosis compared with cells in normal media. The authors proposed that this higher rate of apoptosis and the resulting inflammation could be a mechanism for developing the desquamative or eczematous scaly plaques that are common cutaneous manifestations of zinc deficiency.³⁵

Other cutaneous findings may include angular cheilitis, stomatitis, glossitis, paronychia, onychodystrophy, generalized alopecia, and delayed wound healing.³⁶ The histopathology of these skin lesions is characterized by granular layer loss, epidermal pallor, confluent parakeratosis, spongiosis, dyskeratosis, and psoriasiform hyperplasia.³⁷

Diagnosis and Monitoring—Assessing serum zinc levels is challenging, as they may decrease during states of inflammation.³⁸ A mouse model study showed a 3.1-fold increase (P<.001) in ZIP14 expression in wild-type mice compared with an IL-6 -/- knock-down model after IL-6 exposure. The authors concluded that the upregulation of ZIP14 in the liver due to inflammatory cytokine upregulation decreases zinc availability in serum.³⁹ Additionally, serum zinc can overestimate the level of deficiency in IBD because approximately 75% of serum zinc is bound to albumin, which decreases in the setting of inflammation.^40-42

Alternatively, alkaline phosphatase (AP), a zinc-dependent metalloenzyme, may be a better evaluator of zinc status during periods of inflammation. A study in rats evaluated zinc through serum zinc levels and AP levels after a period of induced stress to mimic a short-term inflammatory state.⁴³ The researchers found that total body stores of zinc were unaffected throughout the experiment; only serum zinc declined throughout the experiment duration while AP did not. Because approximately 75% of serum zinc is bound to serum albumin,⁴² the researchers concluded the induced inflammatory state depleted serum albumin and redistributed zinc to the liver, causing the observed serum zinc changes, while total body zinc levels and AP were largely unaffected in comparison.⁴³ Comorbid conditions such as liver or bone disease can increase AP levels, which limits the utility of AP as a surrogate for zinc in patients with comorbidities.⁴⁴ However, even in the context of active IBD, serum zinc still is currently considered the best biomarker to evaluate zinc status.⁴⁵

Treatment—The recommended dose for zinc supplementation is 20 to 40 mg daily with higher doses (>50 mg/d) for patients with malabsorptive syndromes such as IBD.⁴⁶ It can be administered orally or parenterally. Although rare, zinc replacement therapy may be associated with diarrhea, nausea, vomiting, mild headaches, and fatigue.⁴⁶ Additional considerations should be taken when repleting other micronutrients with zinc, as calcium and folate can inhibit zinc reabsorption, while zinc itself can inhibit iron and copper reabsorption.⁴⁷

Vitamin D and Calcium

Low vitamin D levels (<50 nmol/L) and hypocalcemia (<8.8 mg/dL) are common in patients with IBD.^48,49

Pathophysiology—Vitamin D levels are maintained via 2 mechanisms. The first mechanism is through the skin, as keratinocytes produce 7-dehydrocholesterol after exposure to UV light, which is converted into previtamin D₃ and then thermally isomerizes into vitamin D₃. This vitamin D₃ is then transported to the liver on vitamin D–binding protein.⁵⁰ The second mechanism is through oral vitamin D₃ that is absorbed through vitamin D receptors in intestinal epithelium and transported to the liver, where it is hydroxylated into 25-hydroxyvitamin D (25[OH]D), then to the kidneys for hydroxylation to 1,25(OH)₂D for redistribution throughout the body.⁵⁰ This activated form of vitamin D regulates calcium absorption in the intestine, and optimal vitamin D levels are necessary to absorb calcium efficiently.⁵¹ Inflammation from IBD within the small intestine can downregulate vitamin D receptors, causing malabsorption and decreased serum vitamin D.⁵²

Vitamin D signaling also is vital to maintaining the tight junctions and adherens junctions of the intestinal epithelium. Weakening the permeability of the epithelium further exacerbates malabsorption and subsequent vitamin D deficiency.⁵² A meta-analysis of 27 studies including 8316 patients with IBD showed low vitamin D levels were associated with increased odds of disease activity (OR=1.53; 95% CI, 1.32-1.77), mucosal inflammation (OR=1.25; 95% CI, 1.06-1.47), and future clinical relapse (OR=1.23; 95% CI, 1.03-1.47) in patients with Crohn disease. The authors concluded that low levels of vitamin D could be used as a potential biomarker of inflammatory status in Crohn disease.⁵³

Vitamin D and calcium are further implicated in maintaining skeletal health,⁴⁷ while vitamin D specifically helps maintain intestinal homeostasis⁵⁴ and immune system modulation in the skin.⁵⁵

Cutaneous Manifestations—Vitamin D is thought to play crucial roles in skin differentiation and proliferation, cutaneous innate immunity, hair follicle cycling, photoprotection, and wound healing.⁵⁶ Vitamin D deficiency has been observed in a large range of cutaneous diseases including skin cancer, psoriasis, vitiligo, bullous pemphigoid, atopic dermatitis, and various types of alopecia.^56-59 It is unclear whether vitamin D deficiency facilitates these disease processes or is merely the consequence of a disrupted cutaneous surface with the inability to complete the first step in vitamin D processing. A 2014 meta-analysis of 290 prospective cohort studies and 172 randomized trials concluded that 25(OH)D deficiency was associated with ill health and did not find causal evidence for any specific disease, dermatologic or otherwise.⁶⁰ Calcium deficiency may cause epidermal changes including dry skin, coarse hair, and brittle nails.⁶¹

Diagnosis and Monitoring—The ECCO guidelines recommend obtaining serum 25(OH)D levels every 3 months in patients with IBD.⁶² Levels less than 75 nmol/L are considered deficient, and a value less than 30 nmol/L increases the risk for osteomalacia and nutritional rickets, constituting severe vitamin D deficiency.^63-65

An observational study of 325 patients with IBD showed a statistically significant negative correlation between serum vitamin D and fecal calprotectin (r=−0.19; P<.001), a stool-based marker for gut inflammation, supporting vitamin D as a potential biomarker in IBD.⁶⁶

Evaluation of calcium can be done through serum levels in patients with IBD.⁶⁷ Patients with IBD are at risk for hypoalbuminemia; therefore, consideration should be taken to ensure calcium levels are corrected, as approximately 50% of calcium is bound to albumin or other ions in the body,⁶⁸ which can be done by adjusting the calcium concentration by 0.02 mmol/L for every 1 g/L of albumin above or below 40 g/L. In the most critically ill patients, a direct ionized calcium blood level should be used instead because the previously mentioned correction calculations are inaccurate when albumin is critically low.⁶⁹

Treatment—The ECCO guidelines recommend calcium and vitamin D repletion of 500 to 1000 mg and 800 to 1000 U, respectively, in patients with IBD on systemic corticosteroids to prevent the negative effects of bone loss.⁶² Calcium repletion in patients with IBD who are not on systemic steroids are the same as for the general population.⁶⁵

Vitamin D repletion also may help decrease IBD activity. In a prospective study, 10,000 IU/d of vitamin D in 10 patients with IBD—adjusted over 12 weeks to a target of 100 to 125 nmol/L of serum 25(OH)D—showed a significant reduction in clinical Crohn activity (P=.019) over the study period.⁷⁰ In contrast, 2000 IU/d for 3 months in an RCT of 27 patients with Crohn disease found significantly lower CRP (P=.019) and significantly higher self-reported quality of life (P=.037) but nonsignificant decreases in Crohn activity (P=.082) in patients with 25(OH)D levels of 75 nmol/L or higher compared with those with 25(OH)D levels less than 75 nmol/L.⁷¹

These discrepancies illustrate the need for expanded clinical trials to elucidate the optimal vitamin D dosing for patients with IBD. Ultimately, assessing vitamin D and calcium status and considering repletion in patients with IBD, especially those with comorbid dermatologic diseases such as poor wound healing, psoriasis, or atopic dermatitis, is important.

Vitamin B₆ (Pyridoxine)

Pathophysiology—Pyridoxine is an important coenzyme for many functions including amino acid transamination, fatty acid metabolism, and conversion of tryptophan to niacin. It is absorbed in the jejunum and ileum and subsequently transported to the liver for rephosphorylation and release into its active form.³⁶ An observational study assessing the nutritional status of patients with IBD found that only 5.7% of 105 patients with food records had inadequate dietary intake of pyridoxine, but 29% of all patients with IBD had subnormal pyridoxine levels.⁷² Additionally, they found no significant difference in the prevalence of subnormal pyridoxine levels in patients with active IBD vs IBD in remission. The authors suggested that the subnormal pyridoxine levels in patients with IBD likely were multifactorial and resulted from malabsorption due to active disease, inflammation, and inadequate intake.⁷²

Cutaneous Manifestations—Cutaneous findings associated with pyridoxine deficiency include periorificial and perineal dermatitis,⁷³ angular stomatitis, and cheilitis with associated burning, redness, and tongue edema.³⁶ Additionally, pyridoxine is involved in the conversion of tryptophan to niacin, and its deficiency may manifest with pellagralike findings.⁷⁴

Because pyridoxine is critical to protein metabolism, its deficiency may disrupt key cellular structures that rely on protein concentrations to maintain structural integrity. One such structure in the skin that heavily relies on protein concentrations is the ground substance of the extracellular matrix—the amorphous gelatinous spaces that occupy the areas between the extracellular matrix, which consists of cross-linked glycosaminoglycans and proteins.⁷⁵ Without protein, ground substance increases in viscosity and can disrupt the epidermal barrier, leading to increased transepidermal water loss and ultimately inflammation.⁷⁶ Although this theory has yet to be validated fully, this is a potential mechanistic explanation for the inflammation in dermal papillae that leads to dermatitis observed in pyridoxine deficiency.

Diagnosis and Monitoring—Direct biomarkers of pyridoxine status are in serum, plasma, erythrocytes, and urine, with the most common measurement in plasma as pyridoxal 5′-phosphate (PLP).⁷⁷ Plasma PLP concentrations lower than 20 nmol/L are suggestive of deficiency.⁷⁸ Plasma PLP has shown inverse relationships with acute phase inflammatory markers CRP⁷⁹ and AP,⁷⁸ thereby raising concerns for its validity to assess pyridoxine status in patients with symptomatic IBD.⁸⁰

Alternative evaluations of pyridoxine include tryptophan and methionine loading tests,³⁶ which are measured via urinary excretion and require normal kidney function to be accurate. They should be considered in IBD if necessary, but routine testing, even in patients with symptomatic IBD, is not recommended in the ECCO guidelines. Additional considerations should be taken in patients with altered nutrient requirements such as those who have undergone bowel resection due to highly active disease or those who receive parenteral nutritional supplementation.⁸¹

Treatment—Recommendations for oral pyridoxine supplementation range from 25 to 600 mg daily,⁸² with symptoms typically improving on 100 mg daily.³⁶ Pyridoxine supplementation may have additional benefits for patients with IBD and potentially modulate disease severity. An IL-10 knockout mouse supplemented with pyridoxine had an approximately 60% reduction (P<.05) in inflammation compared to mice deficient in pyridoxine.⁸³ The authors suggest that PLP-dependent enzymes can inhibit further proinflammatory signaling and T-cell migration that can exacerbate IBD. Ultimately, more data is needed before determining the efficacy of pyridoxine supplementation for active IBD.

Vitamin B₁₂ and Vitamin B₉ (Folic Acid)

Pathophysiology—Vitamin B₁₂ is reabsorbed in the terminal ileum, the distal portion of the small intestine. The American Gastroenterological Association recommends that patients with a history of extensive ileal disease or prior ileal surgery, which is the case for many patients with Crohn disease, be monitored for vitamin B₁₂ deficiency.²³ Monitoring and rapid supplementation of vitamin B₁₂ can prevent pernicious anemia and irreversible neurologic damage that may result from deficiency.⁸⁴

Folic acid is primarily absorbed in the duodenum and jejunum of the small intestine. A meta-analysis performed in 2017 assessed studies observing folic acid and vitamin B₁₂ levels in 1086 patients with IBD compared with 1484 healthy controls and found an average difference in serum folate concentration of 0.46 nmol/L (P<.001).⁸⁴ Interestingly, this study did not find a significant difference in serum vitamin B₁₂ levels between patients with IBD and healthy controls, highlighting the mechanism of vitamin B₁₂ deficiency in IBD because only patients with terminal ileal involvement are at risk for malabsorption and subsequent deficiency.

Cutaneous Manifestations—Both vitamin B₁₂ and folic acid deficiency can manifest as cheilitis, glossitis, and/or generalized hyperpigmentation that is accentuated in the flexural areas, palms, soles, and oral cavity.^85,86 Systemic symptoms of patients with vitamin B₁₂ and folic acid deficiency include megaloblastic anemia, pallor, and fatigue. A potential mechanism for the hyperpigmentation observed from vitamin B₁₂ deficiency came from an electron microscope study that showed an increased concentration of melanosomes in a patient with deficiency.⁸⁷

Diagnosis and Monitoring—In patients with suspected vitamin B₁₂ and/or folic acid deficiency, initial evaluation should include a CBC with peripheral smear and serum vitamin B₁₂ and folate levels. In cases for which the diagnosis still is unclear after initial testing, methylmalonic acid and homocysteine levels can help differentiate between the 2 deficiencies. Methylmalonic acid classically is elevated (>260 nmol/L) in vitamin B₁₂ deficiency but not in folate deficiency.⁸⁸ Cut-off values for vitamin B₁₂ deficiency are less than 200 to 250 pg/mL forserum vitamin B₁₂ and/or an elevated level of methylmalonic acid (>0.271 µmol/L).⁸⁹ A serum folic acid value greater than 3 ng/mL and/or erythrocyte folate concentrations greater than 140 ng/mL are considered adequate, whereas an indicator of folic acid deficiency is a homocysteine level less than 10 µmol/L.⁹⁰ A CBC can screen for macrocytic megaloblastic anemias (mean corpuscular volume >100 fl), which are classic diagnostic signs of an underlying vitamin B₁₂ or folate deficiency.

Treatment—According to the Centers for Disease Control and Prevention, supplementation of vitamin B₁₂ can be done orally with 1000 µg daily in patients with deficiency. In patients with active IBD, oral reabsorption of vitamin B₁₂ can be less effective, making subcutaneous or intramuscular administration (1000 µg/wk for 8 weeks, then monthly for life) better options.⁸⁹

Patients with IBD managed with methotrexate should be screened carefully for folate deficiency. Methotrexate is a folate analog that sometimes is used for the treatment of IBD. Reversible competitive inhibition of dihydrofolate reductase can precipitate a systemic folic acid decrease.⁹¹ Typically, oral folic acid (1 to 5 mg/d) is sufficient to treat folate deficiency, with the ESPEN recommending 5 mg once weekly 24 to 72 hours after methotrexate treatment or 1 mg daily for 5 days per week in patients with IBD.¹ Alternative formulations—IV, subcutaneous, or intramuscular—are available for patients who cannot tolerate oral intake.⁹²

Final Thoughts

Dermatologists can be the first to observe the cutaneous manifestations of micronutrient deficiencies. Although the symptoms of each micronutrient deficiency discussed may overlap, attention to small clinical clues in patients with IBD can improve patient outcomes and quality of life. For example, koilonychia with glossitis and xerosis likely is due to iron deficiency, while zinc deficiency should be suspected in patients with scaly eczematous plaques in skin folds. A high level of suspicion for micronutrient deficiencies in patients with IBD should be followed by a complete patient history, review of systems, and thorough clinical examination. A thorough laboratory evaluation can pinpoint nutritional deficiencies in patients with IBD, keeping in mind that specific biomarkers such as ferritin and serum zinc also act as acute phase reactants and should be interpreted in this context. Co-management with gastroenterologists should be a priority in patients with IBD, as gaining control of inflammatory disease is crucial for the prevention of recurrent vitamin and micronutrient deficiencies in addition to long-term health in this population.

In 2023, ESPEN (the European Society for Clinical Nutrition and Metabolism) published consensus recommendations highlighting the importance of regular monitoring and treatment of nutrient deficiencies in patients with inflammatory bowel disease (IBD) for improved prognosis, mortality, and quality of life.¹ Suboptimal nutrition in patients with IBD predominantly results from inflammation of the gastrointestinal (GI) tract leading to malabsorption; however, medications commonly used to manage IBD also can contribute to malnutrition.^2,3 Additionally, patients may develop nausea and food avoidance due to medication or the disease itself, leading to nutritional withdrawal and eventual deficiency.⁴ Even with the development of diets focused on balancing nutritional needs and decreasing inflammation,⁵ offsetting this aversion to food can be difficult to overcome.²

Cutaneous manifestations of IBD are multifaceted and can be secondary to the disease, reactive to or associated with IBD, or effects from nutritional deficiencies. The most common vitamin and nutrient deficiencies in patients with IBD include iron; zinc; calcium; vitamin D; and vitamins B₆ (pyridoxine), B₉ (folic acid), and B₁₂.⁶ Malnutrition may manifest with cutaneous disease, and dermatologists can be the first to identify and assess for nutritional deficiencies. In this article, we review the mechanisms of these micronutrient depletions in the context of IBD, their subsequent dermatologic manifestations (Table), and treatment and monitoring guidelines for each deficiency.

Iron

A systematic review conducted from 2007 to 2012 in European patients with IBD (N=2192) found the overall prevalence of anemia in this population to be 24% (95% CI, 18%-31%), with 57% of patients with anemia experiencing iron deficiency.⁷ Anemia is observed more commonly in patients hospitalized with IBD and is common in patients with both Crohn disease and ulcerative colitis.⁸

Pathophysiology—Iron is critically important in oxygen transportation throughout the body as a major component of hemoglobin. Physiologically, the low pH of the duodenum and proximal jejunum allows divalent metal transporter 1 to transfer dietary Fe³⁺ into enterocytes, where it is reduced to the transportable Fe²⁺.^9,10 Distribution of Fe²⁺ ions from enterocytes relies on ferroportin, an iron-transporting protein, which is heavily regulated by the protein hepcidin.¹¹ Hepcidin, a known acute phase reactant, will increase in the setting of active IBD, causing a depletion of ferroportin and an inability of the body to utilize the stored iron in enterocytes.¹² This poor utilization of iron stores combined with blood loss caused by inflammation in the GI tract is the proposed primary mechanism of iron-deficiency anemia observed in patients with IBD.¹³

Cutaneous Manifestations—From a dermatologic perspective, iron-deficiency anemia can manifest with a wide range of symptoms including glossitis, koilonychia, xerosis and/or pruritus, and brittle hair or hair loss.^14,15 Although the underlying pathophysiology of these cutaneous manifestations is not fully understood, there are several theories assessing the mechanisms behind the skin findings of iron deficiency.

Atrophic glossitis has been observed in many patients with iron deficiency and is thought to manifest due to low iron concentrations in the blood, thereby decreasing oxygen delivery to the papillae of the dorsal tongue with resultant atrophy.^16,17 Similarly, decreased oxygen delivery to the nail bed capillaries may cause deformities in the nail called koilonychia (or “spoon nails”).¹⁸ Iron is a key co-factor in collagen lysyl hydroxylase that promotes collagen binding; iron deficiency may lead to disruptions in the epidermal barrier that can cause pruritus and xerosis.¹⁹ An observational study of 200 healthy patients with a primary concern of pruritus found a correlation between low serum ferritin and a higher degree of pruritus (r=−0.768; P<.00001).²⁰

Evidence for iron’s role in hair growth comes from a mouse model study with a mutation in the serine protease TMPRSS6—a protein that regulates hepcidin and iron absorption—which caused an increase in hepcidin production and subsequent systemic iron deficiency. Mice at 4 weeks of age were devoid of all body hair but had substantial regrowth after initiation of a 2-week iron-rich diet, which suggests a connection between iron repletion and hair growth in mice with iron deficiency.²¹ Additionally, a meta-analysis analyzing the comorbidities of patients with alopecia areata found them to have higher odds (odds ratio [OR]=2.78; 95% CI, 1.23-6.29) of iron-deficiency anemia but no association with IBD (OR=1.48; 95% CI, 0.32-6.82).²²

Diagnosis and Monitoring—The American Gastroenterological Association recommends a complete blood cell count (CBC), serum ferritin, transferrin saturation (TfS), and C-reactive protein (CRP) as standard evaluations for iron deficiency in patients with IBD. Patients with active IBD should be screened every 3 months,and patients with inactive disease should be screened every 6 to 12 months.²³

Although ferritin and TfS often are used as markers for iron status in healthy individuals, they are positive and negative acute phase reactants, respectively. Using them to assess iron status in patients with IBD may inaccurately represent iron status in the setting of inflammation from the disease.²⁴ The European Crohn’s and Colitis Organisation (ECCO) produced guidelines to define iron deficiency as a TfS less than 20% or a ferritin level less than 30 µg/L in patients without evidence of active IBD and a ferritin level less than 100 µg/L for patients with active inflammation.²⁵

A 2020 multicenter observational study of 202 patients with diagnosed IBD found that the ECCO guideline of ferritin less than 30 µg/L had an area under the receiver operating characteristic (AUROC) curve of 0.69, a sensitivity of 0.43, and a specificity of 0.95 in their population.²⁶ In a sensitivity analysis stratifying patients by CRP level (<10 or ≥10 mg/L), the authors found that for patients with ulcerative colitis and a CRP less than 10 mg/L, a cut-off value of ferritin less than 65 µg/L (AUROC=0.78) had a sensitivity of 0.78 and specificity of 0.76, and a TfS value of less than 16% (AUROC=0.88) had a sensitivity of 0.79 and a specificity of 0.9. In patients with a CRP of 10 mg/L or greater, a cut-off value of ferritin 80 µg/L (AUROC=0.76) had a sensitivity of 0.75 and a specificity of 0.82, and a TfS value of less than 11% (AUROC=0.69) had a sensitivity of 0.79 and a specificity of 0.88. There were no ferritin cut-off values associated with good diagnostic performance (defined as both sensitivity and specificity >0.70) for iron deficiency in patients with Crohn disease.²⁶

The authors recommended using an alternative iron measurement such as soluble transferrin receptor (sTfR)/log ferritin ratio (TfR-F) that is not influenced by active inflammation and has a good correlation with ferritin values (TfR-F: r=0.66; P<.001).²⁶ However, both sTfR and TfR-F have high costs and intermethod variability as well as differences in their reference ranges depending on which laboratory performs the analysis, limiting the accessibility and practicality of easily obtaining these tests.²⁷ Although there may be inaccuracies for standard ferritin or TfS under ECCO guidelines, proposed alternatives have their own limitations, which may make ferritin and TfS the most reasonable evaluations of iron status as long as disease activity status at the time of testing is taken into consideration.

Treatment—Treatment of underlying iron deficiency in patients with IBD requires reversing the cause of the deficiency and supplementing iron. In patients with IBD, the options to supplement iron may be limited by active disease, making oral intake less effective. Oral iron supplementation also is associated with notable GI adverse effects that may be exacerbated in patients with IBD. A systematic review of 43 randomized controlled trials (RCTs) evaluating GI adverse effects (eg, nausea, abdominal pain, diarrhea, constipation, and black or tarry stools) of oral ferrous sulfate compared with placebo or intravenous (IV) iron supplementation in healthy nonanemic individuals found a significant increase in GI adverse effects with oral supplementation (placebo: OR=2.32; P<.0001; IV: OR=3.05; P<.0001).²⁸

Therefore, IV iron repletion may be necessary in patients with IBD and may require numerous infusions depending on the formulation of iron. In an RCT conducted in 2011, patients with iron-deficiency anemia with quiescent or mild to moderate IBD were treated with either IV iron sulfate or ferric carboxymaltose.²⁹ With a primary end point of hemoglobin response greater than 2 g/dL, the authors found that 150 of 240 patients responded to ferric carboxymaltose vs 118 of 235 treated with iron sulfate (P=.004). The dosing for ferric carboxymaltose was 1 to 3 infusions of 500 to 1000 mg of iron and for iron sulfate up to 11 infusions of 200 mg of iron.²⁹

Zinc

A systematic review of zinc deficiency in patients with IBD identified 7 studies including 2413 patients and revealed those with Crohn disease had a higher prevalence of zinc deficiency compared with patients with ulcerative colitis (54% vs 41%).³⁰

Pathophysiology—Zinc serves as a catalytic cofactor for enzymatic activity within proteins and immune cells.³¹ The homeostasis of zinc is tightly regulated within the brush border of the small intestine by zinc transporters ZIP4 and ZIP1 from the lumen of enterocytes into the bloodstream.³² Inflammation in the small intestine due to Crohn disease can result in zinc malabsorption.

Ranaldi et al³³ exposed intestinal cells and zinc-depleted intestinal cells to tumor necrosis factor α media to simulate an inflammatory environment. They measured transepithelial electrical resistance as a surrogate for transmembrane permeability and found that zinc-depleted cells had a statistically significantly higher transepithelial electrical resistance percentage (60% reduction after 4 hours; P<1.10^–6) when exposed to tumor necrosis factor α signaling compared with normal intestinal cells. They concluded that zinc deficiency can increase intestinal permeability in the presence of inflammation, creating a cycle of further nutrient malabsorption and inflammation exacerbating IBD symptoms.³³

Cutaneous Manifestations—After absorption in the small intestine, approximately 5% of zinc resides in the skin, with the highest concentration in the stratum spinosum.³⁴ A cell study found that keratinocytes in zinc-deficient environments had higher rates of apoptosis compared with cells in normal media. The authors proposed that this higher rate of apoptosis and the resulting inflammation could be a mechanism for developing the desquamative or eczematous scaly plaques that are common cutaneous manifestations of zinc deficiency.³⁵

Other cutaneous findings may include angular cheilitis, stomatitis, glossitis, paronychia, onychodystrophy, generalized alopecia, and delayed wound healing.³⁶ The histopathology of these skin lesions is characterized by granular layer loss, epidermal pallor, confluent parakeratosis, spongiosis, dyskeratosis, and psoriasiform hyperplasia.³⁷

Diagnosis and Monitoring—Assessing serum zinc levels is challenging, as they may decrease during states of inflammation.³⁸ A mouse model study showed a 3.1-fold increase (P<.001) in ZIP14 expression in wild-type mice compared with an IL-6 -/- knock-down model after IL-6 exposure. The authors concluded that the upregulation of ZIP14 in the liver due to inflammatory cytokine upregulation decreases zinc availability in serum.³⁹ Additionally, serum zinc can overestimate the level of deficiency in IBD because approximately 75% of serum zinc is bound to albumin, which decreases in the setting of inflammation.^40-42

Alternatively, alkaline phosphatase (AP), a zinc-dependent metalloenzyme, may be a better evaluator of zinc status during periods of inflammation. A study in rats evaluated zinc through serum zinc levels and AP levels after a period of induced stress to mimic a short-term inflammatory state.⁴³ The researchers found that total body stores of zinc were unaffected throughout the experiment; only serum zinc declined throughout the experiment duration while AP did not. Because approximately 75% of serum zinc is bound to serum albumin,⁴² the researchers concluded the induced inflammatory state depleted serum albumin and redistributed zinc to the liver, causing the observed serum zinc changes, while total body zinc levels and AP were largely unaffected in comparison.⁴³ Comorbid conditions such as liver or bone disease can increase AP levels, which limits the utility of AP as a surrogate for zinc in patients with comorbidities.⁴⁴ However, even in the context of active IBD, serum zinc still is currently considered the best biomarker to evaluate zinc status.⁴⁵

Treatment—The recommended dose for zinc supplementation is 20 to 40 mg daily with higher doses (>50 mg/d) for patients with malabsorptive syndromes such as IBD.⁴⁶ It can be administered orally or parenterally. Although rare, zinc replacement therapy may be associated with diarrhea, nausea, vomiting, mild headaches, and fatigue.⁴⁶ Additional considerations should be taken when repleting other micronutrients with zinc, as calcium and folate can inhibit zinc reabsorption, while zinc itself can inhibit iron and copper reabsorption.⁴⁷

Vitamin D and Calcium

Low vitamin D levels (<50 nmol/L) and hypocalcemia (<8.8 mg/dL) are common in patients with IBD.^48,49

Pathophysiology—Vitamin D levels are maintained via 2 mechanisms. The first mechanism is through the skin, as keratinocytes produce 7-dehydrocholesterol after exposure to UV light, which is converted into previtamin D₃ and then thermally isomerizes into vitamin D₃. This vitamin D₃ is then transported to the liver on vitamin D–binding protein.⁵⁰ The second mechanism is through oral vitamin D₃ that is absorbed through vitamin D receptors in intestinal epithelium and transported to the liver, where it is hydroxylated into 25-hydroxyvitamin D (25[OH]D), then to the kidneys for hydroxylation to 1,25(OH)₂D for redistribution throughout the body.⁵⁰ This activated form of vitamin D regulates calcium absorption in the intestine, and optimal vitamin D levels are necessary to absorb calcium efficiently.⁵¹ Inflammation from IBD within the small intestine can downregulate vitamin D receptors, causing malabsorption and decreased serum vitamin D.⁵²

Vitamin D signaling also is vital to maintaining the tight junctions and adherens junctions of the intestinal epithelium. Weakening the permeability of the epithelium further exacerbates malabsorption and subsequent vitamin D deficiency.⁵² A meta-analysis of 27 studies including 8316 patients with IBD showed low vitamin D levels were associated with increased odds of disease activity (OR=1.53; 95% CI, 1.32-1.77), mucosal inflammation (OR=1.25; 95% CI, 1.06-1.47), and future clinical relapse (OR=1.23; 95% CI, 1.03-1.47) in patients with Crohn disease. The authors concluded that low levels of vitamin D could be used as a potential biomarker of inflammatory status in Crohn disease.⁵³

Vitamin D and calcium are further implicated in maintaining skeletal health,⁴⁷ while vitamin D specifically helps maintain intestinal homeostasis⁵⁴ and immune system modulation in the skin.⁵⁵

Cutaneous Manifestations—Vitamin D is thought to play crucial roles in skin differentiation and proliferation, cutaneous innate immunity, hair follicle cycling, photoprotection, and wound healing.⁵⁶ Vitamin D deficiency has been observed in a large range of cutaneous diseases including skin cancer, psoriasis, vitiligo, bullous pemphigoid, atopic dermatitis, and various types of alopecia.^56-59 It is unclear whether vitamin D deficiency facilitates these disease processes or is merely the consequence of a disrupted cutaneous surface with the inability to complete the first step in vitamin D processing. A 2014 meta-analysis of 290 prospective cohort studies and 172 randomized trials concluded that 25(OH)D deficiency was associated with ill health and did not find causal evidence for any specific disease, dermatologic or otherwise.⁶⁰ Calcium deficiency may cause epidermal changes including dry skin, coarse hair, and brittle nails.⁶¹

Diagnosis and Monitoring—The ECCO guidelines recommend obtaining serum 25(OH)D levels every 3 months in patients with IBD.⁶² Levels less than 75 nmol/L are considered deficient, and a value less than 30 nmol/L increases the risk for osteomalacia and nutritional rickets, constituting severe vitamin D deficiency.^63-65

An observational study of 325 patients with IBD showed a statistically significant negative correlation between serum vitamin D and fecal calprotectin (r=−0.19; P<.001), a stool-based marker for gut inflammation, supporting vitamin D as a potential biomarker in IBD.⁶⁶

Evaluation of calcium can be done through serum levels in patients with IBD.⁶⁷ Patients with IBD are at risk for hypoalbuminemia; therefore, consideration should be taken to ensure calcium levels are corrected, as approximately 50% of calcium is bound to albumin or other ions in the body,⁶⁸ which can be done by adjusting the calcium concentration by 0.02 mmol/L for every 1 g/L of albumin above or below 40 g/L. In the most critically ill patients, a direct ionized calcium blood level should be used instead because the previously mentioned correction calculations are inaccurate when albumin is critically low.⁶⁹

Treatment—The ECCO guidelines recommend calcium and vitamin D repletion of 500 to 1000 mg and 800 to 1000 U, respectively, in patients with IBD on systemic corticosteroids to prevent the negative effects of bone loss.⁶² Calcium repletion in patients with IBD who are not on systemic steroids are the same as for the general population.⁶⁵

Vitamin D repletion also may help decrease IBD activity. In a prospective study, 10,000 IU/d of vitamin D in 10 patients with IBD—adjusted over 12 weeks to a target of 100 to 125 nmol/L of serum 25(OH)D—showed a significant reduction in clinical Crohn activity (P=.019) over the study period.⁷⁰ In contrast, 2000 IU/d for 3 months in an RCT of 27 patients with Crohn disease found significantly lower CRP (P=.019) and significantly higher self-reported quality of life (P=.037) but nonsignificant decreases in Crohn activity (P=.082) in patients with 25(OH)D levels of 75 nmol/L or higher compared with those with 25(OH)D levels less than 75 nmol/L.⁷¹

These discrepancies illustrate the need for expanded clinical trials to elucidate the optimal vitamin D dosing for patients with IBD. Ultimately, assessing vitamin D and calcium status and considering repletion in patients with IBD, especially those with comorbid dermatologic diseases such as poor wound healing, psoriasis, or atopic dermatitis, is important.

Vitamin B₆ (Pyridoxine)

Pathophysiology—Pyridoxine is an important coenzyme for many functions including amino acid transamination, fatty acid metabolism, and conversion of tryptophan to niacin. It is absorbed in the jejunum and ileum and subsequently transported to the liver for rephosphorylation and release into its active form.³⁶ An observational study assessing the nutritional status of patients with IBD found that only 5.7% of 105 patients with food records had inadequate dietary intake of pyridoxine, but 29% of all patients with IBD had subnormal pyridoxine levels.⁷² Additionally, they found no significant difference in the prevalence of subnormal pyridoxine levels in patients with active IBD vs IBD in remission. The authors suggested that the subnormal pyridoxine levels in patients with IBD likely were multifactorial and resulted from malabsorption due to active disease, inflammation, and inadequate intake.⁷²

Cutaneous Manifestations—Cutaneous findings associated with pyridoxine deficiency include periorificial and perineal dermatitis,⁷³ angular stomatitis, and cheilitis with associated burning, redness, and tongue edema.³⁶ Additionally, pyridoxine is involved in the conversion of tryptophan to niacin, and its deficiency may manifest with pellagralike findings.⁷⁴

Because pyridoxine is critical to protein metabolism, its deficiency may disrupt key cellular structures that rely on protein concentrations to maintain structural integrity. One such structure in the skin that heavily relies on protein concentrations is the ground substance of the extracellular matrix—the amorphous gelatinous spaces that occupy the areas between the extracellular matrix, which consists of cross-linked glycosaminoglycans and proteins.⁷⁵ Without protein, ground substance increases in viscosity and can disrupt the epidermal barrier, leading to increased transepidermal water loss and ultimately inflammation.⁷⁶ Although this theory has yet to be validated fully, this is a potential mechanistic explanation for the inflammation in dermal papillae that leads to dermatitis observed in pyridoxine deficiency.

Diagnosis and Monitoring—Direct biomarkers of pyridoxine status are in serum, plasma, erythrocytes, and urine, with the most common measurement in plasma as pyridoxal 5′-phosphate (PLP).⁷⁷ Plasma PLP concentrations lower than 20 nmol/L are suggestive of deficiency.⁷⁸ Plasma PLP has shown inverse relationships with acute phase inflammatory markers CRP⁷⁹ and AP,⁷⁸ thereby raising concerns for its validity to assess pyridoxine status in patients with symptomatic IBD.⁸⁰

Alternative evaluations of pyridoxine include tryptophan and methionine loading tests,³⁶ which are measured via urinary excretion and require normal kidney function to be accurate. They should be considered in IBD if necessary, but routine testing, even in patients with symptomatic IBD, is not recommended in the ECCO guidelines. Additional considerations should be taken in patients with altered nutrient requirements such as those who have undergone bowel resection due to highly active disease or those who receive parenteral nutritional supplementation.⁸¹

Treatment—Recommendations for oral pyridoxine supplementation range from 25 to 600 mg daily,⁸² with symptoms typically improving on 100 mg daily.³⁶ Pyridoxine supplementation may have additional benefits for patients with IBD and potentially modulate disease severity. An IL-10 knockout mouse supplemented with pyridoxine had an approximately 60% reduction (P<.05) in inflammation compared to mice deficient in pyridoxine.⁸³ The authors suggest that PLP-dependent enzymes can inhibit further proinflammatory signaling and T-cell migration that can exacerbate IBD. Ultimately, more data is needed before determining the efficacy of pyridoxine supplementation for active IBD.

Vitamin B₁₂ and Vitamin B₉ (Folic Acid)

Pathophysiology—Vitamin B₁₂ is reabsorbed in the terminal ileum, the distal portion of the small intestine. The American Gastroenterological Association recommends that patients with a history of extensive ileal disease or prior ileal surgery, which is the case for many patients with Crohn disease, be monitored for vitamin B₁₂ deficiency.²³ Monitoring and rapid supplementation of vitamin B₁₂ can prevent pernicious anemia and irreversible neurologic damage that may result from deficiency.⁸⁴

Folic acid is primarily absorbed in the duodenum and jejunum of the small intestine. A meta-analysis performed in 2017 assessed studies observing folic acid and vitamin B₁₂ levels in 1086 patients with IBD compared with 1484 healthy controls and found an average difference in serum folate concentration of 0.46 nmol/L (P<.001).⁸⁴ Interestingly, this study did not find a significant difference in serum vitamin B₁₂ levels between patients with IBD and healthy controls, highlighting the mechanism of vitamin B₁₂ deficiency in IBD because only patients with terminal ileal involvement are at risk for malabsorption and subsequent deficiency.

Cutaneous Manifestations—Both vitamin B₁₂ and folic acid deficiency can manifest as cheilitis, glossitis, and/or generalized hyperpigmentation that is accentuated in the flexural areas, palms, soles, and oral cavity.^85,86 Systemic symptoms of patients with vitamin B₁₂ and folic acid deficiency include megaloblastic anemia, pallor, and fatigue. A potential mechanism for the hyperpigmentation observed from vitamin B₁₂ deficiency came from an electron microscope study that showed an increased concentration of melanosomes in a patient with deficiency.⁸⁷

Diagnosis and Monitoring—In patients with suspected vitamin B₁₂ and/or folic acid deficiency, initial evaluation should include a CBC with peripheral smear and serum vitamin B₁₂ and folate levels. In cases for which the diagnosis still is unclear after initial testing, methylmalonic acid and homocysteine levels can help differentiate between the 2 deficiencies. Methylmalonic acid classically is elevated (>260 nmol/L) in vitamin B₁₂ deficiency but not in folate deficiency.⁸⁸ Cut-off values for vitamin B₁₂ deficiency are less than 200 to 250 pg/mL forserum vitamin B₁₂ and/or an elevated level of methylmalonic acid (>0.271 µmol/L).⁸⁹ A serum folic acid value greater than 3 ng/mL and/or erythrocyte folate concentrations greater than 140 ng/mL are considered adequate, whereas an indicator of folic acid deficiency is a homocysteine level less than 10 µmol/L.⁹⁰ A CBC can screen for macrocytic megaloblastic anemias (mean corpuscular volume >100 fl), which are classic diagnostic signs of an underlying vitamin B₁₂ or folate deficiency.

Treatment—According to the Centers for Disease Control and Prevention, supplementation of vitamin B₁₂ can be done orally with 1000 µg daily in patients with deficiency. In patients with active IBD, oral reabsorption of vitamin B₁₂ can be less effective, making subcutaneous or intramuscular administration (1000 µg/wk for 8 weeks, then monthly for life) better options.⁸⁹

Patients with IBD managed with methotrexate should be screened carefully for folate deficiency. Methotrexate is a folate analog that sometimes is used for the treatment of IBD. Reversible competitive inhibition of dihydrofolate reductase can precipitate a systemic folic acid decrease.⁹¹ Typically, oral folic acid (1 to 5 mg/d) is sufficient to treat folate deficiency, with the ESPEN recommending 5 mg once weekly 24 to 72 hours after methotrexate treatment or 1 mg daily for 5 days per week in patients with IBD.¹ Alternative formulations—IV, subcutaneous, or intramuscular—are available for patients who cannot tolerate oral intake.⁹²

Final Thoughts

Dermatologists can be the first to observe the cutaneous manifestations of micronutrient deficiencies. Although the symptoms of each micronutrient deficiency discussed may overlap, attention to small clinical clues in patients with IBD can improve patient outcomes and quality of life. For example, koilonychia with glossitis and xerosis likely is due to iron deficiency, while zinc deficiency should be suspected in patients with scaly eczematous plaques in skin folds. A high level of suspicion for micronutrient deficiencies in patients with IBD should be followed by a complete patient history, review of systems, and thorough clinical examination. A thorough laboratory evaluation can pinpoint nutritional deficiencies in patients with IBD, keeping in mind that specific biomarkers such as ferritin and serum zinc also act as acute phase reactants and should be interpreted in this context. Co-management with gastroenterologists should be a priority in patients with IBD, as gaining control of inflammatory disease is crucial for the prevention of recurrent vitamin and micronutrient deficiencies in addition to long-term health in this population.

In 2023, ESPEN (the European Society for Clinical Nutrition and Metabolism) published consensus recommendations highlighting the importance of regular monitoring and treatment of nutrient deficiencies in patients with inflammatory bowel disease (IBD) for improved prognosis, mortality, and quality of life.¹ Suboptimal nutrition in patients with IBD predominantly results from inflammation of the gastrointestinal (GI) tract leading to malabsorption; however, medications commonly used to manage IBD also can contribute to malnutrition.^2,3 Additionally, patients may develop nausea and food avoidance due to medication or the disease itself, leading to nutritional withdrawal and eventual deficiency.⁴ Even with the development of diets focused on balancing nutritional needs and decreasing inflammation,⁵ offsetting this aversion to food can be difficult to overcome.²

Cutaneous manifestations of IBD are multifaceted and can be secondary to the disease, reactive to or associated with IBD, or effects from nutritional deficiencies. The most common vitamin and nutrient deficiencies in patients with IBD include iron; zinc; calcium; vitamin D; and vitamins B₆ (pyridoxine), B₉ (folic acid), and B₁₂.⁶ Malnutrition may manifest with cutaneous disease, and dermatologists can be the first to identify and assess for nutritional deficiencies. In this article, we review the mechanisms of these micronutrient depletions in the context of IBD, their subsequent dermatologic manifestations (Table), and treatment and monitoring guidelines for each deficiency.

Iron

A systematic review conducted from 2007 to 2012 in European patients with IBD (N=2192) found the overall prevalence of anemia in this population to be 24% (95% CI, 18%-31%), with 57% of patients with anemia experiencing iron deficiency.⁷ Anemia is observed more commonly in patients hospitalized with IBD and is common in patients with both Crohn disease and ulcerative colitis.⁸

Pathophysiology—Iron is critically important in oxygen transportation throughout the body as a major component of hemoglobin. Physiologically, the low pH of the duodenum and proximal jejunum allows divalent metal transporter 1 to transfer dietary Fe³⁺ into enterocytes, where it is reduced to the transportable Fe²⁺.^9,10 Distribution of Fe²⁺ ions from enterocytes relies on ferroportin, an iron-transporting protein, which is heavily regulated by the protein hepcidin.¹¹ Hepcidin, a known acute phase reactant, will increase in the setting of active IBD, causing a depletion of ferroportin and an inability of the body to utilize the stored iron in enterocytes.¹² This poor utilization of iron stores combined with blood loss caused by inflammation in the GI tract is the proposed primary mechanism of iron-deficiency anemia observed in patients with IBD.¹³

Cutaneous Manifestations—From a dermatologic perspective, iron-deficiency anemia can manifest with a wide range of symptoms including glossitis, koilonychia, xerosis and/or pruritus, and brittle hair or hair loss.^14,15 Although the underlying pathophysiology of these cutaneous manifestations is not fully understood, there are several theories assessing the mechanisms behind the skin findings of iron deficiency.

Atrophic glossitis has been observed in many patients with iron deficiency and is thought to manifest due to low iron concentrations in the blood, thereby decreasing oxygen delivery to the papillae of the dorsal tongue with resultant atrophy.^16,17 Similarly, decreased oxygen delivery to the nail bed capillaries may cause deformities in the nail called koilonychia (or “spoon nails”).¹⁸ Iron is a key co-factor in collagen lysyl hydroxylase that promotes collagen binding; iron deficiency may lead to disruptions in the epidermal barrier that can cause pruritus and xerosis.¹⁹ An observational study of 200 healthy patients with a primary concern of pruritus found a correlation between low serum ferritin and a higher degree of pruritus (r=−0.768; P<.00001).²⁰

Evidence for iron’s role in hair growth comes from a mouse model study with a mutation in the serine protease TMPRSS6—a protein that regulates hepcidin and iron absorption—which caused an increase in hepcidin production and subsequent systemic iron deficiency. Mice at 4 weeks of age were devoid of all body hair but had substantial regrowth after initiation of a 2-week iron-rich diet, which suggests a connection between iron repletion and hair growth in mice with iron deficiency.²¹ Additionally, a meta-analysis analyzing the comorbidities of patients with alopecia areata found them to have higher odds (odds ratio [OR]=2.78; 95% CI, 1.23-6.29) of iron-deficiency anemia but no association with IBD (OR=1.48; 95% CI, 0.32-6.82).²²

Diagnosis and Monitoring—The American Gastroenterological Association recommends a complete blood cell count (CBC), serum ferritin, transferrin saturation (TfS), and C-reactive protein (CRP) as standard evaluations for iron deficiency in patients with IBD. Patients with active IBD should be screened every 3 months,and patients with inactive disease should be screened every 6 to 12 months.²³

Although ferritin and TfS often are used as markers for iron status in healthy individuals, they are positive and negative acute phase reactants, respectively. Using them to assess iron status in patients with IBD may inaccurately represent iron status in the setting of inflammation from the disease.²⁴ The European Crohn’s and Colitis Organisation (ECCO) produced guidelines to define iron deficiency as a TfS less than 20% or a ferritin level less than 30 µg/L in patients without evidence of active IBD and a ferritin level less than 100 µg/L for patients with active inflammation.²⁵

A 2020 multicenter observational study of 202 patients with diagnosed IBD found that the ECCO guideline of ferritin less than 30 µg/L had an area under the receiver operating characteristic (AUROC) curve of 0.69, a sensitivity of 0.43, and a specificity of 0.95 in their population.²⁶ In a sensitivity analysis stratifying patients by CRP level (<10 or ≥10 mg/L), the authors found that for patients with ulcerative colitis and a CRP less than 10 mg/L, a cut-off value of ferritin less than 65 µg/L (AUROC=0.78) had a sensitivity of 0.78 and specificity of 0.76, and a TfS value of less than 16% (AUROC=0.88) had a sensitivity of 0.79 and a specificity of 0.9. In patients with a CRP of 10 mg/L or greater, a cut-off value of ferritin 80 µg/L (AUROC=0.76) had a sensitivity of 0.75 and a specificity of 0.82, and a TfS value of less than 11% (AUROC=0.69) had a sensitivity of 0.79 and a specificity of 0.88. There were no ferritin cut-off values associated with good diagnostic performance (defined as both sensitivity and specificity >0.70) for iron deficiency in patients with Crohn disease.²⁶

The authors recommended using an alternative iron measurement such as soluble transferrin receptor (sTfR)/log ferritin ratio (TfR-F) that is not influenced by active inflammation and has a good correlation with ferritin values (TfR-F: r=0.66; P<.001).²⁶ However, both sTfR and TfR-F have high costs and intermethod variability as well as differences in their reference ranges depending on which laboratory performs the analysis, limiting the accessibility and practicality of easily obtaining these tests.²⁷ Although there may be inaccuracies for standard ferritin or TfS under ECCO guidelines, proposed alternatives have their own limitations, which may make ferritin and TfS the most reasonable evaluations of iron status as long as disease activity status at the time of testing is taken into consideration.

Treatment—Treatment of underlying iron deficiency in patients with IBD requires reversing the cause of the deficiency and supplementing iron. In patients with IBD, the options to supplement iron may be limited by active disease, making oral intake less effective. Oral iron supplementation also is associated with notable GI adverse effects that may be exacerbated in patients with IBD. A systematic review of 43 randomized controlled trials (RCTs) evaluating GI adverse effects (eg, nausea, abdominal pain, diarrhea, constipation, and black or tarry stools) of oral ferrous sulfate compared with placebo or intravenous (IV) iron supplementation in healthy nonanemic individuals found a significant increase in GI adverse effects with oral supplementation (placebo: OR=2.32; P<.0001; IV: OR=3.05; P<.0001).²⁸

Therefore, IV iron repletion may be necessary in patients with IBD and may require numerous infusions depending on the formulation of iron. In an RCT conducted in 2011, patients with iron-deficiency anemia with quiescent or mild to moderate IBD were treated with either IV iron sulfate or ferric carboxymaltose.²⁹ With a primary end point of hemoglobin response greater than 2 g/dL, the authors found that 150 of 240 patients responded to ferric carboxymaltose vs 118 of 235 treated with iron sulfate (P=.004). The dosing for ferric carboxymaltose was 1 to 3 infusions of 500 to 1000 mg of iron and for iron sulfate up to 11 infusions of 200 mg of iron.²⁹

Zinc

A systematic review of zinc deficiency in patients with IBD identified 7 studies including 2413 patients and revealed those with Crohn disease had a higher prevalence of zinc deficiency compared with patients with ulcerative colitis (54% vs 41%).³⁰

Pathophysiology—Zinc serves as a catalytic cofactor for enzymatic activity within proteins and immune cells.³¹ The homeostasis of zinc is tightly regulated within the brush border of the small intestine by zinc transporters ZIP4 and ZIP1 from the lumen of enterocytes into the bloodstream.³² Inflammation in the small intestine due to Crohn disease can result in zinc malabsorption.

Ranaldi et al³³ exposed intestinal cells and zinc-depleted intestinal cells to tumor necrosis factor α media to simulate an inflammatory environment. They measured transepithelial electrical resistance as a surrogate for transmembrane permeability and found that zinc-depleted cells had a statistically significantly higher transepithelial electrical resistance percentage (60% reduction after 4 hours; P<1.10^–6) when exposed to tumor necrosis factor α signaling compared with normal intestinal cells. They concluded that zinc deficiency can increase intestinal permeability in the presence of inflammation, creating a cycle of further nutrient malabsorption and inflammation exacerbating IBD symptoms.³³

Cutaneous Manifestations—After absorption in the small intestine, approximately 5% of zinc resides in the skin, with the highest concentration in the stratum spinosum.³⁴ A cell study found that keratinocytes in zinc-deficient environments had higher rates of apoptosis compared with cells in normal media. The authors proposed that this higher rate of apoptosis and the resulting inflammation could be a mechanism for developing the desquamative or eczematous scaly plaques that are common cutaneous manifestations of zinc deficiency.³⁵

Other cutaneous findings may include angular cheilitis, stomatitis, glossitis, paronychia, onychodystrophy, generalized alopecia, and delayed wound healing.³⁶ The histopathology of these skin lesions is characterized by granular layer loss, epidermal pallor, confluent parakeratosis, spongiosis, dyskeratosis, and psoriasiform hyperplasia.³⁷

Diagnosis and Monitoring—Assessing serum zinc levels is challenging, as they may decrease during states of inflammation.³⁸ A mouse model study showed a 3.1-fold increase (P<.001) in ZIP14 expression in wild-type mice compared with an IL-6 -/- knock-down model after IL-6 exposure. The authors concluded that the upregulation of ZIP14 in the liver due to inflammatory cytokine upregulation decreases zinc availability in serum.³⁹ Additionally, serum zinc can overestimate the level of deficiency in IBD because approximately 75% of serum zinc is bound to albumin, which decreases in the setting of inflammation.^40-42

Alternatively, alkaline phosphatase (AP), a zinc-dependent metalloenzyme, may be a better evaluator of zinc status during periods of inflammation. A study in rats evaluated zinc through serum zinc levels and AP levels after a period of induced stress to mimic a short-term inflammatory state.⁴³ The researchers found that total body stores of zinc were unaffected throughout the experiment; only serum zinc declined throughout the experiment duration while AP did not. Because approximately 75% of serum zinc is bound to serum albumin,⁴² the researchers concluded the induced inflammatory state depleted serum albumin and redistributed zinc to the liver, causing the observed serum zinc changes, while total body zinc levels and AP were largely unaffected in comparison.⁴³ Comorbid conditions such as liver or bone disease can increase AP levels, which limits the utility of AP as a surrogate for zinc in patients with comorbidities.⁴⁴ However, even in the context of active IBD, serum zinc still is currently considered the best biomarker to evaluate zinc status.⁴⁵

Treatment—The recommended dose for zinc supplementation is 20 to 40 mg daily with higher doses (>50 mg/d) for patients with malabsorptive syndromes such as IBD.⁴⁶ It can be administered orally or parenterally. Although rare, zinc replacement therapy may be associated with diarrhea, nausea, vomiting, mild headaches, and fatigue.⁴⁶ Additional considerations should be taken when repleting other micronutrients with zinc, as calcium and folate can inhibit zinc reabsorption, while zinc itself can inhibit iron and copper reabsorption.⁴⁷

Vitamin D and Calcium

Low vitamin D levels (<50 nmol/L) and hypocalcemia (<8.8 mg/dL) are common in patients with IBD.^48,49

Pathophysiology—Vitamin D levels are maintained via 2 mechanisms. The first mechanism is through the skin, as keratinocytes produce 7-dehydrocholesterol after exposure to UV light, which is converted into previtamin D₃ and then thermally isomerizes into vitamin D₃. This vitamin D₃ is then transported to the liver on vitamin D–binding protein.⁵⁰ The second mechanism is through oral vitamin D₃ that is absorbed through vitamin D receptors in intestinal epithelium and transported to the liver, where it is hydroxylated into 25-hydroxyvitamin D (25[OH]D), then to the kidneys for hydroxylation to 1,25(OH)₂D for redistribution throughout the body.⁵⁰ This activated form of vitamin D regulates calcium absorption in the intestine, and optimal vitamin D levels are necessary to absorb calcium efficiently.⁵¹ Inflammation from IBD within the small intestine can downregulate vitamin D receptors, causing malabsorption and decreased serum vitamin D.⁵²

Vitamin D signaling also is vital to maintaining the tight junctions and adherens junctions of the intestinal epithelium. Weakening the permeability of the epithelium further exacerbates malabsorption and subsequent vitamin D deficiency.⁵² A meta-analysis of 27 studies including 8316 patients with IBD showed low vitamin D levels were associated with increased odds of disease activity (OR=1.53; 95% CI, 1.32-1.77), mucosal inflammation (OR=1.25; 95% CI, 1.06-1.47), and future clinical relapse (OR=1.23; 95% CI, 1.03-1.47) in patients with Crohn disease. The authors concluded that low levels of vitamin D could be used as a potential biomarker of inflammatory status in Crohn disease.⁵³

Vitamin D and calcium are further implicated in maintaining skeletal health,⁴⁷ while vitamin D specifically helps maintain intestinal homeostasis⁵⁴ and immune system modulation in the skin.⁵⁵

Cutaneous Manifestations—Vitamin D is thought to play crucial roles in skin differentiation and proliferation, cutaneous innate immunity, hair follicle cycling, photoprotection, and wound healing.⁵⁶ Vitamin D deficiency has been observed in a large range of cutaneous diseases including skin cancer, psoriasis, vitiligo, bullous pemphigoid, atopic dermatitis, and various types of alopecia.^56-59 It is unclear whether vitamin D deficiency facilitates these disease processes or is merely the consequence of a disrupted cutaneous surface with the inability to complete the first step in vitamin D processing. A 2014 meta-analysis of 290 prospective cohort studies and 172 randomized trials concluded that 25(OH)D deficiency was associated with ill health and did not find causal evidence for any specific disease, dermatologic or otherwise.⁶⁰ Calcium deficiency may cause epidermal changes including dry skin, coarse hair, and brittle nails.⁶¹

Diagnosis and Monitoring—The ECCO guidelines recommend obtaining serum 25(OH)D levels every 3 months in patients with IBD.⁶² Levels less than 75 nmol/L are considered deficient, and a value less than 30 nmol/L increases the risk for osteomalacia and nutritional rickets, constituting severe vitamin D deficiency.^63-65

An observational study of 325 patients with IBD showed a statistically significant negative correlation between serum vitamin D and fecal calprotectin (r=−0.19; P<.001), a stool-based marker for gut inflammation, supporting vitamin D as a potential biomarker in IBD.⁶⁶

Evaluation of calcium can be done through serum levels in patients with IBD.⁶⁷ Patients with IBD are at risk for hypoalbuminemia; therefore, consideration should be taken to ensure calcium levels are corrected, as approximately 50% of calcium is bound to albumin or other ions in the body,⁶⁸ which can be done by adjusting the calcium concentration by 0.02 mmol/L for every 1 g/L of albumin above or below 40 g/L. In the most critically ill patients, a direct ionized calcium blood level should be used instead because the previously mentioned correction calculations are inaccurate when albumin is critically low.⁶⁹

Treatment—The ECCO guidelines recommend calcium and vitamin D repletion of 500 to 1000 mg and 800 to 1000 U, respectively, in patients with IBD on systemic corticosteroids to prevent the negative effects of bone loss.⁶² Calcium repletion in patients with IBD who are not on systemic steroids are the same as for the general population.⁶⁵

Vitamin D repletion also may help decrease IBD activity. In a prospective study, 10,000 IU/d of vitamin D in 10 patients with IBD—adjusted over 12 weeks to a target of 100 to 125 nmol/L of serum 25(OH)D—showed a significant reduction in clinical Crohn activity (P=.019) over the study period.⁷⁰ In contrast, 2000 IU/d for 3 months in an RCT of 27 patients with Crohn disease found significantly lower CRP (P=.019) and significantly higher self-reported quality of life (P=.037) but nonsignificant decreases in Crohn activity (P=.082) in patients with 25(OH)D levels of 75 nmol/L or higher compared with those with 25(OH)D levels less than 75 nmol/L.⁷¹

These discrepancies illustrate the need for expanded clinical trials to elucidate the optimal vitamin D dosing for patients with IBD. Ultimately, assessing vitamin D and calcium status and considering repletion in patients with IBD, especially those with comorbid dermatologic diseases such as poor wound healing, psoriasis, or atopic dermatitis, is important.

Vitamin B₆ (Pyridoxine)

Pathophysiology—Pyridoxine is an important coenzyme for many functions including amino acid transamination, fatty acid metabolism, and conversion of tryptophan to niacin. It is absorbed in the jejunum and ileum and subsequently transported to the liver for rephosphorylation and release into its active form.³⁶ An observational study assessing the nutritional status of patients with IBD found that only 5.7% of 105 patients with food records had inadequate dietary intake of pyridoxine, but 29% of all patients with IBD had subnormal pyridoxine levels.⁷² Additionally, they found no significant difference in the prevalence of subnormal pyridoxine levels in patients with active IBD vs IBD in remission. The authors suggested that the subnormal pyridoxine levels in patients with IBD likely were multifactorial and resulted from malabsorption due to active disease, inflammation, and inadequate intake.⁷²

Cutaneous Manifestations—Cutaneous findings associated with pyridoxine deficiency include periorificial and perineal dermatitis,⁷³ angular stomatitis, and cheilitis with associated burning, redness, and tongue edema.³⁶ Additionally, pyridoxine is involved in the conversion of tryptophan to niacin, and its deficiency may manifest with pellagralike findings.⁷⁴

Because pyridoxine is critical to protein metabolism, its deficiency may disrupt key cellular structures that rely on protein concentrations to maintain structural integrity. One such structure in the skin that heavily relies on protein concentrations is the ground substance of the extracellular matrix—the amorphous gelatinous spaces that occupy the areas between the extracellular matrix, which consists of cross-linked glycosaminoglycans and proteins.⁷⁵ Without protein, ground substance increases in viscosity and can disrupt the epidermal barrier, leading to increased transepidermal water loss and ultimately inflammation.⁷⁶ Although this theory has yet to be validated fully, this is a potential mechanistic explanation for the inflammation in dermal papillae that leads to dermatitis observed in pyridoxine deficiency.

Diagnosis and Monitoring—Direct biomarkers of pyridoxine status are in serum, plasma, erythrocytes, and urine, with the most common measurement in plasma as pyridoxal 5′-phosphate (PLP).⁷⁷ Plasma PLP concentrations lower than 20 nmol/L are suggestive of deficiency.⁷⁸ Plasma PLP has shown inverse relationships with acute phase inflammatory markers CRP⁷⁹ and AP,⁷⁸ thereby raising concerns for its validity to assess pyridoxine status in patients with symptomatic IBD.⁸⁰

Alternative evaluations of pyridoxine include tryptophan and methionine loading tests,³⁶ which are measured via urinary excretion and require normal kidney function to be accurate. They should be considered in IBD if necessary, but routine testing, even in patients with symptomatic IBD, is not recommended in the ECCO guidelines. Additional considerations should be taken in patients with altered nutrient requirements such as those who have undergone bowel resection due to highly active disease or those who receive parenteral nutritional supplementation.⁸¹

Treatment—Recommendations for oral pyridoxine supplementation range from 25 to 600 mg daily,⁸² with symptoms typically improving on 100 mg daily.³⁶ Pyridoxine supplementation may have additional benefits for patients with IBD and potentially modulate disease severity. An IL-10 knockout mouse supplemented with pyridoxine had an approximately 60% reduction (P<.05) in inflammation compared to mice deficient in pyridoxine.⁸³ The authors suggest that PLP-dependent enzymes can inhibit further proinflammatory signaling and T-cell migration that can exacerbate IBD. Ultimately, more data is needed before determining the efficacy of pyridoxine supplementation for active IBD.

Vitamin B₁₂ and Vitamin B₉ (Folic Acid)

Pathophysiology—Vitamin B₁₂ is reabsorbed in the terminal ileum, the distal portion of the small intestine. The American Gastroenterological Association recommends that patients with a history of extensive ileal disease or prior ileal surgery, which is the case for many patients with Crohn disease, be monitored for vitamin B₁₂ deficiency.²³ Monitoring and rapid supplementation of vitamin B₁₂ can prevent pernicious anemia and irreversible neurologic damage that may result from deficiency.⁸⁴

Folic acid is primarily absorbed in the duodenum and jejunum of the small intestine. A meta-analysis performed in 2017 assessed studies observing folic acid and vitamin B₁₂ levels in 1086 patients with IBD compared with 1484 healthy controls and found an average difference in serum folate concentration of 0.46 nmol/L (P<.001).⁸⁴ Interestingly, this study did not find a significant difference in serum vitamin B₁₂ levels between patients with IBD and healthy controls, highlighting the mechanism of vitamin B₁₂ deficiency in IBD because only patients with terminal ileal involvement are at risk for malabsorption and subsequent deficiency.

Cutaneous Manifestations—Both vitamin B₁₂ and folic acid deficiency can manifest as cheilitis, glossitis, and/or generalized hyperpigmentation that is accentuated in the flexural areas, palms, soles, and oral cavity.^85,86 Systemic symptoms of patients with vitamin B₁₂ and folic acid deficiency include megaloblastic anemia, pallor, and fatigue. A potential mechanism for the hyperpigmentation observed from vitamin B₁₂ deficiency came from an electron microscope study that showed an increased concentration of melanosomes in a patient with deficiency.⁸⁷

Diagnosis and Monitoring—In patients with suspected vitamin B₁₂ and/or folic acid deficiency, initial evaluation should include a CBC with peripheral smear and serum vitamin B₁₂ and folate levels. In cases for which the diagnosis still is unclear after initial testing, methylmalonic acid and homocysteine levels can help differentiate between the 2 deficiencies. Methylmalonic acid classically is elevated (>260 nmol/L) in vitamin B₁₂ deficiency but not in folate deficiency.⁸⁸ Cut-off values for vitamin B₁₂ deficiency are less than 200 to 250 pg/mL forserum vitamin B₁₂ and/or an elevated level of methylmalonic acid (>0.271 µmol/L).⁸⁹ A serum folic acid value greater than 3 ng/mL and/or erythrocyte folate concentrations greater than 140 ng/mL are considered adequate, whereas an indicator of folic acid deficiency is a homocysteine level less than 10 µmol/L.⁹⁰ A CBC can screen for macrocytic megaloblastic anemias (mean corpuscular volume >100 fl), which are classic diagnostic signs of an underlying vitamin B₁₂ or folate deficiency.

Treatment—According to the Centers for Disease Control and Prevention, supplementation of vitamin B₁₂ can be done orally with 1000 µg daily in patients with deficiency. In patients with active IBD, oral reabsorption of vitamin B₁₂ can be less effective, making subcutaneous or intramuscular administration (1000 µg/wk for 8 weeks, then monthly for life) better options.⁸⁹

Patients with IBD managed with methotrexate should be screened carefully for folate deficiency. Methotrexate is a folate analog that sometimes is used for the treatment of IBD. Reversible competitive inhibition of dihydrofolate reductase can precipitate a systemic folic acid decrease.⁹¹ Typically, oral folic acid (1 to 5 mg/d) is sufficient to treat folate deficiency, with the ESPEN recommending 5 mg once weekly 24 to 72 hours after methotrexate treatment or 1 mg daily for 5 days per week in patients with IBD.¹ Alternative formulations—IV, subcutaneous, or intramuscular—are available for patients who cannot tolerate oral intake.⁹²

Final Thoughts

Dermatologists can be the first to observe the cutaneous manifestations of micronutrient deficiencies. Although the symptoms of each micronutrient deficiency discussed may overlap, attention to small clinical clues in patients with IBD can improve patient outcomes and quality of life. For example, koilonychia with glossitis and xerosis likely is due to iron deficiency, while zinc deficiency should be suspected in patients with scaly eczematous plaques in skin folds. A high level of suspicion for micronutrient deficiencies in patients with IBD should be followed by a complete patient history, review of systems, and thorough clinical examination. A thorough laboratory evaluation can pinpoint nutritional deficiencies in patients with IBD, keeping in mind that specific biomarkers such as ferritin and serum zinc also act as acute phase reactants and should be interpreted in this context. Co-management with gastroenterologists should be a priority in patients with IBD, as gaining control of inflammatory disease is crucial for the prevention of recurrent vitamin and micronutrient deficiencies in addition to long-term health in this population.

A longtime Kaiser Permanente surgeon is suing a fellow physician for allegedly submitting false medical board complaints against him in an attempt to get him fired.

Joseph Stalfire III, MD, claims Ming Hsieh, MD, began a campaign to harm his reputation after Dr. Stalfire hurt his leg and went on medical leave. Dr. Stalfire, a board-certified ob.gyn., has worked for Kaiser Permanente in western Oregon for more than 20 years, including several years as a regional chief surgical officer.

Dr. Stalfire is accusing Dr. Hsieh of defamation and intentional emotional distress, according to the March 25 lawsuit filed in Marion County Circuit Court. Northwest Permanente P.C., a Kaiser subsidiary, is also named as a defendant.

Dr. Stalfire is asking for $1.2 million in economic damages and $300,000 in noneconomic damages. Dr. Hsieh has not yet responded to the legal complaint.

Dr. Stalfire’s attorney did not respond to a message seeking comment. Dr. Hsieh is representing himself, according to court records. A Kaiser Permanente spokeswoman told this news organization that Kaiser does not comment on pending litigation.

The conflict began in February 2023, after Dr. Stalfire underwent surgery to correct issues stemming from severe injuries when a tree fell on his leg, according to court records. 

Dr. Hsieh, a Kaiser ob.gyn., senior physician, and quality assurance lead, allegedly contacted Dr. Stalfire after the surgery and demanded he return to work earlier than medically recommended. Dr. Stalfire claims Dr. Hsieh questioned his retirement plans and his ability to continue working to pressure him into quitting. 

Dr. Stalfire reported Dr. Hsieh’s conduct to Kaiser’s human resources department. However, the complaint contends Dr. Hsieh’s actions only escalated after the report was made. According to the complaint, Dr. Hsieh began telling coworkers Dr. Stalfire was “lying” about his injuries. Dr. Hsieh also allegedly contacted administrators and schedulers to ask about Dr. Stalfire’s injuries and suggested that he was not “legitimately recovering from serious injuries.” The complaint claims that Dr. Hsieh told Dr. Stalfire’s colleagues that he was a “con man,” a “criminal,” and “despicable.”

According to Dr. Stalfire’s complaint, in August 2023, Dr. Hsieh submitted numerous anonymous complaints about Dr. Stalfire to the Washington Medical Commission, the Oregon Medical Board, and other governmental agencies. Dr. Stalfire defended himself against the complaints, and they were dismissed. The lawsuit does not specify the nature of the complaints.

Dr. Stalfire later made public record requests for the complaints and discovered Dr. Hsieh had used his deceased mother-in-law’s phone number as his contact information, according to the lawsuit. 

Despite multiple reports about Dr. Hsieh’s conduct, Dr. Stalfire claims Kaiser retained Dr. Hsieh as an employee and took no action to prevent him from making false statements about Dr. Stalfire. 

He claims Dr. Hsieh’s harassment and Kaiser’s inaction harmed his professional reputation, caused lost work time, and resulted in severe emotional distress that required mental health treatment. The harm caused continues to impact his ability to work, the suit contends. 
 

A version of this article appeared on Medscape.com.

A longtime Kaiser Permanente surgeon is suing a fellow physician for allegedly submitting false medical board complaints against him in an attempt to get him fired.

Joseph Stalfire III, MD, claims Ming Hsieh, MD, began a campaign to harm his reputation after Dr. Stalfire hurt his leg and went on medical leave. Dr. Stalfire, a board-certified ob.gyn., has worked for Kaiser Permanente in western Oregon for more than 20 years, including several years as a regional chief surgical officer.

Dr. Stalfire is accusing Dr. Hsieh of defamation and intentional emotional distress, according to the March 25 lawsuit filed in Marion County Circuit Court. Northwest Permanente P.C., a Kaiser subsidiary, is also named as a defendant.

Dr. Stalfire is asking for $1.2 million in economic damages and $300,000 in noneconomic damages. Dr. Hsieh has not yet responded to the legal complaint.

Dr. Stalfire’s attorney did not respond to a message seeking comment. Dr. Hsieh is representing himself, according to court records. A Kaiser Permanente spokeswoman told this news organization that Kaiser does not comment on pending litigation.

The conflict began in February 2023, after Dr. Stalfire underwent surgery to correct issues stemming from severe injuries when a tree fell on his leg, according to court records. 

Dr. Hsieh, a Kaiser ob.gyn., senior physician, and quality assurance lead, allegedly contacted Dr. Stalfire after the surgery and demanded he return to work earlier than medically recommended. Dr. Stalfire claims Dr. Hsieh questioned his retirement plans and his ability to continue working to pressure him into quitting. 

Dr. Stalfire reported Dr. Hsieh’s conduct to Kaiser’s human resources department. However, the complaint contends Dr. Hsieh’s actions only escalated after the report was made. According to the complaint, Dr. Hsieh began telling coworkers Dr. Stalfire was “lying” about his injuries. Dr. Hsieh also allegedly contacted administrators and schedulers to ask about Dr. Stalfire’s injuries and suggested that he was not “legitimately recovering from serious injuries.” The complaint claims that Dr. Hsieh told Dr. Stalfire’s colleagues that he was a “con man,” a “criminal,” and “despicable.”

According to Dr. Stalfire’s complaint, in August 2023, Dr. Hsieh submitted numerous anonymous complaints about Dr. Stalfire to the Washington Medical Commission, the Oregon Medical Board, and other governmental agencies. Dr. Stalfire defended himself against the complaints, and they were dismissed. The lawsuit does not specify the nature of the complaints.

Dr. Stalfire later made public record requests for the complaints and discovered Dr. Hsieh had used his deceased mother-in-law’s phone number as his contact information, according to the lawsuit. 

Despite multiple reports about Dr. Hsieh’s conduct, Dr. Stalfire claims Kaiser retained Dr. Hsieh as an employee and took no action to prevent him from making false statements about Dr. Stalfire. 

He claims Dr. Hsieh’s harassment and Kaiser’s inaction harmed his professional reputation, caused lost work time, and resulted in severe emotional distress that required mental health treatment. The harm caused continues to impact his ability to work, the suit contends. 
 

A version of this article appeared on Medscape.com.

A longtime Kaiser Permanente surgeon is suing a fellow physician for allegedly submitting false medical board complaints against him in an attempt to get him fired.

Joseph Stalfire III, MD, claims Ming Hsieh, MD, began a campaign to harm his reputation after Dr. Stalfire hurt his leg and went on medical leave. Dr. Stalfire, a board-certified ob.gyn., has worked for Kaiser Permanente in western Oregon for more than 20 years, including several years as a regional chief surgical officer.

Dr. Stalfire is accusing Dr. Hsieh of defamation and intentional emotional distress, according to the March 25 lawsuit filed in Marion County Circuit Court. Northwest Permanente P.C., a Kaiser subsidiary, is also named as a defendant.

Dr. Stalfire is asking for $1.2 million in economic damages and $300,000 in noneconomic damages. Dr. Hsieh has not yet responded to the legal complaint.

Dr. Stalfire’s attorney did not respond to a message seeking comment. Dr. Hsieh is representing himself, according to court records. A Kaiser Permanente spokeswoman told this news organization that Kaiser does not comment on pending litigation.

The conflict began in February 2023, after Dr. Stalfire underwent surgery to correct issues stemming from severe injuries when a tree fell on his leg, according to court records. 

Dr. Hsieh, a Kaiser ob.gyn., senior physician, and quality assurance lead, allegedly contacted Dr. Stalfire after the surgery and demanded he return to work earlier than medically recommended. Dr. Stalfire claims Dr. Hsieh questioned his retirement plans and his ability to continue working to pressure him into quitting. 

Dr. Stalfire reported Dr. Hsieh’s conduct to Kaiser’s human resources department. However, the complaint contends Dr. Hsieh’s actions only escalated after the report was made. According to the complaint, Dr. Hsieh began telling coworkers Dr. Stalfire was “lying” about his injuries. Dr. Hsieh also allegedly contacted administrators and schedulers to ask about Dr. Stalfire’s injuries and suggested that he was not “legitimately recovering from serious injuries.” The complaint claims that Dr. Hsieh told Dr. Stalfire’s colleagues that he was a “con man,” a “criminal,” and “despicable.”

According to Dr. Stalfire’s complaint, in August 2023, Dr. Hsieh submitted numerous anonymous complaints about Dr. Stalfire to the Washington Medical Commission, the Oregon Medical Board, and other governmental agencies. Dr. Stalfire defended himself against the complaints, and they were dismissed. The lawsuit does not specify the nature of the complaints.

Dr. Stalfire later made public record requests for the complaints and discovered Dr. Hsieh had used his deceased mother-in-law’s phone number as his contact information, according to the lawsuit. 

Despite multiple reports about Dr. Hsieh’s conduct, Dr. Stalfire claims Kaiser retained Dr. Hsieh as an employee and took no action to prevent him from making false statements about Dr. Stalfire. 

He claims Dr. Hsieh’s harassment and Kaiser’s inaction harmed his professional reputation, caused lost work time, and resulted in severe emotional distress that required mental health treatment. The harm caused continues to impact his ability to work, the suit contends. 
 

A version of this article appeared on Medscape.com.