CASE Attempted suicide?

Ms. S, a 16-year-old Yemeni-American girl, is brought to the emergency department (ED) by her mother and brother after ingesting an overdose of painkillers and fainting. During the initial evaluation, Ms. S says she had in the past attempted suicide by knife. The medical team suspects that the current overdose is a suicide attempt, and they call the consultation-liaison (C-L) psychiatry/psychology team. Ms. S’s brother strongly denies that his sister had previously attempted suicide, stating, “She’s from a good family, and she is smart. She cannot feel that way.” He also requests the name of the clinician who documented this information in the medical record.

During the consultation, Ms. S reports that the previous morning, she developed strong abdominal pain and discovered that she was menstruating for the first time. She explains that she did not understand what was happening to her and that no one had discussed menstruation with her before. Ms. S took her mother’s opioid pain medication. Ms. S reports she took one pill, but when it did not immediately alleviate her pain, she ingested several more. After this, Ms. S says she went to play with her siblings, but gradually became dizzy and confused, and informed her sister and mother of this. The family was fasting in observance of Ramadan, and as they walked toward the mosque, Ms. S fainted, which prompted her family to bring her to the ED.

During the C-L consultation, Ms. S’s brother, who speaks English, is present, as is her mother, who speaks only Arabic and thus needs a phone interpreter. As the C-L team asks Ms. S a question, it is translated to her mother, and then Ms. S’s response is also translated, and then finally, the mother shares her own response. At times, her brother provides translation. Ms. S speaks in English, but often asks for the translation of words or questions.

Ms. S reports that she and her family emigrated from Yemen to the United States 9 months ago. Ms. S says that she enjoys school and is doing well academically. She denies experiencing any anxiety, worry, or stress related to her life in Yemen, her move to a new country, her parents’ health, school, or other domains. Ms. S also denies any history of depressive episodes or previous suicidal ideation, intention, or attempt, which contradicts her endorsement of a previous suicide attempt to one clinician when she was initially evaluated.

[polldaddy:10040204]

Continue to: The authors' observation

The C-L team determined that Ms. S did not meet criteria for major depressive disorder. She did not endorse current feelings of depression and denied anhedonia and other associated symptoms included in DSM-5 criteria for major depressive disorder or adjustment disorder with depressed mood (Table 1¹). Ms. S also denied having a history of depressive episodes or previous suicidal ideation, intention, or attempt, despite having said during the initial evaluation that she had a previous suicide attempt.

Although Ms. S and her family recently emigrated from Yemen, she did not report any symptoms consistent with an adjustment disorder with depression. Further, because she denied having any anxiety, worry, or stress related to her life in Yemen, her move to the United States, her parents’ health, school, or any other domains, she did not meet criteria for posttraumatic stress disorder, acute stress disorder (Table 2¹), or an anxiety disorder. Similarly, there was no evidence of a substance use disorder.

Accurate case conceptualization and diagnosis is particularly crucial in C-L services, where there is an urgency for clinical decision-making after an initial evaluation without the luxury of amending conceptualization in follow-up sessions. Providing a diagnosis for which a patient does not fully or accurately meet the criteria can have deleterious effects. An inaccurate diagnosis for Ms. S would have unnecessarily added the perceived stigma of a mental disorder to her medical record. Additionally, misdiagnosing or pathologizing a natural process of acculturation could have led to inappropriate or even harmful treatment.

The C-L team evaluated alternative explanations for Ms. S’s statements that suggested she was suicidal. First, they considered her mental status at the time she presented to the ED. An overdose of opioids alters mental status. Complicating reversal of opioid overdose is that some opioids have longer half-lives than naloxone, an opioid antagonist, so the individual can become reintoxicated. Similarly, some opioids are more potent and difficult to reverse.² An altered mental status may have limited Ms. S’s ability to comprehend and answer questions accurately when she first presented to the ED.

Continue to: Cultural factors and the clinical evaluation

Next, the C-L team considered Ms. S’s clinical picture as it related to her cultural background. Cultural factors interact with the clinical evaluation in a complex manner, influencing the way patients approach the encounter, the symptoms they report, and the language they use to describe their experiences. While these variables are thoroughly evaluated during comprehensive psychological assessments, within the inpatient consultation service, the goal for pediatric C-L clinicians is to conduct a focused assessment to answer specific and critically important questions about a youth’s psychological functioning. Thus, the fundamental challenge of inpatient consultation is to answer the referral question in a brief period and in a culturally informed manner, to appraise the referring medical team about the relevant clinical and cultural issues, with the goal of ethical and clinically sound decision-making.

The C-L team considered key cultural factors in its assessment of Ms. S (Table 3¹). Several issues were of concern. First, language is often cited as the top barrier to health care access by Arab Americans, even by those with competency in English.³ Ms. S spoke English, but she often asked for the translation of words or questions, and her mother spoke only Arabic, and was assisted by a phone interpreter to communicate with the clinicians caring for her daughter. Conducting the interview with the phone interpreter added complexity to the interactions, interrupted the natural flow of the conversation, and was felt to hinder openness of disclosure.

Experts in culture argue that even with access to interpreters, many words and phrases lack direct translation, and their implicit meaning may be difficult to reveal. Additionally, at times more significance is placed on nonverbal cues and unspoken expectations.⁴ This can create barriers to communication with clinicians, especially in the context of an inpatient psychiatric consultation, when thorough understanding of an adolescent and family often needs to occur in a single encounter, and clinicians may not appreciate the subtle nuances of nonverbal communication.

The language barrier also may have influenced Ms. S’s initial endorsement of a previous suicide attempt by knife because the medical staff first interviewed Ms. S without an interpreter. For instance, many medical and psychosocial providers probe patients regarding suicidality with questions such as “Have you ever hurt yourself?” or “Have you ever tried to hurt yourself?” It is possible that in another language, an individual might interpret that question as, “Have you ever gotten hurt?” This interpretation completely alters the meaning of the question and eliminates intention or motivation to harm oneself. Language ambiguity and lack of shared cultural understanding may have influenced Ms. S’s interpretation of and response to such questions. Ms. S and her family were perplexed by the C-L team’s reference to the knife and continued to deny the incident.

Continue to: Cultural attitudes to puberty

Cultural attitudes to puberty

Cultures vary with respect to education of sensitive topics such as puberty. The medical providers assumed that Ms. S was informed about the onset of menses. Therefore, they could not consider the strong impact of such an event on an unsuspecting adolescent. Many adolescent girls in Yemen have poor health and lack menstruation-related knowledge, and many are “prescribed” medications by their mothers without contacting a physician.⁵ Ms. S reported to the C-L team that no one from her family had discussed menstruation with her. She reported that since arriving at the hospital, nurses had educated her about menstruation, and that she was no longer afraid. She also noted that if she experienced such pain again, she would go to the hospital or “just deal with it.”

Family identification and attitudes toward mental health

Ms. S’s strong identification with her family and attitudes toward mental health may have limited what she chose to disclose regarding her experiences of loss related to leaving her country of origin, adjustment, and acculturation to the new environment, as well as feelings of sadness. Family has a central and critical role in Arab cultures. Commitment to a family’s well-being and enhancement of honor and status is highly valued and encouraged.⁴ Conversely, being concerned with individual needs may be a source of guilt and feelings of betraying the family.⁶ Arab Americans tend not to discuss personal problems with people outside their extended family, including counselors and therapists, partly because of cultural stigma against mental illness^7,8 and partly because revealing family problems to strangers (ie, clinicians) may be considered a cultural taboo⁹ and a threat to family honor.¹⁰ Although Ms. S was interviewed privately when she first came to the ED and also during the psychiatric consultation, the stigma of psychiatric problems¹¹ and possible concerns about protecting her family’s name may have influenced her readiness to reveal intimate information to “strangers.”

Additionally, family statements that appeared to imply negative beliefs about mental health would have strongly deterred Ms. S from expressing any psychological concerns. For example, Ms. S’s brother took offense when the C-L team said it was evaluating his sister because she had said she had previously attempted suicide.

The tenets of Islam may have provided a framework through which Ms. S interprets emotional concerns and may have defined her explanatory models of psychological stress. For instance, it is not uncommon among American Muslims to view mental health problems as rising from “loss of faith in God,”⁹ and suicidal ideation may not be disclosed because suicide is forbidden in Islam.¹² Therefore, it might be particularly difficult to assess suicidal ideation in a patient who is Muslim, especially those who are less acculturated to Western culture.¹³

Continue to: Directly asking Ms. S...

Directly asking Ms. S if she had thoughts of harming herself may have been too frightening or guilt-provoking for an adolescent with her background. Asking about passive expression of suicidal ideation would have been more culturally appropriate. For example, asking, “Do you wish that God would let you die?”¹² may have elicited more meaningful clinical information about Ms. S’s emotional state and possibly suicide risk.

Furthermore, Ms. S’s identification of coping strategies (ie, “just deal with it”) may have sounded limited to a Western clinician, but this may have been consistent with cultural norms of emotional expression of limiting complaints.⁴ Also, among Arab Americans, psychiatric symptoms often are expressed through somatization.^7,14 Expressing psychological pain through physical symptoms appears protective against public stigma. Public image and opinion is important, and behaviors that would reflect well to others are dictated by the family. These attitudes, beliefs, and values likely impact how Ms. S presented her psychological concerns.

[polldaddy:10040206]

The authors’ observations

Although inpatient hospitalization was initially considered, it was not pursued due to denial of past and current suicidal ideation or suicide attempts, the lack of comorbidity, age-appropriate functioning, and a supportive family environment. Similarly, due to the absence of acute psychiatric symptoms, partial hospitalization was not pursued. The C-L team evaluated treatment options with extreme caution and sensitivity because recommending the wrong treatment option could have deleterious effects on Ms. S and her family’s life. If inpatient hospitalization had been pursued, it could have likely caused the family unnecessary suffering and could have negatively affected familial relationships. Strong feelings of shame, betrayal, and guilt would be intensified, impairing the family’s cohesion, removing environmental and family supports, and putting Ms. S at further risk of developing more severe symptoms of low mood.

Although there were significant concerns about making the wrong recommendation to the family, the C-L team’s highest priority was Ms. S’s safety. Despite cultural concerns, the team would have recommended hospitalization if Ms. S’s clinical picture had warranted this decision.

Continue to: OUTCOME Culturally-appropriate outpatient therapy

Due to the lack of substantial evidence of apparent risk for self-harm, the presence of a supportive family, and Ms. S’s high academic performance and future orientation, the C-L team concludes that Ms. S’s concerns were most likely the result of the challenges of acculturation related to the language barrier and a lack of health knowledge. However, the C-L team remains cautious that Ms. S may have minimized or denied her mental health concerns due to various cultural factors. The team recommends that Ms. S seek outpatient psychotherapy from a clinician who specializes in working with Arab American individuals and families in their native language. The C-L team communicates these conclusions to the medical team verbally and in writing.

The authors’ observations

Cultural issues experienced during this consultation may not generalize to other Arab American adolescents and their families because there is diversity even within groups that share common cultural characteristics. Nevertheless, this case underscores the challenge of accurately assessing suicide risk, and making a differential diagnosis in the presence of complex cultural data and the dilemmas clinicians may encounter when attempting to answer important referral questions such as, “Is this adolescent suicidal and in need of psychiatric hospitalization?”

Bottom Line 

Cultural factors and attitudes toward mental health and language barriers may play a large role in how patients answer clinical questions. Cultural issues may add a level of intricacy not easily resolved within the restrictions of an inpatient setting, and this complexity may influence clinical judgment, recommendations, and possibly health outcomes. Culturally appropriate psychotherapy is key for patients experiencing difficulty with acculturation.

Related Resources

• Adam B. Caring for Muslim patients: Understanding cultural and religious factors. Current Psychiatry. 2017;16(12):56-57.
• Nassar-McMillan SC, Hakim-Larson J. Counseling considerations among Arab Americans. Journal of Counseling & Development. 2003;81(2):150-159.  
• Sue DW. Multidimensional facets of cultural competence. The Counseling Psychologist. 2001;29(6):790-821. 

Drug Brand Name

Naloxone • Narcan

CASE Attempted suicide?

Ms. S, a 16-year-old Yemeni-American girl, is brought to the emergency department (ED) by her mother and brother after ingesting an overdose of painkillers and fainting. During the initial evaluation, Ms. S says she had in the past attempted suicide by knife. The medical team suspects that the current overdose is a suicide attempt, and they call the consultation-liaison (C-L) psychiatry/psychology team. Ms. S’s brother strongly denies that his sister had previously attempted suicide, stating, “She’s from a good family, and she is smart. She cannot feel that way.” He also requests the name of the clinician who documented this information in the medical record.

During the consultation, Ms. S reports that the previous morning, she developed strong abdominal pain and discovered that she was menstruating for the first time. She explains that she did not understand what was happening to her and that no one had discussed menstruation with her before. Ms. S took her mother’s opioid pain medication. Ms. S reports she took one pill, but when it did not immediately alleviate her pain, she ingested several more. After this, Ms. S says she went to play with her siblings, but gradually became dizzy and confused, and informed her sister and mother of this. The family was fasting in observance of Ramadan, and as they walked toward the mosque, Ms. S fainted, which prompted her family to bring her to the ED.

During the C-L consultation, Ms. S’s brother, who speaks English, is present, as is her mother, who speaks only Arabic and thus needs a phone interpreter. As the C-L team asks Ms. S a question, it is translated to her mother, and then Ms. S’s response is also translated, and then finally, the mother shares her own response. At times, her brother provides translation. Ms. S speaks in English, but often asks for the translation of words or questions.

Ms. S reports that she and her family emigrated from Yemen to the United States 9 months ago. Ms. S says that she enjoys school and is doing well academically. She denies experiencing any anxiety, worry, or stress related to her life in Yemen, her move to a new country, her parents’ health, school, or other domains. Ms. S also denies any history of depressive episodes or previous suicidal ideation, intention, or attempt, which contradicts her endorsement of a previous suicide attempt to one clinician when she was initially evaluated.

[polldaddy:10040204]

Continue to: The authors' observation

The C-L team determined that Ms. S did not meet criteria for major depressive disorder. She did not endorse current feelings of depression and denied anhedonia and other associated symptoms included in DSM-5 criteria for major depressive disorder or adjustment disorder with depressed mood (Table 1¹). Ms. S also denied having a history of depressive episodes or previous suicidal ideation, intention, or attempt, despite having said during the initial evaluation that she had a previous suicide attempt.

Although Ms. S and her family recently emigrated from Yemen, she did not report any symptoms consistent with an adjustment disorder with depression. Further, because she denied having any anxiety, worry, or stress related to her life in Yemen, her move to the United States, her parents’ health, school, or any other domains, she did not meet criteria for posttraumatic stress disorder, acute stress disorder (Table 2¹), or an anxiety disorder. Similarly, there was no evidence of a substance use disorder.

Accurate case conceptualization and diagnosis is particularly crucial in C-L services, where there is an urgency for clinical decision-making after an initial evaluation without the luxury of amending conceptualization in follow-up sessions. Providing a diagnosis for which a patient does not fully or accurately meet the criteria can have deleterious effects. An inaccurate diagnosis for Ms. S would have unnecessarily added the perceived stigma of a mental disorder to her medical record. Additionally, misdiagnosing or pathologizing a natural process of acculturation could have led to inappropriate or even harmful treatment.

The C-L team evaluated alternative explanations for Ms. S’s statements that suggested she was suicidal. First, they considered her mental status at the time she presented to the ED. An overdose of opioids alters mental status. Complicating reversal of opioid overdose is that some opioids have longer half-lives than naloxone, an opioid antagonist, so the individual can become reintoxicated. Similarly, some opioids are more potent and difficult to reverse.² An altered mental status may have limited Ms. S’s ability to comprehend and answer questions accurately when she first presented to the ED.

Continue to: Cultural factors and the clinical evaluation

Next, the C-L team considered Ms. S’s clinical picture as it related to her cultural background. Cultural factors interact with the clinical evaluation in a complex manner, influencing the way patients approach the encounter, the symptoms they report, and the language they use to describe their experiences. While these variables are thoroughly evaluated during comprehensive psychological assessments, within the inpatient consultation service, the goal for pediatric C-L clinicians is to conduct a focused assessment to answer specific and critically important questions about a youth’s psychological functioning. Thus, the fundamental challenge of inpatient consultation is to answer the referral question in a brief period and in a culturally informed manner, to appraise the referring medical team about the relevant clinical and cultural issues, with the goal of ethical and clinically sound decision-making.

The C-L team considered key cultural factors in its assessment of Ms. S (Table 3¹). Several issues were of concern. First, language is often cited as the top barrier to health care access by Arab Americans, even by those with competency in English.³ Ms. S spoke English, but she often asked for the translation of words or questions, and her mother spoke only Arabic, and was assisted by a phone interpreter to communicate with the clinicians caring for her daughter. Conducting the interview with the phone interpreter added complexity to the interactions, interrupted the natural flow of the conversation, and was felt to hinder openness of disclosure.

Experts in culture argue that even with access to interpreters, many words and phrases lack direct translation, and their implicit meaning may be difficult to reveal. Additionally, at times more significance is placed on nonverbal cues and unspoken expectations.⁴ This can create barriers to communication with clinicians, especially in the context of an inpatient psychiatric consultation, when thorough understanding of an adolescent and family often needs to occur in a single encounter, and clinicians may not appreciate the subtle nuances of nonverbal communication.

The language barrier also may have influenced Ms. S’s initial endorsement of a previous suicide attempt by knife because the medical staff first interviewed Ms. S without an interpreter. For instance, many medical and psychosocial providers probe patients regarding suicidality with questions such as “Have you ever hurt yourself?” or “Have you ever tried to hurt yourself?” It is possible that in another language, an individual might interpret that question as, “Have you ever gotten hurt?” This interpretation completely alters the meaning of the question and eliminates intention or motivation to harm oneself. Language ambiguity and lack of shared cultural understanding may have influenced Ms. S’s interpretation of and response to such questions. Ms. S and her family were perplexed by the C-L team’s reference to the knife and continued to deny the incident.

Continue to: Cultural attitudes to puberty

Cultural attitudes to puberty

Cultures vary with respect to education of sensitive topics such as puberty. The medical providers assumed that Ms. S was informed about the onset of menses. Therefore, they could not consider the strong impact of such an event on an unsuspecting adolescent. Many adolescent girls in Yemen have poor health and lack menstruation-related knowledge, and many are “prescribed” medications by their mothers without contacting a physician.⁵ Ms. S reported to the C-L team that no one from her family had discussed menstruation with her. She reported that since arriving at the hospital, nurses had educated her about menstruation, and that she was no longer afraid. She also noted that if she experienced such pain again, she would go to the hospital or “just deal with it.”

Family identification and attitudes toward mental health

Ms. S’s strong identification with her family and attitudes toward mental health may have limited what she chose to disclose regarding her experiences of loss related to leaving her country of origin, adjustment, and acculturation to the new environment, as well as feelings of sadness. Family has a central and critical role in Arab cultures. Commitment to a family’s well-being and enhancement of honor and status is highly valued and encouraged.⁴ Conversely, being concerned with individual needs may be a source of guilt and feelings of betraying the family.⁶ Arab Americans tend not to discuss personal problems with people outside their extended family, including counselors and therapists, partly because of cultural stigma against mental illness^7,8 and partly because revealing family problems to strangers (ie, clinicians) may be considered a cultural taboo⁹ and a threat to family honor.¹⁰ Although Ms. S was interviewed privately when she first came to the ED and also during the psychiatric consultation, the stigma of psychiatric problems¹¹ and possible concerns about protecting her family’s name may have influenced her readiness to reveal intimate information to “strangers.”

Additionally, family statements that appeared to imply negative beliefs about mental health would have strongly deterred Ms. S from expressing any psychological concerns. For example, Ms. S’s brother took offense when the C-L team said it was evaluating his sister because she had said she had previously attempted suicide.

The tenets of Islam may have provided a framework through which Ms. S interprets emotional concerns and may have defined her explanatory models of psychological stress. For instance, it is not uncommon among American Muslims to view mental health problems as rising from “loss of faith in God,”⁹ and suicidal ideation may not be disclosed because suicide is forbidden in Islam.¹² Therefore, it might be particularly difficult to assess suicidal ideation in a patient who is Muslim, especially those who are less acculturated to Western culture.¹³

Continue to: Directly asking Ms. S...

Directly asking Ms. S if she had thoughts of harming herself may have been too frightening or guilt-provoking for an adolescent with her background. Asking about passive expression of suicidal ideation would have been more culturally appropriate. For example, asking, “Do you wish that God would let you die?”¹² may have elicited more meaningful clinical information about Ms. S’s emotional state and possibly suicide risk.

Furthermore, Ms. S’s identification of coping strategies (ie, “just deal with it”) may have sounded limited to a Western clinician, but this may have been consistent with cultural norms of emotional expression of limiting complaints.⁴ Also, among Arab Americans, psychiatric symptoms often are expressed through somatization.^7,14 Expressing psychological pain through physical symptoms appears protective against public stigma. Public image and opinion is important, and behaviors that would reflect well to others are dictated by the family. These attitudes, beliefs, and values likely impact how Ms. S presented her psychological concerns.

[polldaddy:10040206]

The authors’ observations

Although inpatient hospitalization was initially considered, it was not pursued due to denial of past and current suicidal ideation or suicide attempts, the lack of comorbidity, age-appropriate functioning, and a supportive family environment. Similarly, due to the absence of acute psychiatric symptoms, partial hospitalization was not pursued. The C-L team evaluated treatment options with extreme caution and sensitivity because recommending the wrong treatment option could have deleterious effects on Ms. S and her family’s life. If inpatient hospitalization had been pursued, it could have likely caused the family unnecessary suffering and could have negatively affected familial relationships. Strong feelings of shame, betrayal, and guilt would be intensified, impairing the family’s cohesion, removing environmental and family supports, and putting Ms. S at further risk of developing more severe symptoms of low mood.

Although there were significant concerns about making the wrong recommendation to the family, the C-L team’s highest priority was Ms. S’s safety. Despite cultural concerns, the team would have recommended hospitalization if Ms. S’s clinical picture had warranted this decision.

Continue to: OUTCOME Culturally-appropriate outpatient therapy

Due to the lack of substantial evidence of apparent risk for self-harm, the presence of a supportive family, and Ms. S’s high academic performance and future orientation, the C-L team concludes that Ms. S’s concerns were most likely the result of the challenges of acculturation related to the language barrier and a lack of health knowledge. However, the C-L team remains cautious that Ms. S may have minimized or denied her mental health concerns due to various cultural factors. The team recommends that Ms. S seek outpatient psychotherapy from a clinician who specializes in working with Arab American individuals and families in their native language. The C-L team communicates these conclusions to the medical team verbally and in writing.

The authors’ observations

Cultural issues experienced during this consultation may not generalize to other Arab American adolescents and their families because there is diversity even within groups that share common cultural characteristics. Nevertheless, this case underscores the challenge of accurately assessing suicide risk, and making a differential diagnosis in the presence of complex cultural data and the dilemmas clinicians may encounter when attempting to answer important referral questions such as, “Is this adolescent suicidal and in need of psychiatric hospitalization?”

Bottom Line 

Cultural factors and attitudes toward mental health and language barriers may play a large role in how patients answer clinical questions. Cultural issues may add a level of intricacy not easily resolved within the restrictions of an inpatient setting, and this complexity may influence clinical judgment, recommendations, and possibly health outcomes. Culturally appropriate psychotherapy is key for patients experiencing difficulty with acculturation.

Related Resources

• Adam B. Caring for Muslim patients: Understanding cultural and religious factors. Current Psychiatry. 2017;16(12):56-57.
• Nassar-McMillan SC, Hakim-Larson J. Counseling considerations among Arab Americans. Journal of Counseling & Development. 2003;81(2):150-159.  
• Sue DW. Multidimensional facets of cultural competence. The Counseling Psychologist. 2001;29(6):790-821. 

Drug Brand Name

Naloxone • Narcan

CASE Attempted suicide?

Ms. S, a 16-year-old Yemeni-American girl, is brought to the emergency department (ED) by her mother and brother after ingesting an overdose of painkillers and fainting. During the initial evaluation, Ms. S says she had in the past attempted suicide by knife. The medical team suspects that the current overdose is a suicide attempt, and they call the consultation-liaison (C-L) psychiatry/psychology team. Ms. S’s brother strongly denies that his sister had previously attempted suicide, stating, “She’s from a good family, and she is smart. She cannot feel that way.” He also requests the name of the clinician who documented this information in the medical record.

During the consultation, Ms. S reports that the previous morning, she developed strong abdominal pain and discovered that she was menstruating for the first time. She explains that she did not understand what was happening to her and that no one had discussed menstruation with her before. Ms. S took her mother’s opioid pain medication. Ms. S reports she took one pill, but when it did not immediately alleviate her pain, she ingested several more. After this, Ms. S says she went to play with her siblings, but gradually became dizzy and confused, and informed her sister and mother of this. The family was fasting in observance of Ramadan, and as they walked toward the mosque, Ms. S fainted, which prompted her family to bring her to the ED.

During the C-L consultation, Ms. S’s brother, who speaks English, is present, as is her mother, who speaks only Arabic and thus needs a phone interpreter. As the C-L team asks Ms. S a question, it is translated to her mother, and then Ms. S’s response is also translated, and then finally, the mother shares her own response. At times, her brother provides translation. Ms. S speaks in English, but often asks for the translation of words or questions.

Ms. S reports that she and her family emigrated from Yemen to the United States 9 months ago. Ms. S says that she enjoys school and is doing well academically. She denies experiencing any anxiety, worry, or stress related to her life in Yemen, her move to a new country, her parents’ health, school, or other domains. Ms. S also denies any history of depressive episodes or previous suicidal ideation, intention, or attempt, which contradicts her endorsement of a previous suicide attempt to one clinician when she was initially evaluated.

[polldaddy:10040204]

Continue to: The authors' observation

The C-L team determined that Ms. S did not meet criteria for major depressive disorder. She did not endorse current feelings of depression and denied anhedonia and other associated symptoms included in DSM-5 criteria for major depressive disorder or adjustment disorder with depressed mood (Table 1¹). Ms. S also denied having a history of depressive episodes or previous suicidal ideation, intention, or attempt, despite having said during the initial evaluation that she had a previous suicide attempt.

Although Ms. S and her family recently emigrated from Yemen, she did not report any symptoms consistent with an adjustment disorder with depression. Further, because she denied having any anxiety, worry, or stress related to her life in Yemen, her move to the United States, her parents’ health, school, or any other domains, she did not meet criteria for posttraumatic stress disorder, acute stress disorder (Table 2¹), or an anxiety disorder. Similarly, there was no evidence of a substance use disorder.

Accurate case conceptualization and diagnosis is particularly crucial in C-L services, where there is an urgency for clinical decision-making after an initial evaluation without the luxury of amending conceptualization in follow-up sessions. Providing a diagnosis for which a patient does not fully or accurately meet the criteria can have deleterious effects. An inaccurate diagnosis for Ms. S would have unnecessarily added the perceived stigma of a mental disorder to her medical record. Additionally, misdiagnosing or pathologizing a natural process of acculturation could have led to inappropriate or even harmful treatment.

The C-L team evaluated alternative explanations for Ms. S’s statements that suggested she was suicidal. First, they considered her mental status at the time she presented to the ED. An overdose of opioids alters mental status. Complicating reversal of opioid overdose is that some opioids have longer half-lives than naloxone, an opioid antagonist, so the individual can become reintoxicated. Similarly, some opioids are more potent and difficult to reverse.² An altered mental status may have limited Ms. S’s ability to comprehend and answer questions accurately when she first presented to the ED.

Continue to: Cultural factors and the clinical evaluation

Next, the C-L team considered Ms. S’s clinical picture as it related to her cultural background. Cultural factors interact with the clinical evaluation in a complex manner, influencing the way patients approach the encounter, the symptoms they report, and the language they use to describe their experiences. While these variables are thoroughly evaluated during comprehensive psychological assessments, within the inpatient consultation service, the goal for pediatric C-L clinicians is to conduct a focused assessment to answer specific and critically important questions about a youth’s psychological functioning. Thus, the fundamental challenge of inpatient consultation is to answer the referral question in a brief period and in a culturally informed manner, to appraise the referring medical team about the relevant clinical and cultural issues, with the goal of ethical and clinically sound decision-making.

The C-L team considered key cultural factors in its assessment of Ms. S (Table 3¹). Several issues were of concern. First, language is often cited as the top barrier to health care access by Arab Americans, even by those with competency in English.³ Ms. S spoke English, but she often asked for the translation of words or questions, and her mother spoke only Arabic, and was assisted by a phone interpreter to communicate with the clinicians caring for her daughter. Conducting the interview with the phone interpreter added complexity to the interactions, interrupted the natural flow of the conversation, and was felt to hinder openness of disclosure.

Experts in culture argue that even with access to interpreters, many words and phrases lack direct translation, and their implicit meaning may be difficult to reveal. Additionally, at times more significance is placed on nonverbal cues and unspoken expectations.⁴ This can create barriers to communication with clinicians, especially in the context of an inpatient psychiatric consultation, when thorough understanding of an adolescent and family often needs to occur in a single encounter, and clinicians may not appreciate the subtle nuances of nonverbal communication.

The language barrier also may have influenced Ms. S’s initial endorsement of a previous suicide attempt by knife because the medical staff first interviewed Ms. S without an interpreter. For instance, many medical and psychosocial providers probe patients regarding suicidality with questions such as “Have you ever hurt yourself?” or “Have you ever tried to hurt yourself?” It is possible that in another language, an individual might interpret that question as, “Have you ever gotten hurt?” This interpretation completely alters the meaning of the question and eliminates intention or motivation to harm oneself. Language ambiguity and lack of shared cultural understanding may have influenced Ms. S’s interpretation of and response to such questions. Ms. S and her family were perplexed by the C-L team’s reference to the knife and continued to deny the incident.

Continue to: Cultural attitudes to puberty

Cultural attitudes to puberty

Cultures vary with respect to education of sensitive topics such as puberty. The medical providers assumed that Ms. S was informed about the onset of menses. Therefore, they could not consider the strong impact of such an event on an unsuspecting adolescent. Many adolescent girls in Yemen have poor health and lack menstruation-related knowledge, and many are “prescribed” medications by their mothers without contacting a physician.⁵ Ms. S reported to the C-L team that no one from her family had discussed menstruation with her. She reported that since arriving at the hospital, nurses had educated her about menstruation, and that she was no longer afraid. She also noted that if she experienced such pain again, she would go to the hospital or “just deal with it.”

Family identification and attitudes toward mental health

Ms. S’s strong identification with her family and attitudes toward mental health may have limited what she chose to disclose regarding her experiences of loss related to leaving her country of origin, adjustment, and acculturation to the new environment, as well as feelings of sadness. Family has a central and critical role in Arab cultures. Commitment to a family’s well-being and enhancement of honor and status is highly valued and encouraged.⁴ Conversely, being concerned with individual needs may be a source of guilt and feelings of betraying the family.⁶ Arab Americans tend not to discuss personal problems with people outside their extended family, including counselors and therapists, partly because of cultural stigma against mental illness^7,8 and partly because revealing family problems to strangers (ie, clinicians) may be considered a cultural taboo⁹ and a threat to family honor.¹⁰ Although Ms. S was interviewed privately when she first came to the ED and also during the psychiatric consultation, the stigma of psychiatric problems¹¹ and possible concerns about protecting her family’s name may have influenced her readiness to reveal intimate information to “strangers.”

Additionally, family statements that appeared to imply negative beliefs about mental health would have strongly deterred Ms. S from expressing any psychological concerns. For example, Ms. S’s brother took offense when the C-L team said it was evaluating his sister because she had said she had previously attempted suicide.

The tenets of Islam may have provided a framework through which Ms. S interprets emotional concerns and may have defined her explanatory models of psychological stress. For instance, it is not uncommon among American Muslims to view mental health problems as rising from “loss of faith in God,”⁹ and suicidal ideation may not be disclosed because suicide is forbidden in Islam.¹² Therefore, it might be particularly difficult to assess suicidal ideation in a patient who is Muslim, especially those who are less acculturated to Western culture.¹³

Continue to: Directly asking Ms. S...

Directly asking Ms. S if she had thoughts of harming herself may have been too frightening or guilt-provoking for an adolescent with her background. Asking about passive expression of suicidal ideation would have been more culturally appropriate. For example, asking, “Do you wish that God would let you die?”¹² may have elicited more meaningful clinical information about Ms. S’s emotional state and possibly suicide risk.

Furthermore, Ms. S’s identification of coping strategies (ie, “just deal with it”) may have sounded limited to a Western clinician, but this may have been consistent with cultural norms of emotional expression of limiting complaints.⁴ Also, among Arab Americans, psychiatric symptoms often are expressed through somatization.^7,14 Expressing psychological pain through physical symptoms appears protective against public stigma. Public image and opinion is important, and behaviors that would reflect well to others are dictated by the family. These attitudes, beliefs, and values likely impact how Ms. S presented her psychological concerns.

[polldaddy:10040206]

The authors’ observations

Although inpatient hospitalization was initially considered, it was not pursued due to denial of past and current suicidal ideation or suicide attempts, the lack of comorbidity, age-appropriate functioning, and a supportive family environment. Similarly, due to the absence of acute psychiatric symptoms, partial hospitalization was not pursued. The C-L team evaluated treatment options with extreme caution and sensitivity because recommending the wrong treatment option could have deleterious effects on Ms. S and her family’s life. If inpatient hospitalization had been pursued, it could have likely caused the family unnecessary suffering and could have negatively affected familial relationships. Strong feelings of shame, betrayal, and guilt would be intensified, impairing the family’s cohesion, removing environmental and family supports, and putting Ms. S at further risk of developing more severe symptoms of low mood.

Although there were significant concerns about making the wrong recommendation to the family, the C-L team’s highest priority was Ms. S’s safety. Despite cultural concerns, the team would have recommended hospitalization if Ms. S’s clinical picture had warranted this decision.

Continue to: OUTCOME Culturally-appropriate outpatient therapy

Due to the lack of substantial evidence of apparent risk for self-harm, the presence of a supportive family, and Ms. S’s high academic performance and future orientation, the C-L team concludes that Ms. S’s concerns were most likely the result of the challenges of acculturation related to the language barrier and a lack of health knowledge. However, the C-L team remains cautious that Ms. S may have minimized or denied her mental health concerns due to various cultural factors. The team recommends that Ms. S seek outpatient psychotherapy from a clinician who specializes in working with Arab American individuals and families in their native language. The C-L team communicates these conclusions to the medical team verbally and in writing.

The authors’ observations

Cultural issues experienced during this consultation may not generalize to other Arab American adolescents and their families because there is diversity even within groups that share common cultural characteristics. Nevertheless, this case underscores the challenge of accurately assessing suicide risk, and making a differential diagnosis in the presence of complex cultural data and the dilemmas clinicians may encounter when attempting to answer important referral questions such as, “Is this adolescent suicidal and in need of psychiatric hospitalization?”

Bottom Line 

Cultural factors and attitudes toward mental health and language barriers may play a large role in how patients answer clinical questions. Cultural issues may add a level of intricacy not easily resolved within the restrictions of an inpatient setting, and this complexity may influence clinical judgment, recommendations, and possibly health outcomes. Culturally appropriate psychotherapy is key for patients experiencing difficulty with acculturation.

Related Resources

• Adam B. Caring for Muslim patients: Understanding cultural and religious factors. Current Psychiatry. 2017;16(12):56-57.
• Nassar-McMillan SC, Hakim-Larson J. Counseling considerations among Arab Americans. Journal of Counseling & Development. 2003;81(2):150-159.  
• Sue DW. Multidimensional facets of cultural competence. The Counseling Psychologist. 2001;29(6):790-821. 

Drug Brand Name

Naloxone • Narcan

I read your editorial with appreciation this morning. In my practice, I have worked with adolescents and young adults for more than 30 years, so the fact that many mass shooters are so young has caught my attention.

Of course, there is never just one cause for such horrific actions. But it seems to me that there are two recurring themes in these situations: (1) many shooters are socially isolated and (2) in our culture, the use of guns is glorified as a representation of power and a source of satisfaction. Here are my thoughts on each:

1. Shooters are often loners who exhibit behavior that is deviant or in some way socially unacceptable; this varies from public masturbation or the voicing of scary thoughts and ideas to simply exhibiting social awkwardness. When the lonely, shunned child has access to powerful, multiple-shot weapons, this is a setup for a shooting.

Perhaps society inadvertently causes harm by forcing classroom integration. About 30 years ago, with the hope to normalize abnormal social interactions and to help students understand and accept those who are different from them, schools began to mainstream students with serious learning difficulties, including students with mental illnesses. These children lost their “group,” their classroom community of those similar to themselves. They are still assigned personalized curricula and work one-on-one with special education teachers, but they do not have much of a peer group anymore. These students are put with a group of students—normal kids—that frequently rejects them.

Part of the problem has to do with the demonization of the term “normal”; it is now politically incorrect to designate a student as normal or not, despite the persistence of the bell-shaped curve. If normal, nonviolent behavior is desired, we need to be able to name abnormal behaviors as such.

Parents, understandably, want this type of social integration for their child. But when these students are bullied throughout the day, it takes a toll. We, as parents or providers, may not fully recognize how children experience this bullying, and those affected may not be able to describe it. They then withdraw, not finding anyone to share their feelings and experiences with, to cope. Some of these kids live as loners in school, and around ages 16 to 25, this lifestyle can become intolerable. They may become depressed from the emotional pain, seek revenge, and wish to die.

The desire to die—and to get lots of attention from it—is recognized in many adolescents. Lonely, troubled teens imagine what others will say about them when they are dead, and think of themselves looking down from heaven or somewhere, watching the grief and surprise overtake their peers.

Continue to: To take out others with themselves...

To take out others with themselves makes dying less of a lonely act. Killing themselves and either people they hate or someone they love, to keep them company in the afterlife or to make sure they both suffer together, both make some sense. And both are tragic.

We need to better identify these lonely teens and help them find a friend. They need regular social interaction and monitoring by the same people daily. Red flags often exist. If they are depressed, more intense care and monitoring are needed.

2. The glorification of guns stems from the need of every civilization for warriors to protect them from invaders. Soldiers, war, and weapons of destruction thus become known—to young men, in particular—because there is a need for youth to join the military and train, even if just for a few years. We honor brave soldiers who die in the line of duty.

Some of these men develop expertise in the use of military machine guns—rapid-fire weapons that can kill many people from afar in minutes. They may wish to continue using their skills upon separating from the military; they want military-grade guns at home. This makes sense, for they mastered and practiced this skill for years and can handle guns safely.

Gun shows allow the purchase of military-grade weapons fairly easily in many states. In the right hands, no problem. But our laws about guns are minimal and do not check to ensure that the buyer is one of these healthy, normal, skilled men.

Continue to: This accessibility is compounded with...

This accessibility is compounded with the popularity of violent video games among teens and young adults, which often involve shooting animated characters and animals in realistic scenarios. There is apparently a sense of adventure, satisfaction, and power that comes from this.

The desire to hunt in the real world, with real weapons, for a heightened sense of accomplishment or power as a follow-up to this fantastical activity seems a normal progression of behavior. Shooting ranges, wild animal hunting farms, and deer hunting in autumn are usual and customary ways to fulfill this desire. Families in western New York, where I live, often teach their sons and daughters to use a gun starting at age 12 and take them on annual hunting trips. This is not a problem.

When a teen or young person becomes despondent and lonely, the feelings of power and satisfaction from hunting or killing something can act as an antidote to the negative feelings. If anger or jealousy are part of the problem, the weapon can be turned on the perceived source of those feelings. The shooters in these devastating massacres seem to be able to use their chosen weapon competently. Where does this familiarity come from? Often, the weapon was accessible in their own home.

Teens and young adults with depression or feelings of loneliness, anger, or jealousy should be evaluated for access to weapons, and for their knowledge of use of these weapons, as part of the care plan. Parents and other adults should be queried and warned to keep weapons away from them until their mood has stabilized. There is reluctance to do this in our society. Health care and law enforcement professionals need to put out public announcements that give this warning to everyone.

Alone, these two ideas I’ve outlined will not prevent all mass shootings. But a more rapid reaction to the red flags of loneliness, mood changes, and social changes in a young person, and seeking to change that dynamic, might reduce the prevalence. Public health is at stake, and prevention will require a willingness to see and react to troubled people—before the police need to be called for a crime.

Sandra Glantz, MSN, MPA, FNP-BC
Pittsford, NY

I read your editorial with appreciation this morning. In my practice, I have worked with adolescents and young adults for more than 30 years, so the fact that many mass shooters are so young has caught my attention.

Of course, there is never just one cause for such horrific actions. But it seems to me that there are two recurring themes in these situations: (1) many shooters are socially isolated and (2) in our culture, the use of guns is glorified as a representation of power and a source of satisfaction. Here are my thoughts on each:

1. Shooters are often loners who exhibit behavior that is deviant or in some way socially unacceptable; this varies from public masturbation or the voicing of scary thoughts and ideas to simply exhibiting social awkwardness. When the lonely, shunned child has access to powerful, multiple-shot weapons, this is a setup for a shooting.

Perhaps society inadvertently causes harm by forcing classroom integration. About 30 years ago, with the hope to normalize abnormal social interactions and to help students understand and accept those who are different from them, schools began to mainstream students with serious learning difficulties, including students with mental illnesses. These children lost their “group,” their classroom community of those similar to themselves. They are still assigned personalized curricula and work one-on-one with special education teachers, but they do not have much of a peer group anymore. These students are put with a group of students—normal kids—that frequently rejects them.

Part of the problem has to do with the demonization of the term “normal”; it is now politically incorrect to designate a student as normal or not, despite the persistence of the bell-shaped curve. If normal, nonviolent behavior is desired, we need to be able to name abnormal behaviors as such.

Parents, understandably, want this type of social integration for their child. But when these students are bullied throughout the day, it takes a toll. We, as parents or providers, may not fully recognize how children experience this bullying, and those affected may not be able to describe it. They then withdraw, not finding anyone to share their feelings and experiences with, to cope. Some of these kids live as loners in school, and around ages 16 to 25, this lifestyle can become intolerable. They may become depressed from the emotional pain, seek revenge, and wish to die.

The desire to die—and to get lots of attention from it—is recognized in many adolescents. Lonely, troubled teens imagine what others will say about them when they are dead, and think of themselves looking down from heaven or somewhere, watching the grief and surprise overtake their peers.

Continue to: To take out others with themselves...

To take out others with themselves makes dying less of a lonely act. Killing themselves and either people they hate or someone they love, to keep them company in the afterlife or to make sure they both suffer together, both make some sense. And both are tragic.

We need to better identify these lonely teens and help them find a friend. They need regular social interaction and monitoring by the same people daily. Red flags often exist. If they are depressed, more intense care and monitoring are needed.

2. The glorification of guns stems from the need of every civilization for warriors to protect them from invaders. Soldiers, war, and weapons of destruction thus become known—to young men, in particular—because there is a need for youth to join the military and train, even if just for a few years. We honor brave soldiers who die in the line of duty.

Some of these men develop expertise in the use of military machine guns—rapid-fire weapons that can kill many people from afar in minutes. They may wish to continue using their skills upon separating from the military; they want military-grade guns at home. This makes sense, for they mastered and practiced this skill for years and can handle guns safely.

Gun shows allow the purchase of military-grade weapons fairly easily in many states. In the right hands, no problem. But our laws about guns are minimal and do not check to ensure that the buyer is one of these healthy, normal, skilled men.

Continue to: This accessibility is compounded with...

This accessibility is compounded with the popularity of violent video games among teens and young adults, which often involve shooting animated characters and animals in realistic scenarios. There is apparently a sense of adventure, satisfaction, and power that comes from this.

The desire to hunt in the real world, with real weapons, for a heightened sense of accomplishment or power as a follow-up to this fantastical activity seems a normal progression of behavior. Shooting ranges, wild animal hunting farms, and deer hunting in autumn are usual and customary ways to fulfill this desire. Families in western New York, where I live, often teach their sons and daughters to use a gun starting at age 12 and take them on annual hunting trips. This is not a problem.

When a teen or young person becomes despondent and lonely, the feelings of power and satisfaction from hunting or killing something can act as an antidote to the negative feelings. If anger or jealousy are part of the problem, the weapon can be turned on the perceived source of those feelings. The shooters in these devastating massacres seem to be able to use their chosen weapon competently. Where does this familiarity come from? Often, the weapon was accessible in their own home.

Teens and young adults with depression or feelings of loneliness, anger, or jealousy should be evaluated for access to weapons, and for their knowledge of use of these weapons, as part of the care plan. Parents and other adults should be queried and warned to keep weapons away from them until their mood has stabilized. There is reluctance to do this in our society. Health care and law enforcement professionals need to put out public announcements that give this warning to everyone.

Alone, these two ideas I’ve outlined will not prevent all mass shootings. But a more rapid reaction to the red flags of loneliness, mood changes, and social changes in a young person, and seeking to change that dynamic, might reduce the prevalence. Public health is at stake, and prevention will require a willingness to see and react to troubled people—before the police need to be called for a crime.

Sandra Glantz, MSN, MPA, FNP-BC
Pittsford, NY

I read your editorial with appreciation this morning. In my practice, I have worked with adolescents and young adults for more than 30 years, so the fact that many mass shooters are so young has caught my attention.

Of course, there is never just one cause for such horrific actions. But it seems to me that there are two recurring themes in these situations: (1) many shooters are socially isolated and (2) in our culture, the use of guns is glorified as a representation of power and a source of satisfaction. Here are my thoughts on each:

1. Shooters are often loners who exhibit behavior that is deviant or in some way socially unacceptable; this varies from public masturbation or the voicing of scary thoughts and ideas to simply exhibiting social awkwardness. When the lonely, shunned child has access to powerful, multiple-shot weapons, this is a setup for a shooting.

Perhaps society inadvertently causes harm by forcing classroom integration. About 30 years ago, with the hope to normalize abnormal social interactions and to help students understand and accept those who are different from them, schools began to mainstream students with serious learning difficulties, including students with mental illnesses. These children lost their “group,” their classroom community of those similar to themselves. They are still assigned personalized curricula and work one-on-one with special education teachers, but they do not have much of a peer group anymore. These students are put with a group of students—normal kids—that frequently rejects them.

Part of the problem has to do with the demonization of the term “normal”; it is now politically incorrect to designate a student as normal or not, despite the persistence of the bell-shaped curve. If normal, nonviolent behavior is desired, we need to be able to name abnormal behaviors as such.

Parents, understandably, want this type of social integration for their child. But when these students are bullied throughout the day, it takes a toll. We, as parents or providers, may not fully recognize how children experience this bullying, and those affected may not be able to describe it. They then withdraw, not finding anyone to share their feelings and experiences with, to cope. Some of these kids live as loners in school, and around ages 16 to 25, this lifestyle can become intolerable. They may become depressed from the emotional pain, seek revenge, and wish to die.

The desire to die—and to get lots of attention from it—is recognized in many adolescents. Lonely, troubled teens imagine what others will say about them when they are dead, and think of themselves looking down from heaven or somewhere, watching the grief and surprise overtake their peers.

Continue to: To take out others with themselves...

To take out others with themselves makes dying less of a lonely act. Killing themselves and either people they hate or someone they love, to keep them company in the afterlife or to make sure they both suffer together, both make some sense. And both are tragic.

We need to better identify these lonely teens and help them find a friend. They need regular social interaction and monitoring by the same people daily. Red flags often exist. If they are depressed, more intense care and monitoring are needed.

2. The glorification of guns stems from the need of every civilization for warriors to protect them from invaders. Soldiers, war, and weapons of destruction thus become known—to young men, in particular—because there is a need for youth to join the military and train, even if just for a few years. We honor brave soldiers who die in the line of duty.

Some of these men develop expertise in the use of military machine guns—rapid-fire weapons that can kill many people from afar in minutes. They may wish to continue using their skills upon separating from the military; they want military-grade guns at home. This makes sense, for they mastered and practiced this skill for years and can handle guns safely.

Gun shows allow the purchase of military-grade weapons fairly easily in many states. In the right hands, no problem. But our laws about guns are minimal and do not check to ensure that the buyer is one of these healthy, normal, skilled men.

Continue to: This accessibility is compounded with...

This accessibility is compounded with the popularity of violent video games among teens and young adults, which often involve shooting animated characters and animals in realistic scenarios. There is apparently a sense of adventure, satisfaction, and power that comes from this.

The desire to hunt in the real world, with real weapons, for a heightened sense of accomplishment or power as a follow-up to this fantastical activity seems a normal progression of behavior. Shooting ranges, wild animal hunting farms, and deer hunting in autumn are usual and customary ways to fulfill this desire. Families in western New York, where I live, often teach their sons and daughters to use a gun starting at age 12 and take them on annual hunting trips. This is not a problem.

When a teen or young person becomes despondent and lonely, the feelings of power and satisfaction from hunting or killing something can act as an antidote to the negative feelings. If anger or jealousy are part of the problem, the weapon can be turned on the perceived source of those feelings. The shooters in these devastating massacres seem to be able to use their chosen weapon competently. Where does this familiarity come from? Often, the weapon was accessible in their own home.

Teens and young adults with depression or feelings of loneliness, anger, or jealousy should be evaluated for access to weapons, and for their knowledge of use of these weapons, as part of the care plan. Parents and other adults should be queried and warned to keep weapons away from them until their mood has stabilized. There is reluctance to do this in our society. Health care and law enforcement professionals need to put out public announcements that give this warning to everyone.

Alone, these two ideas I’ve outlined will not prevent all mass shootings. But a more rapid reaction to the red flags of loneliness, mood changes, and social changes in a young person, and seeking to change that dynamic, might reduce the prevalence. Public health is at stake, and prevention will require a willingness to see and react to troubled people—before the police need to be called for a crime.

Sandra Glantz, MSN, MPA, FNP-BC
Pittsford, NY

EVIDENCE SUMMARY

A 2016 systematic review and meta-analysis of 3 RCTs that included 3200 women with late preterm labor (between 34 weeks 0 days and 36 weeks 6 days) found that women who were given betamethasone had a significantly lower incidence of transient tachypnea of the newborn (number needed to treat [NNT]=37; relative risk [RR]=0.72; 95% confidence interval [CI], 0.56-0.92), severe respiratory distress syndrome (NNT=114; RR=0.60; 95% CI, 0.33-0.94), and use of surfactant (NNT=92; RR=0.61; 95% CI, 0.38-0.99).¹

A composite outcome measure also favors betamethasone

In addition to these 3 outcomes, the largest RCT in the meta-analysis evaluated a composite outcome and found that betamethasone improved it by 20%. The RCT, comparing 1427 women in the experimental arm with 1400 controls, found benefit to administering 12 mg betamethasone intramuscularly every 24 hours for 2 days for women at high risk of late preterm delivery.² Enrollment criteria included women with 3 cm dilation or 75% effacement, preterm premature rupture of membranes, or a planned delivery scheduled in the late preterm period.

The primary outcome was a composite score based on one or more of the following within 72 hours after birth: continuous positive airway pressure or high-flow nasal cannula for at least 2 continuous hours, supplemental oxygen with a fraction of inspired oxygen of 0.30 or more for at least 4 continuous hours, mechanical ventilation, stillbirth or neonatal death, or the need for extracorporeal circulation membrane oxygenation. The betamethasone group had 165 women (11.6%) with the primary outcome compared with 202 (14.4%) in the control arm (NNT=34; RR=0.80; 95% CI, 0.66–0.97; P<.02).

Neonatal hypoglycemia may increase, but not dangerously

The same RCT explored the risks of late preterm betamethasone. There was no increase in chorioamnionitis nor neonatal sepsis in the betamethasone group.² Although neonatal hypoglycemia increased (24% vs 15%; number needed to harm=11.1; RR=1.60; 95% CI, 1.37-1.87; P<.001), no increase was seen in intermediate care nursery or ICU stays (41.8% vs 44.9%; RR=0.93; 95% CI, 0.85-1.01; P=.09) nor length of hospital stay (7 vs 8 days; P=.20).

Three letters to the editor questioned whether hypoglycemia from late-term corticosteroids may lead to long-term neurocognitive delays.³ The authors responded that meta-analyses of RCTs haven’t found an association between antenatal steroid use and neurocognitive delay and that studies that have found an association between hypoglycemia and neurocognitive delay looked at profound and prolonged hypoglycemia, which wasn’t seen in the late preterm betamethasone study.

Continue to: RECOMMENDATIONS

Both the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have published recommendations supporting corticosteroids for threatened late preterm delivery with certain caveats.^4-6 Because of a lack of evidence, maternity care providers shouldn’t give corticosteroids for threatened late preterm delivery to women with multiple gestation, diabetes, previous exposure to steroids during pregnancy, or pregnancies with major nonlethal fetal malformations.^4-6 Evidence doesn’t support tocolysis when steroids are given in the late preterm period.^4,5

EVIDENCE SUMMARY

A 2016 systematic review and meta-analysis of 3 RCTs that included 3200 women with late preterm labor (between 34 weeks 0 days and 36 weeks 6 days) found that women who were given betamethasone had a significantly lower incidence of transient tachypnea of the newborn (number needed to treat [NNT]=37; relative risk [RR]=0.72; 95% confidence interval [CI], 0.56-0.92), severe respiratory distress syndrome (NNT=114; RR=0.60; 95% CI, 0.33-0.94), and use of surfactant (NNT=92; RR=0.61; 95% CI, 0.38-0.99).¹

A composite outcome measure also favors betamethasone

In addition to these 3 outcomes, the largest RCT in the meta-analysis evaluated a composite outcome and found that betamethasone improved it by 20%. The RCT, comparing 1427 women in the experimental arm with 1400 controls, found benefit to administering 12 mg betamethasone intramuscularly every 24 hours for 2 days for women at high risk of late preterm delivery.² Enrollment criteria included women with 3 cm dilation or 75% effacement, preterm premature rupture of membranes, or a planned delivery scheduled in the late preterm period.

The primary outcome was a composite score based on one or more of the following within 72 hours after birth: continuous positive airway pressure or high-flow nasal cannula for at least 2 continuous hours, supplemental oxygen with a fraction of inspired oxygen of 0.30 or more for at least 4 continuous hours, mechanical ventilation, stillbirth or neonatal death, or the need for extracorporeal circulation membrane oxygenation. The betamethasone group had 165 women (11.6%) with the primary outcome compared with 202 (14.4%) in the control arm (NNT=34; RR=0.80; 95% CI, 0.66–0.97; P<.02).

Neonatal hypoglycemia may increase, but not dangerously

The same RCT explored the risks of late preterm betamethasone. There was no increase in chorioamnionitis nor neonatal sepsis in the betamethasone group.² Although neonatal hypoglycemia increased (24% vs 15%; number needed to harm=11.1; RR=1.60; 95% CI, 1.37-1.87; P<.001), no increase was seen in intermediate care nursery or ICU stays (41.8% vs 44.9%; RR=0.93; 95% CI, 0.85-1.01; P=.09) nor length of hospital stay (7 vs 8 days; P=.20).

Three letters to the editor questioned whether hypoglycemia from late-term corticosteroids may lead to long-term neurocognitive delays.³ The authors responded that meta-analyses of RCTs haven’t found an association between antenatal steroid use and neurocognitive delay and that studies that have found an association between hypoglycemia and neurocognitive delay looked at profound and prolonged hypoglycemia, which wasn’t seen in the late preterm betamethasone study.

Continue to: RECOMMENDATIONS

Both the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have published recommendations supporting corticosteroids for threatened late preterm delivery with certain caveats.^4-6 Because of a lack of evidence, maternity care providers shouldn’t give corticosteroids for threatened late preterm delivery to women with multiple gestation, diabetes, previous exposure to steroids during pregnancy, or pregnancies with major nonlethal fetal malformations.^4-6 Evidence doesn’t support tocolysis when steroids are given in the late preterm period.^4,5

EVIDENCE SUMMARY

A 2016 systematic review and meta-analysis of 3 RCTs that included 3200 women with late preterm labor (between 34 weeks 0 days and 36 weeks 6 days) found that women who were given betamethasone had a significantly lower incidence of transient tachypnea of the newborn (number needed to treat [NNT]=37; relative risk [RR]=0.72; 95% confidence interval [CI], 0.56-0.92), severe respiratory distress syndrome (NNT=114; RR=0.60; 95% CI, 0.33-0.94), and use of surfactant (NNT=92; RR=0.61; 95% CI, 0.38-0.99).¹

A composite outcome measure also favors betamethasone

In addition to these 3 outcomes, the largest RCT in the meta-analysis evaluated a composite outcome and found that betamethasone improved it by 20%. The RCT, comparing 1427 women in the experimental arm with 1400 controls, found benefit to administering 12 mg betamethasone intramuscularly every 24 hours for 2 days for women at high risk of late preterm delivery.² Enrollment criteria included women with 3 cm dilation or 75% effacement, preterm premature rupture of membranes, or a planned delivery scheduled in the late preterm period.

The primary outcome was a composite score based on one or more of the following within 72 hours after birth: continuous positive airway pressure or high-flow nasal cannula for at least 2 continuous hours, supplemental oxygen with a fraction of inspired oxygen of 0.30 or more for at least 4 continuous hours, mechanical ventilation, stillbirth or neonatal death, or the need for extracorporeal circulation membrane oxygenation. The betamethasone group had 165 women (11.6%) with the primary outcome compared with 202 (14.4%) in the control arm (NNT=34; RR=0.80; 95% CI, 0.66–0.97; P<.02).

Neonatal hypoglycemia may increase, but not dangerously

The same RCT explored the risks of late preterm betamethasone. There was no increase in chorioamnionitis nor neonatal sepsis in the betamethasone group.² Although neonatal hypoglycemia increased (24% vs 15%; number needed to harm=11.1; RR=1.60; 95% CI, 1.37-1.87; P<.001), no increase was seen in intermediate care nursery or ICU stays (41.8% vs 44.9%; RR=0.93; 95% CI, 0.85-1.01; P=.09) nor length of hospital stay (7 vs 8 days; P=.20).

Three letters to the editor questioned whether hypoglycemia from late-term corticosteroids may lead to long-term neurocognitive delays.³ The authors responded that meta-analyses of RCTs haven’t found an association between antenatal steroid use and neurocognitive delay and that studies that have found an association between hypoglycemia and neurocognitive delay looked at profound and prolonged hypoglycemia, which wasn’t seen in the late preterm betamethasone study.

Continue to: RECOMMENDATIONS

Both the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have published recommendations supporting corticosteroids for threatened late preterm delivery with certain caveats.^4-6 Because of a lack of evidence, maternity care providers shouldn’t give corticosteroids for threatened late preterm delivery to women with multiple gestation, diabetes, previous exposure to steroids during pregnancy, or pregnancies with major nonlethal fetal malformations.^4-6 Evidence doesn’t support tocolysis when steroids are given in the late preterm period.^4,5

EVIDENCE SUMMARY

Three meta-analyses that included only randomized controlled trials (RCTs) compared various CBT delivery methods with controls (wait-listed for treatment or general sleep hygiene education) to assess sleep outcomes for adults with insomnia.^1-3 TABLE 1^1-3 summarizes the results.

CBT is comparable to pharmacotherapy

A 2002 comparative meta-analysis of 21 RCTs with a total of 470 patients examined the effectiveness of CBT (stimulus control and/or sleep restriction) compared with pharmacotherapy (benzodiazepines or benzodiazepine agonists) for treating primary insomnia of longer than one month’s duration in adults with no comorbid medical or psychiatric diagnoses.⁴ The CBT group received intervention over an average of 5 weeks, and the pharmacotherapy group received intervention over an average of 2 weeks.

CBT produced greater reductions in sleep onset latency than pharmacotherapy based on mean weighted effect size (1.05 vs 0.45 weighted effect size; 95% confidence interval, 0.17-1.04; P=.01). Although both CBT and pharmacotherapy improved sleep outcomes, no statistical differences were found in wake after sleep onset time, total sleep time, number of awakenings, or sleep quality ratings (TABLE 2⁴).

Continue to: CBT has significant benefit for comorbid insomnia

A 2015 meta-analysis of 23 studies enrolling a total of 1379 adults with a number of illnesses (chronic pain, alcohol dependence, breast cancer, psychiatric disorders, chronic obstructive pulmonary disease, fibromyalgia) and comorbid insomnia investigated the qualitative effectiveness of individual or group CBT therapy.⁵ Subjects received at least 4 face-to-face sessions and at least 2 components of CBT.

The primary outcome showed that sleep quality improved, as measured by a 6.36-point reduction in the Insomnia Severity Index (ISI; a 7-question scale on which 0=no insomnia and 28=severe insomnia) and a 3.3-point reduction in the Pittsburgh Sleep Quality Index (PSQI; a 7-category assessment tool on which 0=perfect quality and 21=poor quality). The effect size was large for both ISI and PSQI, as indicated by standard mean differences greater than 0.8 (1.22 and 0.88, respectively) and was sustained for as long as 18 months.

RECOMMENDATIONS

The American College of Physicians strongly recommends that all adult patients receive CBT as initial treatment for chronic insomnia disorder. It can be performed in multiple settings, including the primary care setting. Compared with hypnotics, CBT is unlikely to have any adverse effects.⁶

EVIDENCE SUMMARY

Three meta-analyses that included only randomized controlled trials (RCTs) compared various CBT delivery methods with controls (wait-listed for treatment or general sleep hygiene education) to assess sleep outcomes for adults with insomnia.^1-3 TABLE 1^1-3 summarizes the results.

CBT is comparable to pharmacotherapy

A 2002 comparative meta-analysis of 21 RCTs with a total of 470 patients examined the effectiveness of CBT (stimulus control and/or sleep restriction) compared with pharmacotherapy (benzodiazepines or benzodiazepine agonists) for treating primary insomnia of longer than one month’s duration in adults with no comorbid medical or psychiatric diagnoses.⁴ The CBT group received intervention over an average of 5 weeks, and the pharmacotherapy group received intervention over an average of 2 weeks.

CBT produced greater reductions in sleep onset latency than pharmacotherapy based on mean weighted effect size (1.05 vs 0.45 weighted effect size; 95% confidence interval, 0.17-1.04; P=.01). Although both CBT and pharmacotherapy improved sleep outcomes, no statistical differences were found in wake after sleep onset time, total sleep time, number of awakenings, or sleep quality ratings (TABLE 2⁴).

Continue to: CBT has significant benefit for comorbid insomnia

A 2015 meta-analysis of 23 studies enrolling a total of 1379 adults with a number of illnesses (chronic pain, alcohol dependence, breast cancer, psychiatric disorders, chronic obstructive pulmonary disease, fibromyalgia) and comorbid insomnia investigated the qualitative effectiveness of individual or group CBT therapy.⁵ Subjects received at least 4 face-to-face sessions and at least 2 components of CBT.

The primary outcome showed that sleep quality improved, as measured by a 6.36-point reduction in the Insomnia Severity Index (ISI; a 7-question scale on which 0=no insomnia and 28=severe insomnia) and a 3.3-point reduction in the Pittsburgh Sleep Quality Index (PSQI; a 7-category assessment tool on which 0=perfect quality and 21=poor quality). The effect size was large for both ISI and PSQI, as indicated by standard mean differences greater than 0.8 (1.22 and 0.88, respectively) and was sustained for as long as 18 months.

RECOMMENDATIONS

The American College of Physicians strongly recommends that all adult patients receive CBT as initial treatment for chronic insomnia disorder. It can be performed in multiple settings, including the primary care setting. Compared with hypnotics, CBT is unlikely to have any adverse effects.⁶

EVIDENCE SUMMARY

Three meta-analyses that included only randomized controlled trials (RCTs) compared various CBT delivery methods with controls (wait-listed for treatment or general sleep hygiene education) to assess sleep outcomes for adults with insomnia.^1-3 TABLE 1^1-3 summarizes the results.

CBT is comparable to pharmacotherapy

A 2002 comparative meta-analysis of 21 RCTs with a total of 470 patients examined the effectiveness of CBT (stimulus control and/or sleep restriction) compared with pharmacotherapy (benzodiazepines or benzodiazepine agonists) for treating primary insomnia of longer than one month’s duration in adults with no comorbid medical or psychiatric diagnoses.⁴ The CBT group received intervention over an average of 5 weeks, and the pharmacotherapy group received intervention over an average of 2 weeks.

CBT produced greater reductions in sleep onset latency than pharmacotherapy based on mean weighted effect size (1.05 vs 0.45 weighted effect size; 95% confidence interval, 0.17-1.04; P=.01). Although both CBT and pharmacotherapy improved sleep outcomes, no statistical differences were found in wake after sleep onset time, total sleep time, number of awakenings, or sleep quality ratings (TABLE 2⁴).

Continue to: CBT has significant benefit for comorbid insomnia

A 2015 meta-analysis of 23 studies enrolling a total of 1379 adults with a number of illnesses (chronic pain, alcohol dependence, breast cancer, psychiatric disorders, chronic obstructive pulmonary disease, fibromyalgia) and comorbid insomnia investigated the qualitative effectiveness of individual or group CBT therapy.⁵ Subjects received at least 4 face-to-face sessions and at least 2 components of CBT.

The primary outcome showed that sleep quality improved, as measured by a 6.36-point reduction in the Insomnia Severity Index (ISI; a 7-question scale on which 0=no insomnia and 28=severe insomnia) and a 3.3-point reduction in the Pittsburgh Sleep Quality Index (PSQI; a 7-category assessment tool on which 0=perfect quality and 21=poor quality). The effect size was large for both ISI and PSQI, as indicated by standard mean differences greater than 0.8 (1.22 and 0.88, respectively) and was sustained for as long as 18 months.

RECOMMENDATIONS

The American College of Physicians strongly recommends that all adult patients receive CBT as initial treatment for chronic insomnia disorder. It can be performed in multiple settings, including the primary care setting. Compared with hypnotics, CBT is unlikely to have any adverse effects.⁶

A 44-year-old African-American woman with sickle cell trait presented to the clinic to establish care. She complained of polyarthralgias that she’d had since adolescence; the pain was worst in her right shoulder. She reported morning stiffness that lasted up to 8 hours, an intermittent facial rash, oral ulcers, joint edema (of which she had pictures on her phone), and photosensitivity. She took ibuprofen and acetaminophen as needed for pain. She once worked as a medical assistant but hadn’t been able to work since 2014 due to pain. She reported having been told as a teenager that she might have juvenile arthritis, but she didn’t recall ever having diagnostic tests performed or receiving treatment other than anti-inflammatories.

A couple of weeks after an initial visit with a rheumatologist, the patient returned to the family medicine clinic. She said she was upset that the specialist had x-rayed her hands, but had not checked her shoulder, which was the primary source of her pain. She also had pain in her hands, hips, feet, and knees.

On physical exam, the patient looked fatigued. A musculoskeletal exam revealed no joint effusions or edema, but was significant for right shoulder pain with reduced abduction to 90°. Gross motor strength was 5/5 in all 4 extremities. Laboratory testing revealed an antinuclear antibody titer of 1:160 and was negative for double-stranded DNA. Bilateral hand and foot x-rays showed no joint erosions. An x-ray of the right shoulder was obtained, which showed evidence of osteopenia and an erosion in the humeral head (FIGURES 1A and 1B).

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

The patient’s history of morning stiffness and the joint erosion observed on x-ray were highly suggestive of rheumatoid arthritis (RA).

Joint stiffness due to osteoarthritis is worse with activity and generally lasts only a few minutes, while joint stiffness due to rheumatoid arthritis is worse at rest and lasts 30 minutes or more.

RA is a symmetric, inflammatory, peripheral polyarthritis of unknown etiology. It is the most common form of inflammatory arthritis, affecting 1% of the population worldwide.¹ It causes cartilage and bone to erode, leading to the deformation and destruction of joints. If RA is left untreated or is unresponsive to therapy, it can eventually lead to loss of physical function.

Making the diagnosis

The distinctive signs of RA are joint erosions and rheumatoid nodules, which are often absent on initial presentation.

Classification criteria. The 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA² are based on the presence of synovitis in at least one joint, the absence of an alternative diagnosis that better explains the synovitis, and a cumulative score of at least 6/10 from the following 4 domains:

1. Number and site of involved joints
   • 2 to 10 large joints (shoulders, elbows, hips, knees, ankles)=1 point
   • 1 to 3 small joints (metacarpophalangeal [MCP] joints, proximal interphalangeal [PIP] joints, 2nd-5th metatarsophalangeal joints, thumb interphalangeal joints, wrists)=2 points
   • 4 to 10 small joints=3 points
   • More than 10 joints (including at least 1 small joint)=5 points
2. Serologic abnormality (rheumatoid factor [RF] and anti-cyclic citrullinated peptide)
   • Low positive=2 points
   • High positive=3 points
3. Elevated acute phase response (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP])=1 point
4. Symptom duration of at least 6 weeks=1 point.

These criteria are best suited for early disease. For patients with longstanding symptoms, diagnosis is based on an erosive disease with a history of criteria fulfillment, or a currently inactive longstanding disease, with or without treatment, that has previously fulfilled the criteria.³

Continue to: The differential Dx is extensive

The differential includes polyarthralgias such as viral polyarthritis, systemic rheumatic diseases, and osteoarthritis.

Viral polyarthritis is caused by rubella, parvovirus B19⁴, alphaviruses, and hepatitis B. Symptoms can last from 3 days to several weeks, but rarely persist beyond 6 weeks; alphaviruses, however, can last 3 to 6 months.⁵ The common symptom triad includes fever, arthritis, and rash. Chikungunya is an example of an alphavirus that has become a global disease. Alphavirus arthritis can mimic seronegative RA and even satisfy the classification criteria for RA if the initial symptoms of fever and rash and history of travel to endemic regions are not appreciated.⁵

Systemic rheumatic diseases. Early RA may mimic the arthritis of systemic lupus erythematosus (SLE), Sjögren’s syndrome, dermatomyositis, or mixed connective tissue disease.⁶ In contrast to RA, these disorders generally have systemic features, such as rashes, dry mouth and eyes, myositis, or nephritis, and generate autobodies, which are not seen with RA. The CRP is often normal in patients with active SLE, even when the ESR is elevated.

Immediate treatment with disease-modifying antirheumatic drugs is important to achieve disease control and prevent disability.

Osteoarthritis (OA) can be confused with RA, particularly when small joints are involved. A thorough history helps elucidate the diagnosis. For example, OA of the fingers affects distal interphalangeal joints and is associated with Heberden’s nodes, while RA more commonly affects MCP and PIP joints. Swelling from OA is typically firm, while swelling due to RA is warm, boggy, and tender. Joint stiffness due to OA is worse with activity and generally lasts only a few minutes, while joint stiffness due to RA is worse at rest and lasts 30 minutes or more. X-rays show joint-space narrowing with OA, but no erosions or cysts. RF may be present at low levels in older patients with OA, while it is usually associated with high levels in patients with seropositive RA.

Continue to: Treat with disease-modifying antirheumatic drugs

Immediate treatment of RA with disease-modifying antirheumatic drugs (DMARDs) is important to achieve control of the disease and prevent disability.

Our patient. We ordered a purified protein derivative skin test in preparation for the patient to start therapy with a DMARD. Our patient followed up with Rheumatology and was started on indomethacin, with an initial dose of 25 mg bid. (DMARDs are first-line therapy; indomethacin is a second-line choice. In this case, the patient declined DMARDs after hearing they lowered the body’s ability to fight infection.) An RF level measured 6.74 IU/ml, which is within normal limits. The patient was subsequently lost to follow-up.

CORRESPONDENCE
Barbara Kiersz, DO, 6835 Austin Center Blvd., Austin, TX 78731; [email protected].

A 44-year-old African-American woman with sickle cell trait presented to the clinic to establish care. She complained of polyarthralgias that she’d had since adolescence; the pain was worst in her right shoulder. She reported morning stiffness that lasted up to 8 hours, an intermittent facial rash, oral ulcers, joint edema (of which she had pictures on her phone), and photosensitivity. She took ibuprofen and acetaminophen as needed for pain. She once worked as a medical assistant but hadn’t been able to work since 2014 due to pain. She reported having been told as a teenager that she might have juvenile arthritis, but she didn’t recall ever having diagnostic tests performed or receiving treatment other than anti-inflammatories.

A couple of weeks after an initial visit with a rheumatologist, the patient returned to the family medicine clinic. She said she was upset that the specialist had x-rayed her hands, but had not checked her shoulder, which was the primary source of her pain. She also had pain in her hands, hips, feet, and knees.

On physical exam, the patient looked fatigued. A musculoskeletal exam revealed no joint effusions or edema, but was significant for right shoulder pain with reduced abduction to 90°. Gross motor strength was 5/5 in all 4 extremities. Laboratory testing revealed an antinuclear antibody titer of 1:160 and was negative for double-stranded DNA. Bilateral hand and foot x-rays showed no joint erosions. An x-ray of the right shoulder was obtained, which showed evidence of osteopenia and an erosion in the humeral head (FIGURES 1A and 1B).

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

The patient’s history of morning stiffness and the joint erosion observed on x-ray were highly suggestive of rheumatoid arthritis (RA).

Joint stiffness due to osteoarthritis is worse with activity and generally lasts only a few minutes, while joint stiffness due to rheumatoid arthritis is worse at rest and lasts 30 minutes or more.

RA is a symmetric, inflammatory, peripheral polyarthritis of unknown etiology. It is the most common form of inflammatory arthritis, affecting 1% of the population worldwide.¹ It causes cartilage and bone to erode, leading to the deformation and destruction of joints. If RA is left untreated or is unresponsive to therapy, it can eventually lead to loss of physical function.

Making the diagnosis

The distinctive signs of RA are joint erosions and rheumatoid nodules, which are often absent on initial presentation.

Classification criteria. The 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA² are based on the presence of synovitis in at least one joint, the absence of an alternative diagnosis that better explains the synovitis, and a cumulative score of at least 6/10 from the following 4 domains:

1. Number and site of involved joints
   • 2 to 10 large joints (shoulders, elbows, hips, knees, ankles)=1 point
   • 1 to 3 small joints (metacarpophalangeal [MCP] joints, proximal interphalangeal [PIP] joints, 2nd-5th metatarsophalangeal joints, thumb interphalangeal joints, wrists)=2 points
   • 4 to 10 small joints=3 points
   • More than 10 joints (including at least 1 small joint)=5 points
2. Serologic abnormality (rheumatoid factor [RF] and anti-cyclic citrullinated peptide)
   • Low positive=2 points
   • High positive=3 points
3. Elevated acute phase response (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP])=1 point
4. Symptom duration of at least 6 weeks=1 point.

These criteria are best suited for early disease. For patients with longstanding symptoms, diagnosis is based on an erosive disease with a history of criteria fulfillment, or a currently inactive longstanding disease, with or without treatment, that has previously fulfilled the criteria.³

Continue to: The differential Dx is extensive

The differential includes polyarthralgias such as viral polyarthritis, systemic rheumatic diseases, and osteoarthritis.

Viral polyarthritis is caused by rubella, parvovirus B19⁴, alphaviruses, and hepatitis B. Symptoms can last from 3 days to several weeks, but rarely persist beyond 6 weeks; alphaviruses, however, can last 3 to 6 months.⁵ The common symptom triad includes fever, arthritis, and rash. Chikungunya is an example of an alphavirus that has become a global disease. Alphavirus arthritis can mimic seronegative RA and even satisfy the classification criteria for RA if the initial symptoms of fever and rash and history of travel to endemic regions are not appreciated.⁵

Systemic rheumatic diseases. Early RA may mimic the arthritis of systemic lupus erythematosus (SLE), Sjögren’s syndrome, dermatomyositis, or mixed connective tissue disease.⁶ In contrast to RA, these disorders generally have systemic features, such as rashes, dry mouth and eyes, myositis, or nephritis, and generate autobodies, which are not seen with RA. The CRP is often normal in patients with active SLE, even when the ESR is elevated.

Immediate treatment with disease-modifying antirheumatic drugs is important to achieve disease control and prevent disability.

Osteoarthritis (OA) can be confused with RA, particularly when small joints are involved. A thorough history helps elucidate the diagnosis. For example, OA of the fingers affects distal interphalangeal joints and is associated with Heberden’s nodes, while RA more commonly affects MCP and PIP joints. Swelling from OA is typically firm, while swelling due to RA is warm, boggy, and tender. Joint stiffness due to OA is worse with activity and generally lasts only a few minutes, while joint stiffness due to RA is worse at rest and lasts 30 minutes or more. X-rays show joint-space narrowing with OA, but no erosions or cysts. RF may be present at low levels in older patients with OA, while it is usually associated with high levels in patients with seropositive RA.

Continue to: Treat with disease-modifying antirheumatic drugs

Immediate treatment of RA with disease-modifying antirheumatic drugs (DMARDs) is important to achieve control of the disease and prevent disability.

Our patient. We ordered a purified protein derivative skin test in preparation for the patient to start therapy with a DMARD. Our patient followed up with Rheumatology and was started on indomethacin, with an initial dose of 25 mg bid. (DMARDs are first-line therapy; indomethacin is a second-line choice. In this case, the patient declined DMARDs after hearing they lowered the body’s ability to fight infection.) An RF level measured 6.74 IU/ml, which is within normal limits. The patient was subsequently lost to follow-up.

CORRESPONDENCE
Barbara Kiersz, DO, 6835 Austin Center Blvd., Austin, TX 78731; [email protected].

A 44-year-old African-American woman with sickle cell trait presented to the clinic to establish care. She complained of polyarthralgias that she’d had since adolescence; the pain was worst in her right shoulder. She reported morning stiffness that lasted up to 8 hours, an intermittent facial rash, oral ulcers, joint edema (of which she had pictures on her phone), and photosensitivity. She took ibuprofen and acetaminophen as needed for pain. She once worked as a medical assistant but hadn’t been able to work since 2014 due to pain. She reported having been told as a teenager that she might have juvenile arthritis, but she didn’t recall ever having diagnostic tests performed or receiving treatment other than anti-inflammatories.

A couple of weeks after an initial visit with a rheumatologist, the patient returned to the family medicine clinic. She said she was upset that the specialist had x-rayed her hands, but had not checked her shoulder, which was the primary source of her pain. She also had pain in her hands, hips, feet, and knees.

On physical exam, the patient looked fatigued. A musculoskeletal exam revealed no joint effusions or edema, but was significant for right shoulder pain with reduced abduction to 90°. Gross motor strength was 5/5 in all 4 extremities. Laboratory testing revealed an antinuclear antibody titer of 1:160 and was negative for double-stranded DNA. Bilateral hand and foot x-rays showed no joint erosions. An x-ray of the right shoulder was obtained, which showed evidence of osteopenia and an erosion in the humeral head (FIGURES 1A and 1B).

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

The patient’s history of morning stiffness and the joint erosion observed on x-ray were highly suggestive of rheumatoid arthritis (RA).

Joint stiffness due to osteoarthritis is worse with activity and generally lasts only a few minutes, while joint stiffness due to rheumatoid arthritis is worse at rest and lasts 30 minutes or more.

RA is a symmetric, inflammatory, peripheral polyarthritis of unknown etiology. It is the most common form of inflammatory arthritis, affecting 1% of the population worldwide.¹ It causes cartilage and bone to erode, leading to the deformation and destruction of joints. If RA is left untreated or is unresponsive to therapy, it can eventually lead to loss of physical function.

Making the diagnosis

The distinctive signs of RA are joint erosions and rheumatoid nodules, which are often absent on initial presentation.

Classification criteria. The 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA² are based on the presence of synovitis in at least one joint, the absence of an alternative diagnosis that better explains the synovitis, and a cumulative score of at least 6/10 from the following 4 domains:

1. Number and site of involved joints
   • 2 to 10 large joints (shoulders, elbows, hips, knees, ankles)=1 point
   • 1 to 3 small joints (metacarpophalangeal [MCP] joints, proximal interphalangeal [PIP] joints, 2nd-5th metatarsophalangeal joints, thumb interphalangeal joints, wrists)=2 points
   • 4 to 10 small joints=3 points
   • More than 10 joints (including at least 1 small joint)=5 points
2. Serologic abnormality (rheumatoid factor [RF] and anti-cyclic citrullinated peptide)
   • Low positive=2 points
   • High positive=3 points
3. Elevated acute phase response (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP])=1 point
4. Symptom duration of at least 6 weeks=1 point.

These criteria are best suited for early disease. For patients with longstanding symptoms, diagnosis is based on an erosive disease with a history of criteria fulfillment, or a currently inactive longstanding disease, with or without treatment, that has previously fulfilled the criteria.³

Continue to: The differential Dx is extensive

The differential includes polyarthralgias such as viral polyarthritis, systemic rheumatic diseases, and osteoarthritis.

Viral polyarthritis is caused by rubella, parvovirus B19⁴, alphaviruses, and hepatitis B. Symptoms can last from 3 days to several weeks, but rarely persist beyond 6 weeks; alphaviruses, however, can last 3 to 6 months.⁵ The common symptom triad includes fever, arthritis, and rash. Chikungunya is an example of an alphavirus that has become a global disease. Alphavirus arthritis can mimic seronegative RA and even satisfy the classification criteria for RA if the initial symptoms of fever and rash and history of travel to endemic regions are not appreciated.⁵

Systemic rheumatic diseases. Early RA may mimic the arthritis of systemic lupus erythematosus (SLE), Sjögren’s syndrome, dermatomyositis, or mixed connective tissue disease.⁶ In contrast to RA, these disorders generally have systemic features, such as rashes, dry mouth and eyes, myositis, or nephritis, and generate autobodies, which are not seen with RA. The CRP is often normal in patients with active SLE, even when the ESR is elevated.

Immediate treatment with disease-modifying antirheumatic drugs is important to achieve disease control and prevent disability.

Osteoarthritis (OA) can be confused with RA, particularly when small joints are involved. A thorough history helps elucidate the diagnosis. For example, OA of the fingers affects distal interphalangeal joints and is associated with Heberden’s nodes, while RA more commonly affects MCP and PIP joints. Swelling from OA is typically firm, while swelling due to RA is warm, boggy, and tender. Joint stiffness due to OA is worse with activity and generally lasts only a few minutes, while joint stiffness due to RA is worse at rest and lasts 30 minutes or more. X-rays show joint-space narrowing with OA, but no erosions or cysts. RF may be present at low levels in older patients with OA, while it is usually associated with high levels in patients with seropositive RA.

Continue to: Treat with disease-modifying antirheumatic drugs

Immediate treatment of RA with disease-modifying antirheumatic drugs (DMARDs) is important to achieve control of the disease and prevent disability.

Our patient. We ordered a purified protein derivative skin test in preparation for the patient to start therapy with a DMARD. Our patient followed up with Rheumatology and was started on indomethacin, with an initial dose of 25 mg bid. (DMARDs are first-line therapy; indomethacin is a second-line choice. In this case, the patient declined DMARDs after hearing they lowered the body’s ability to fight infection.) An RF level measured 6.74 IU/ml, which is within normal limits. The patient was subsequently lost to follow-up.

CORRESPONDENCE
Barbara Kiersz, DO, 6835 Austin Center Blvd., Austin, TX 78731; [email protected].

Thrombocytopenia and neutropenia are commonly encountered laboratory abnormalities. The presence of either requires that you promptly evaluate for life-threatening causes and identify the appropriate etiology. This article identifies key questions to ask. It also includes algorithms and tables that will facilitate your evaluation of patients with isolated thrombocytopenia or isolated neutropenia and speed the way toward appropriate treatment.

Thrombocytopenia: A look at the numbers

Thrombocytopenia is defined as a platelet count <150,000/mcL.¹ The blood abnormality is either suspected based on the patient’s signs or symptoms, such as ecchymoses, petechiae, purpura, epistaxis, gingival bleeding, or melena, or it is incidentally discovered during review of a complete blood count (CBC).

The development of clinical symptoms is closely related to the severity of the thrombocytopenia, with platelet counts <30,000/mcL more likely to result in clinical symptoms with minor trauma and counts <5,000/mcL potentially resulting in spontaneous bleeding. While most patients will have asymptomatic, incidentally-found thrombocytopenia, and likely a benign etiology, those with the signs/symptoms just described, evidence of infection, or thrombosis are more likely to have a serious etiology and require an expedited work-up. Although pregnancy may be associated with thrombocytopenia, this review confines itself to the causes of thrombocytopenia in non-pregnant adults.

Rule out pseudothrombocytopenia

When isolated thrombocytopenia is discovered incidentally in an asymptomatic person, the first step is to perform a repeat CBC with a peripheral smear to confirm the presence of thrombocytopenia, rule out laboratory error, and assess for platelet clumping. If thrombocytopenia is confirmed and platelet clumping is present, it may be due to the calcium chelator in the ethylenediaminetetraacetic anticoagulant contained within the laboratory transport tube; this cause of pseudothrombocytopenia occurs in up to 0.29% of the population.¹ Obtaining a platelet count from a citrated or heparinized tube avoids this phenomenon.

Is the patient’s thrombocytopenia drug induced?

Once true thrombocytopenia is confirmed, the next step is to review the patient’s prescribed medications, as well as any illicit drugs used, for potential causes of drug-induced thrombocytopenia. DITP can be either immune-mediated or nonimmune-mediated.

Immune-mediated drug-induced thrombocytopenia typically occurs within 1 to 2 weeks of medication exposure and begins to improve within 1 to 2 days of stopping the offending drug.

Immune-mediated DITP typically occurs within 1 to 2 weeks of medication exposure and begins to improve within 1 to 2 days of stopping the offending drug.² (See TABLE 1³ for a list of medications that can induce thrombocytopenia.) It should be noted that most patients who take the medications listed in TABLE 1 do not experience thrombocytopenia; nonetheless, it is a potential risk associated with their use.

Heparin-induced thrombocytopenia (HIT) is a unique form of immune-mediated DITP in that it is caused by antibody complexes, resulting in platelet activation, clumping, and thrombotic events.⁴ HIT occurs <1% of patients in intensive care units, but can occur in any patient on long-term heparin therapy. It manifests as a >50% drop in platelet count within 5 to 14 days of the introduction of heparin; however, in those previously exposed to heparin, it can occur within 24 hours.^4,5

Continue to: Non-immune-mediated DITP

Non-immune-mediated DITP, resulting from myelosuppression, chemotherapeutic agents, or valproic acid, is less common.^1,2

Acute and chronic alcohol use. Although alcohol is not a drug per se, it can also result in thrombocytopenia. The mechanism is the direct suppression of bone marrow, although alcohol also causes B12 and folate deficiency, further contributing to the development of the blood abnormality.¹

Is there thrombosis?

In addition to exploring a connection between thrombocytopenia and the drugs a patient is taking, it’s also important to look for evidence of thrombosis. The causes of thrombocytopenia that paradoxically result in thrombosis are: disseminated intravascular coagulation, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, catastrophic antiphospholipid antibody syndrome, and the previously mentioned HIT. TABLE 2^4,6-9 outlines the clinical settings, laboratory findings, and treatments of thrombocytopenia associated with thrombosis.

Is an infectious cause to blame?

If the patient is ill, consider infectious causes of thrombocytopenia. Thrombocytopenia associated with infection may result from an immune-mediated response to an illness itself, to treatment of an illness, to splenic sequestration, or to bone marrow suppression. TABLE 3^1,9-11 lists common infections that may cause thrombocytopenia.

Of note, infection with Helicobacter pylori can cause asymptomatic thrombocytopenia via an immune-mediated mechanism.¹² Eradication of H pylori results in a variable elevation in platelets, on average 30,000/mcL in 50% of patients with the infection.¹³

Is there pancytopenia?

A review of the peripheral smear, with attention to abnormalities in other cell lines, may assist in arriving at a diagnosis. If the peripheral smear reveals pancytopenia, then, in addition to many of the etiologies described earlier, one should also consider vitamin B12 or folate deficiency, copper deficiency, drug- and viral-induced aplastic anemia, paroxysmal nocturnal hemoglobinuria, leukemias, myelodysplastic disorders, and systemic lupus erythematosis.¹⁴ Pancytopenia is also seen with hypersplenism, which is often associated with cirrhosis.¹⁵ If the etiology isn’t readily apparent, a bone marrow biopsy may be required.

Continue to: Is immune thrombocytopenia to blame?

Immune thrombocytopenia (ITP) is an autoimmune disorder resulting in the destruction of normal platelets and may be primary or secondary to processes described previously (HIT, H pylori infection, etc). Consider ITP if, after a thorough work-up, a cause of isolated thrombocytopenia is not identified.¹⁶ Treatment for ITP is outlined in TABLE 4.¹⁶ FIGURE 1 is an algorithm for the complete evaluation of thrombocytopenia in adults.

Treatment: Platelet transfusions

In general, patients who are not actively bleeding are considered stable and do not require platelet transfusions to minimize their risk of bleeding or prevent bleeding during a planned procedure unless their platelet count falls below the levels specified in TABLE 5.¹⁷ For patients who are actively bleeding, a more aggressive approach may be required. Locally-derived transfusion protocols typically guide transfusions for the actively hemorrhaging patient. The American Association of Blood Banks has put forth evidence-based guidelines for platelet transfusions when a patient is given a diagnosis of thrombocytopenia (see TABLE 5).¹⁷ Single-donor platelets have a shelf life of 3 to 5 days, and one unit will raise platelets 30,000 to 50,000/mcL.

Neutropenia: Prevalence varies by ethnicity

An absolute neutrophil count (ANC) of <1500 cells/mcL traditionally defines neutropenia, with an ANC of 1000 to 1500 cells/mcL constituting mild neutropenia; 500 to 999 cells/mcL, moderate; and <500 cells/mcL, severe.¹⁸ Similar to the evaluation of thrombocytopenia, it is important to repeat the CBC prior to initiating a work-up in order to confirm that the neutropenia is not a laboratory error. Additionally, patients with signs or symptoms of infection should be worked up expeditiously.

Heparin-induced thrombocytopenia occurs in <1% of patients in intensive care units and typically is manifested by a ≥50% drop in platelet count within 5 to 14 days of introducing heparin.

The prevalence of neutropenia varies by ethnicity. According to the National Health and Nutrition Examination Survey 1999 to 2004, the prevalence was 4.5%, 0.79%, and 0.38% in black, white, and Mexican-American participants, respectively.¹⁹ FIGURE 2 outlines the outpatient work-up of adult patients with neutropenia not related to chemotherapy.

Continue to: Is the patient severely ill?

The prognosis of the patient is related both to the etiology of the neutropenia, as well as to the nadir of the neutrophil count. Patients who have an ANC <500 cells/mcL or who have inadequate bone marrow reserves are at highest risk for an overwhelming infection.^20,21 The absence of oral ulcers and gingivitis and/or the presence of purulent material at the site of an infection are signs of adequate bone marrow reserves.

Additionally, neutropenia may be the source—or the result—of a serious life-threatening illness. This distinction may not be readily apparent at the time of the patient’s presentation. If signs or symptoms of a severe illness are apparent (fever, hypotension, tachycardia, ANC <500 cells/mcL), admit the patient to the hospital for evaluation and initiation of antibiotics. 

Is the neutropenia chronic?

A review of previous CBCs will identify whether this condition is new or chronic. A persistent, mild neutropenia (ANC 1000-1500 cells/mcL) in a healthy individual is consistent with benign familial or ethnic neutropenia (see TABLE 6).²⁰ If prior CBCs are unavailable, then a diagnosis of chronic neutropenia may be established by verifying the persistence of mild neutropenia over time.

Cyclic neutropenia is a periodic neutropenia (occurring every 2-5 weeks) associated with mild illnesses that are related to the nadir of the neutrophil count. The diagnosis is established by obtaining serial CBCs twice weekly for 4 to 6 weeks, which reflect cycling of the neutrophil count.^20,22

Are any medications contributing to the neutropenia?

Medications that suppress bone marrow or that interfere with other immune-mediated processes are the most common cause of acquired neutropenia.²³ Drug-induced agranulocytosis is defined as an ANC <500 cells/mcL due to exposure to a drug that results in immunologic or cytotoxic destruction of neutrophils.²⁴

A persistent, mild neutropenia in a healthy individual is consistent with benign familial or ethnic neutropenia.

A systematic review of case reports of drug-induced agranulocytosis (a decrease in peripheral neutrophil count to <500 cells/mcL) revealed that although at least 125 drugs were probably related to agranulocytosis, only 11 drugs were responsible for 50% of cases (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine), and fatality rates were higher (10% vs 3%) among those patients with a nadir <100 cells/mcL.²⁵ TABLE 7²⁵ lists medications that can be associated with agranulocytosis. Depending on prior exposure to a drug, neutropenia/agranulocytosis can occur within hours to months of exposure to the causal drug and can take a few days to 3 weeks to resolve after cessation.^25,26

Continue to: Has the patient had any recent illnesses?

The usual response to an infection is an increase in neutrophil count. However, certain bacterial, rickettsial, parasitic, and viral infections can result in neutropenia (see TABLE 8^23,27-29). Viral infections may cause transient neutropenia because of either bone marrow suppression or increased peripheral destruction, while neutropenia related to an overwhelming bacterial infection results from the depletion of bone marrow reserves.^23,27

Do you suspect a nutritional deficiency?

Patients with a nutritional deficiency of B12, folate, or copper are likely to exhibit a deficiency in more than just neutrophils.^23,27 In developed countries, people with neutropenia may have a history of malnutrition due to a disease (eg, anorexia nervosa) or surgery (eg, gastric bypass) that causes severe calorie restriction.²⁰

Does your patient have symptoms of a connective tissue disease?

In developed countries, people with neutropenia may have a history of malnutrition due to a disease (eg, anorexia nervosa) or surgery (eg, gastric bypass) that causes severe calorie restriction.

Neutropenia, in association with arthralgias, joint swelling, splenomegaly, or rash may be a manifestation of an underlying collagen vascular disorder, such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).²⁰ If the clinical scenario supports one of these diagnoses, undertake or refer the patient for a rheumatologic evaluation. This may include studies of anti-cyclic citrullinated peptide antibodies, rheumatoid factor to evaluate for RA, and/or antinuclear antibodies to evaluate for SLE.^30,31 While most neutropenias associated with autoimmune disease are mild, neutropenia associated with Felty syndrome (RA, splenomegaly, and neutropenia) may be severe (ANC <100 cells/mcL).^20,23

Is the etiology unclear?

Patients with moderate to severe neutropenia without an apparent etiology, in the setting of aplastic anemia, or in the presence of splenomegaly and/or lymphadenopathy, should undergo a hematologic evaluation and/or bone marrow biopsy, given that hematologic malignancy is a potential cause.^20,27

The treatment of neutropenia hinges on correctly identifying the etiology of the diminished neutrophil count. If the cause is a medication, infection, underlying rheumatologic condition, or nutritional deficiency, then either treating the entity or withdrawing the offending medication should result in resolution of the neutropenia. If the cause is determined to be familial or ethnic, then patient reassurance is all that is required.

CORRESPONDENCE
Richard W. Temple, MD, FAAFP, CDR MC USN, Camp Lejeune Family Medicine Residency, Naval Medical Center Camp Lejeune, 100 Brewster Blvd, Camp Lejeune, NC 28547-2538; [email protected].

Thrombocytopenia and neutropenia are commonly encountered laboratory abnormalities. The presence of either requires that you promptly evaluate for life-threatening causes and identify the appropriate etiology. This article identifies key questions to ask. It also includes algorithms and tables that will facilitate your evaluation of patients with isolated thrombocytopenia or isolated neutropenia and speed the way toward appropriate treatment.

Thrombocytopenia: A look at the numbers

Thrombocytopenia is defined as a platelet count <150,000/mcL.¹ The blood abnormality is either suspected based on the patient’s signs or symptoms, such as ecchymoses, petechiae, purpura, epistaxis, gingival bleeding, or melena, or it is incidentally discovered during review of a complete blood count (CBC).

The development of clinical symptoms is closely related to the severity of the thrombocytopenia, with platelet counts <30,000/mcL more likely to result in clinical symptoms with minor trauma and counts <5,000/mcL potentially resulting in spontaneous bleeding. While most patients will have asymptomatic, incidentally-found thrombocytopenia, and likely a benign etiology, those with the signs/symptoms just described, evidence of infection, or thrombosis are more likely to have a serious etiology and require an expedited work-up. Although pregnancy may be associated with thrombocytopenia, this review confines itself to the causes of thrombocytopenia in non-pregnant adults.

Rule out pseudothrombocytopenia

When isolated thrombocytopenia is discovered incidentally in an asymptomatic person, the first step is to perform a repeat CBC with a peripheral smear to confirm the presence of thrombocytopenia, rule out laboratory error, and assess for platelet clumping. If thrombocytopenia is confirmed and platelet clumping is present, it may be due to the calcium chelator in the ethylenediaminetetraacetic anticoagulant contained within the laboratory transport tube; this cause of pseudothrombocytopenia occurs in up to 0.29% of the population.¹ Obtaining a platelet count from a citrated or heparinized tube avoids this phenomenon.

Is the patient’s thrombocytopenia drug induced?

Once true thrombocytopenia is confirmed, the next step is to review the patient’s prescribed medications, as well as any illicit drugs used, for potential causes of drug-induced thrombocytopenia. DITP can be either immune-mediated or nonimmune-mediated.

Immune-mediated drug-induced thrombocytopenia typically occurs within 1 to 2 weeks of medication exposure and begins to improve within 1 to 2 days of stopping the offending drug.

Immune-mediated DITP typically occurs within 1 to 2 weeks of medication exposure and begins to improve within 1 to 2 days of stopping the offending drug.² (See TABLE 1³ for a list of medications that can induce thrombocytopenia.) It should be noted that most patients who take the medications listed in TABLE 1 do not experience thrombocytopenia; nonetheless, it is a potential risk associated with their use.

Heparin-induced thrombocytopenia (HIT) is a unique form of immune-mediated DITP in that it is caused by antibody complexes, resulting in platelet activation, clumping, and thrombotic events.⁴ HIT occurs <1% of patients in intensive care units, but can occur in any patient on long-term heparin therapy. It manifests as a >50% drop in platelet count within 5 to 14 days of the introduction of heparin; however, in those previously exposed to heparin, it can occur within 24 hours.^4,5

Continue to: Non-immune-mediated DITP

Non-immune-mediated DITP, resulting from myelosuppression, chemotherapeutic agents, or valproic acid, is less common.^1,2

Acute and chronic alcohol use. Although alcohol is not a drug per se, it can also result in thrombocytopenia. The mechanism is the direct suppression of bone marrow, although alcohol also causes B12 and folate deficiency, further contributing to the development of the blood abnormality.¹

Is there thrombosis?

In addition to exploring a connection between thrombocytopenia and the drugs a patient is taking, it’s also important to look for evidence of thrombosis. The causes of thrombocytopenia that paradoxically result in thrombosis are: disseminated intravascular coagulation, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, catastrophic antiphospholipid antibody syndrome, and the previously mentioned HIT. TABLE 2^4,6-9 outlines the clinical settings, laboratory findings, and treatments of thrombocytopenia associated with thrombosis.

Is an infectious cause to blame?

If the patient is ill, consider infectious causes of thrombocytopenia. Thrombocytopenia associated with infection may result from an immune-mediated response to an illness itself, to treatment of an illness, to splenic sequestration, or to bone marrow suppression. TABLE 3^1,9-11 lists common infections that may cause thrombocytopenia.

Of note, infection with Helicobacter pylori can cause asymptomatic thrombocytopenia via an immune-mediated mechanism.¹² Eradication of H pylori results in a variable elevation in platelets, on average 30,000/mcL in 50% of patients with the infection.¹³

Is there pancytopenia?

A review of the peripheral smear, with attention to abnormalities in other cell lines, may assist in arriving at a diagnosis. If the peripheral smear reveals pancytopenia, then, in addition to many of the etiologies described earlier, one should also consider vitamin B12 or folate deficiency, copper deficiency, drug- and viral-induced aplastic anemia, paroxysmal nocturnal hemoglobinuria, leukemias, myelodysplastic disorders, and systemic lupus erythematosis.¹⁴ Pancytopenia is also seen with hypersplenism, which is often associated with cirrhosis.¹⁵ If the etiology isn’t readily apparent, a bone marrow biopsy may be required.

Continue to: Is immune thrombocytopenia to blame?

Immune thrombocytopenia (ITP) is an autoimmune disorder resulting in the destruction of normal platelets and may be primary or secondary to processes described previously (HIT, H pylori infection, etc). Consider ITP if, after a thorough work-up, a cause of isolated thrombocytopenia is not identified.¹⁶ Treatment for ITP is outlined in TABLE 4.¹⁶ FIGURE 1 is an algorithm for the complete evaluation of thrombocytopenia in adults.

Treatment: Platelet transfusions

In general, patients who are not actively bleeding are considered stable and do not require platelet transfusions to minimize their risk of bleeding or prevent bleeding during a planned procedure unless their platelet count falls below the levels specified in TABLE 5.¹⁷ For patients who are actively bleeding, a more aggressive approach may be required. Locally-derived transfusion protocols typically guide transfusions for the actively hemorrhaging patient. The American Association of Blood Banks has put forth evidence-based guidelines for platelet transfusions when a patient is given a diagnosis of thrombocytopenia (see TABLE 5).¹⁷ Single-donor platelets have a shelf life of 3 to 5 days, and one unit will raise platelets 30,000 to 50,000/mcL.

Neutropenia: Prevalence varies by ethnicity

An absolute neutrophil count (ANC) of <1500 cells/mcL traditionally defines neutropenia, with an ANC of 1000 to 1500 cells/mcL constituting mild neutropenia; 500 to 999 cells/mcL, moderate; and <500 cells/mcL, severe.¹⁸ Similar to the evaluation of thrombocytopenia, it is important to repeat the CBC prior to initiating a work-up in order to confirm that the neutropenia is not a laboratory error. Additionally, patients with signs or symptoms of infection should be worked up expeditiously.

Heparin-induced thrombocytopenia occurs in <1% of patients in intensive care units and typically is manifested by a ≥50% drop in platelet count within 5 to 14 days of introducing heparin.

The prevalence of neutropenia varies by ethnicity. According to the National Health and Nutrition Examination Survey 1999 to 2004, the prevalence was 4.5%, 0.79%, and 0.38% in black, white, and Mexican-American participants, respectively.¹⁹ FIGURE 2 outlines the outpatient work-up of adult patients with neutropenia not related to chemotherapy.

Continue to: Is the patient severely ill?

The prognosis of the patient is related both to the etiology of the neutropenia, as well as to the nadir of the neutrophil count. Patients who have an ANC <500 cells/mcL or who have inadequate bone marrow reserves are at highest risk for an overwhelming infection.^20,21 The absence of oral ulcers and gingivitis and/or the presence of purulent material at the site of an infection are signs of adequate bone marrow reserves.

Additionally, neutropenia may be the source—or the result—of a serious life-threatening illness. This distinction may not be readily apparent at the time of the patient’s presentation. If signs or symptoms of a severe illness are apparent (fever, hypotension, tachycardia, ANC <500 cells/mcL), admit the patient to the hospital for evaluation and initiation of antibiotics. 

Is the neutropenia chronic?

A review of previous CBCs will identify whether this condition is new or chronic. A persistent, mild neutropenia (ANC 1000-1500 cells/mcL) in a healthy individual is consistent with benign familial or ethnic neutropenia (see TABLE 6).²⁰ If prior CBCs are unavailable, then a diagnosis of chronic neutropenia may be established by verifying the persistence of mild neutropenia over time.

Cyclic neutropenia is a periodic neutropenia (occurring every 2-5 weeks) associated with mild illnesses that are related to the nadir of the neutrophil count. The diagnosis is established by obtaining serial CBCs twice weekly for 4 to 6 weeks, which reflect cycling of the neutrophil count.^20,22

Are any medications contributing to the neutropenia?

Medications that suppress bone marrow or that interfere with other immune-mediated processes are the most common cause of acquired neutropenia.²³ Drug-induced agranulocytosis is defined as an ANC <500 cells/mcL due to exposure to a drug that results in immunologic or cytotoxic destruction of neutrophils.²⁴

A persistent, mild neutropenia in a healthy individual is consistent with benign familial or ethnic neutropenia.

A systematic review of case reports of drug-induced agranulocytosis (a decrease in peripheral neutrophil count to <500 cells/mcL) revealed that although at least 125 drugs were probably related to agranulocytosis, only 11 drugs were responsible for 50% of cases (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine), and fatality rates were higher (10% vs 3%) among those patients with a nadir <100 cells/mcL.²⁵ TABLE 7²⁵ lists medications that can be associated with agranulocytosis. Depending on prior exposure to a drug, neutropenia/agranulocytosis can occur within hours to months of exposure to the causal drug and can take a few days to 3 weeks to resolve after cessation.^25,26

Continue to: Has the patient had any recent illnesses?

The usual response to an infection is an increase in neutrophil count. However, certain bacterial, rickettsial, parasitic, and viral infections can result in neutropenia (see TABLE 8^23,27-29). Viral infections may cause transient neutropenia because of either bone marrow suppression or increased peripheral destruction, while neutropenia related to an overwhelming bacterial infection results from the depletion of bone marrow reserves.^23,27

Do you suspect a nutritional deficiency?

Patients with a nutritional deficiency of B12, folate, or copper are likely to exhibit a deficiency in more than just neutrophils.^23,27 In developed countries, people with neutropenia may have a history of malnutrition due to a disease (eg, anorexia nervosa) or surgery (eg, gastric bypass) that causes severe calorie restriction.²⁰

Does your patient have symptoms of a connective tissue disease?

In developed countries, people with neutropenia may have a history of malnutrition due to a disease (eg, anorexia nervosa) or surgery (eg, gastric bypass) that causes severe calorie restriction.

Neutropenia, in association with arthralgias, joint swelling, splenomegaly, or rash may be a manifestation of an underlying collagen vascular disorder, such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).²⁰ If the clinical scenario supports one of these diagnoses, undertake or refer the patient for a rheumatologic evaluation. This may include studies of anti-cyclic citrullinated peptide antibodies, rheumatoid factor to evaluate for RA, and/or antinuclear antibodies to evaluate for SLE.^30,31 While most neutropenias associated with autoimmune disease are mild, neutropenia associated with Felty syndrome (RA, splenomegaly, and neutropenia) may be severe (ANC <100 cells/mcL).^20,23

Is the etiology unclear?

Patients with moderate to severe neutropenia without an apparent etiology, in the setting of aplastic anemia, or in the presence of splenomegaly and/or lymphadenopathy, should undergo a hematologic evaluation and/or bone marrow biopsy, given that hematologic malignancy is a potential cause.^20,27

The treatment of neutropenia hinges on correctly identifying the etiology of the diminished neutrophil count. If the cause is a medication, infection, underlying rheumatologic condition, or nutritional deficiency, then either treating the entity or withdrawing the offending medication should result in resolution of the neutropenia. If the cause is determined to be familial or ethnic, then patient reassurance is all that is required.

CORRESPONDENCE
Richard W. Temple, MD, FAAFP, CDR MC USN, Camp Lejeune Family Medicine Residency, Naval Medical Center Camp Lejeune, 100 Brewster Blvd, Camp Lejeune, NC 28547-2538; [email protected].

Thrombocytopenia and neutropenia are commonly encountered laboratory abnormalities. The presence of either requires that you promptly evaluate for life-threatening causes and identify the appropriate etiology. This article identifies key questions to ask. It also includes algorithms and tables that will facilitate your evaluation of patients with isolated thrombocytopenia or isolated neutropenia and speed the way toward appropriate treatment.

Thrombocytopenia: A look at the numbers

Thrombocytopenia is defined as a platelet count <150,000/mcL.¹ The blood abnormality is either suspected based on the patient’s signs or symptoms, such as ecchymoses, petechiae, purpura, epistaxis, gingival bleeding, or melena, or it is incidentally discovered during review of a complete blood count (CBC).

The development of clinical symptoms is closely related to the severity of the thrombocytopenia, with platelet counts <30,000/mcL more likely to result in clinical symptoms with minor trauma and counts <5,000/mcL potentially resulting in spontaneous bleeding. While most patients will have asymptomatic, incidentally-found thrombocytopenia, and likely a benign etiology, those with the signs/symptoms just described, evidence of infection, or thrombosis are more likely to have a serious etiology and require an expedited work-up. Although pregnancy may be associated with thrombocytopenia, this review confines itself to the causes of thrombocytopenia in non-pregnant adults.

Rule out pseudothrombocytopenia

When isolated thrombocytopenia is discovered incidentally in an asymptomatic person, the first step is to perform a repeat CBC with a peripheral smear to confirm the presence of thrombocytopenia, rule out laboratory error, and assess for platelet clumping. If thrombocytopenia is confirmed and platelet clumping is present, it may be due to the calcium chelator in the ethylenediaminetetraacetic anticoagulant contained within the laboratory transport tube; this cause of pseudothrombocytopenia occurs in up to 0.29% of the population.¹ Obtaining a platelet count from a citrated or heparinized tube avoids this phenomenon.

Is the patient’s thrombocytopenia drug induced?

Once true thrombocytopenia is confirmed, the next step is to review the patient’s prescribed medications, as well as any illicit drugs used, for potential causes of drug-induced thrombocytopenia. DITP can be either immune-mediated or nonimmune-mediated.

Immune-mediated drug-induced thrombocytopenia typically occurs within 1 to 2 weeks of medication exposure and begins to improve within 1 to 2 days of stopping the offending drug.

Immune-mediated DITP typically occurs within 1 to 2 weeks of medication exposure and begins to improve within 1 to 2 days of stopping the offending drug.² (See TABLE 1³ for a list of medications that can induce thrombocytopenia.) It should be noted that most patients who take the medications listed in TABLE 1 do not experience thrombocytopenia; nonetheless, it is a potential risk associated with their use.

Heparin-induced thrombocytopenia (HIT) is a unique form of immune-mediated DITP in that it is caused by antibody complexes, resulting in platelet activation, clumping, and thrombotic events.⁴ HIT occurs <1% of patients in intensive care units, but can occur in any patient on long-term heparin therapy. It manifests as a >50% drop in platelet count within 5 to 14 days of the introduction of heparin; however, in those previously exposed to heparin, it can occur within 24 hours.^4,5

Continue to: Non-immune-mediated DITP

Non-immune-mediated DITP, resulting from myelosuppression, chemotherapeutic agents, or valproic acid, is less common.^1,2

Acute and chronic alcohol use. Although alcohol is not a drug per se, it can also result in thrombocytopenia. The mechanism is the direct suppression of bone marrow, although alcohol also causes B12 and folate deficiency, further contributing to the development of the blood abnormality.¹

Is there thrombosis?

In addition to exploring a connection between thrombocytopenia and the drugs a patient is taking, it’s also important to look for evidence of thrombosis. The causes of thrombocytopenia that paradoxically result in thrombosis are: disseminated intravascular coagulation, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, catastrophic antiphospholipid antibody syndrome, and the previously mentioned HIT. TABLE 2^4,6-9 outlines the clinical settings, laboratory findings, and treatments of thrombocytopenia associated with thrombosis.

Is an infectious cause to blame?

If the patient is ill, consider infectious causes of thrombocytopenia. Thrombocytopenia associated with infection may result from an immune-mediated response to an illness itself, to treatment of an illness, to splenic sequestration, or to bone marrow suppression. TABLE 3^1,9-11 lists common infections that may cause thrombocytopenia.

Of note, infection with Helicobacter pylori can cause asymptomatic thrombocytopenia via an immune-mediated mechanism.¹² Eradication of H pylori results in a variable elevation in platelets, on average 30,000/mcL in 50% of patients with the infection.¹³

Is there pancytopenia?

A review of the peripheral smear, with attention to abnormalities in other cell lines, may assist in arriving at a diagnosis. If the peripheral smear reveals pancytopenia, then, in addition to many of the etiologies described earlier, one should also consider vitamin B12 or folate deficiency, copper deficiency, drug- and viral-induced aplastic anemia, paroxysmal nocturnal hemoglobinuria, leukemias, myelodysplastic disorders, and systemic lupus erythematosis.¹⁴ Pancytopenia is also seen with hypersplenism, which is often associated with cirrhosis.¹⁵ If the etiology isn’t readily apparent, a bone marrow biopsy may be required.

Continue to: Is immune thrombocytopenia to blame?

Immune thrombocytopenia (ITP) is an autoimmune disorder resulting in the destruction of normal platelets and may be primary or secondary to processes described previously (HIT, H pylori infection, etc). Consider ITP if, after a thorough work-up, a cause of isolated thrombocytopenia is not identified.¹⁶ Treatment for ITP is outlined in TABLE 4.¹⁶ FIGURE 1 is an algorithm for the complete evaluation of thrombocytopenia in adults.

Treatment: Platelet transfusions

In general, patients who are not actively bleeding are considered stable and do not require platelet transfusions to minimize their risk of bleeding or prevent bleeding during a planned procedure unless their platelet count falls below the levels specified in TABLE 5.¹⁷ For patients who are actively bleeding, a more aggressive approach may be required. Locally-derived transfusion protocols typically guide transfusions for the actively hemorrhaging patient. The American Association of Blood Banks has put forth evidence-based guidelines for platelet transfusions when a patient is given a diagnosis of thrombocytopenia (see TABLE 5).¹⁷ Single-donor platelets have a shelf life of 3 to 5 days, and one unit will raise platelets 30,000 to 50,000/mcL.

Neutropenia: Prevalence varies by ethnicity

An absolute neutrophil count (ANC) of <1500 cells/mcL traditionally defines neutropenia, with an ANC of 1000 to 1500 cells/mcL constituting mild neutropenia; 500 to 999 cells/mcL, moderate; and <500 cells/mcL, severe.¹⁸ Similar to the evaluation of thrombocytopenia, it is important to repeat the CBC prior to initiating a work-up in order to confirm that the neutropenia is not a laboratory error. Additionally, patients with signs or symptoms of infection should be worked up expeditiously.

Heparin-induced thrombocytopenia occurs in <1% of patients in intensive care units and typically is manifested by a ≥50% drop in platelet count within 5 to 14 days of introducing heparin.

The prevalence of neutropenia varies by ethnicity. According to the National Health and Nutrition Examination Survey 1999 to 2004, the prevalence was 4.5%, 0.79%, and 0.38% in black, white, and Mexican-American participants, respectively.¹⁹ FIGURE 2 outlines the outpatient work-up of adult patients with neutropenia not related to chemotherapy.

Continue to: Is the patient severely ill?

The prognosis of the patient is related both to the etiology of the neutropenia, as well as to the nadir of the neutrophil count. Patients who have an ANC <500 cells/mcL or who have inadequate bone marrow reserves are at highest risk for an overwhelming infection.^20,21 The absence of oral ulcers and gingivitis and/or the presence of purulent material at the site of an infection are signs of adequate bone marrow reserves.

Additionally, neutropenia may be the source—or the result—of a serious life-threatening illness. This distinction may not be readily apparent at the time of the patient’s presentation. If signs or symptoms of a severe illness are apparent (fever, hypotension, tachycardia, ANC <500 cells/mcL), admit the patient to the hospital for evaluation and initiation of antibiotics. 

Is the neutropenia chronic?

A review of previous CBCs will identify whether this condition is new or chronic. A persistent, mild neutropenia (ANC 1000-1500 cells/mcL) in a healthy individual is consistent with benign familial or ethnic neutropenia (see TABLE 6).²⁰ If prior CBCs are unavailable, then a diagnosis of chronic neutropenia may be established by verifying the persistence of mild neutropenia over time.

Cyclic neutropenia is a periodic neutropenia (occurring every 2-5 weeks) associated with mild illnesses that are related to the nadir of the neutrophil count. The diagnosis is established by obtaining serial CBCs twice weekly for 4 to 6 weeks, which reflect cycling of the neutrophil count.^20,22

Are any medications contributing to the neutropenia?

Medications that suppress bone marrow or that interfere with other immune-mediated processes are the most common cause of acquired neutropenia.²³ Drug-induced agranulocytosis is defined as an ANC <500 cells/mcL due to exposure to a drug that results in immunologic or cytotoxic destruction of neutrophils.²⁴

A persistent, mild neutropenia in a healthy individual is consistent with benign familial or ethnic neutropenia.

A systematic review of case reports of drug-induced agranulocytosis (a decrease in peripheral neutrophil count to <500 cells/mcL) revealed that although at least 125 drugs were probably related to agranulocytosis, only 11 drugs were responsible for 50% of cases (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine), and fatality rates were higher (10% vs 3%) among those patients with a nadir <100 cells/mcL.²⁵ TABLE 7²⁵ lists medications that can be associated with agranulocytosis. Depending on prior exposure to a drug, neutropenia/agranulocytosis can occur within hours to months of exposure to the causal drug and can take a few days to 3 weeks to resolve after cessation.^25,26

Continue to: Has the patient had any recent illnesses?

The usual response to an infection is an increase in neutrophil count. However, certain bacterial, rickettsial, parasitic, and viral infections can result in neutropenia (see TABLE 8^23,27-29). Viral infections may cause transient neutropenia because of either bone marrow suppression or increased peripheral destruction, while neutropenia related to an overwhelming bacterial infection results from the depletion of bone marrow reserves.^23,27

Do you suspect a nutritional deficiency?

Patients with a nutritional deficiency of B12, folate, or copper are likely to exhibit a deficiency in more than just neutrophils.^23,27 In developed countries, people with neutropenia may have a history of malnutrition due to a disease (eg, anorexia nervosa) or surgery (eg, gastric bypass) that causes severe calorie restriction.²⁰

Does your patient have symptoms of a connective tissue disease?

In developed countries, people with neutropenia may have a history of malnutrition due to a disease (eg, anorexia nervosa) or surgery (eg, gastric bypass) that causes severe calorie restriction.

Neutropenia, in association with arthralgias, joint swelling, splenomegaly, or rash may be a manifestation of an underlying collagen vascular disorder, such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).²⁰ If the clinical scenario supports one of these diagnoses, undertake or refer the patient for a rheumatologic evaluation. This may include studies of anti-cyclic citrullinated peptide antibodies, rheumatoid factor to evaluate for RA, and/or antinuclear antibodies to evaluate for SLE.^30,31 While most neutropenias associated with autoimmune disease are mild, neutropenia associated with Felty syndrome (RA, splenomegaly, and neutropenia) may be severe (ANC <100 cells/mcL).^20,23

Is the etiology unclear?

Patients with moderate to severe neutropenia without an apparent etiology, in the setting of aplastic anemia, or in the presence of splenomegaly and/or lymphadenopathy, should undergo a hematologic evaluation and/or bone marrow biopsy, given that hematologic malignancy is a potential cause.^20,27

The treatment of neutropenia hinges on correctly identifying the etiology of the diminished neutrophil count. If the cause is a medication, infection, underlying rheumatologic condition, or nutritional deficiency, then either treating the entity or withdrawing the offending medication should result in resolution of the neutropenia. If the cause is determined to be familial or ethnic, then patient reassurance is all that is required.

CORRESPONDENCE
Richard W. Temple, MD, FAAFP, CDR MC USN, Camp Lejeune Family Medicine Residency, Naval Medical Center Camp Lejeune, 100 Brewster Blvd, Camp Lejeune, NC 28547-2538; [email protected].

CASE

A 44-year-old nurse describes persistent fatigue and itching over the last 2 months. She is taking ramipril 5 mg/d for hypertension and has a family history of rheumatic disease. Lab tests reveal a recurrent moderate elevation of gamma glutamyl-transpeptidase (gGT; 75 U/L) associated with, on some occasions, mild elevation of alanine aminotransferase (ALT) levels (100 U/L) of unknown origin. She has no history of hepatitis virus infection, hepatotoxic medications, or alcohol intake. She is overweight with a body mass index of 28.5 kg/m² and a waist circumference of 99 cm (39 inches). Liver ultrasonography detects an enlarged liver with diffuse echostructure dishomogeneity, but no signs of cirrhosis or portal hypertension. The patient’s biliary tree is not dilated.

How would you proceed with the care of this patient?

Cholestasis is characterized by the alteration of bile flow through any part of the biliary system, from the hepatocyte basocellular membrane to the duodenum. The condition is classified as intrahepatic when the cause is a defect of hepatocellular function or obstruction of the biliary tree within the liver. The extrahepatic form includes all conditions obstructing bile flow in the main biliary tract (choledochus, common bile duct).

Suspect intrahepatic cholestasis in a patient with chronic itching, normal transaminases, and mildly elevated gamma glutamyl-transpeptidase.

The key to successfully managing cholestasis lies in the early identification of subtle signs and symptoms before serious complications can arise. In the review that follows, we provide guidance for evaluating laboratory and imaging results that are vital to the accurate diagnosis of intrahepatic and extrahepatic cholestasis. We also detail treatment recommendations.

Clues—subtle and otherwise—of cholestasis

Clinical features of cholestasis include fatigue and itching all over the skin. The latter likely is caused by induction of the enzyme autotaxin, which produces the neuronal activator lysophosphatidic acid. Retention of pruritogenic substances that normally are excreted into bile might contribute to pruritus as well.¹ Jaundice, dark urine, and pale and fatty stools occur with advanced disease. However, a cholestatic condition can be detected in asymptomatic patients with elevated biochemical markers.

Continue to: Mildly elevated gGT and/or alkaline phosphatase (ALP)

Mildly elevated gGT and/or alkaline phosphatase (ALP) (0.5-2.5 times the upper normal limit [UNL] or 19-95 U/L and 60-300 U/L, respectively²) in the presence of normal transaminase levels (<20 U/L) in an asymptomatic patient can indicate chronic liver disease. Signs suggestive of significant liver disease have been reported in many patients with gGT or ALP elevation with good sensitivity (65%) and specificity (83%) for a diagnosis of intrahepatic cholestasis.³ However, because abnormal gGT values are common and often resolve spontaneously, family physicians (FPs) may pay little attention to this finding, thus missing an opportunity for early identification and treatment.

Patient’s history can provide important clues

A thorough patient history is especially important when cholestasis is suspected. Details about the patient’s occupation, environment, and lifestyle are key, as are the specifics of prescribed or over-the-counter medications and supplements that could be hepatotoxic (TABLE 4¹⁰). A number of exogenous substances can cause liver injury, and the use of some herbal products (senna, black cohosh, greater celandine, kava) have been linked to hepatitis and cholestasis.¹¹ Ask patients about alcohol use and history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders.

Continue to: Indicators pointing to cholestasis? It's time for ultrasonography

Abdominal ultrasonography is a first-line diagnostic tool for cholestasis.

While biopsy is considered the gold standard for diagnosing and staging chronic cholestatic liver disease and can exclude an extrahepatic obstruction, it should be employed only if blood tests have been confirmed, second-level tests have been performed, and ultrasound is inconclusive.¹² (More on biopsy in a bit.)

Ultrasonography is a low-cost, widely available, noninvasive test that allows easy identification of extrahepatic dilatation of the biliary tree and sometimes the underlying cause, as well. Ultrasonography identifies extrahepatic cholestasis by allowing visualization of an enlarged choledochus (>7 mm) or common hepatic duct (>5 mm) and an intrahepatic bile duct diameter that is more than 40% larger than adjacent branches of the portal vein.¹³ However, ultrasonography has a low diagnostic sensitivity for many conditions (eg, 15% to 89% for detecting common bile duct stones),¹⁴ requiring other diagnostic procedures, such as endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP), before reaching a diagnosis.

For asymptomatic patients with cirrhosis or those at an early stage of liver disease, ultrasound at 6-month intervals combined with serum liver function tests can be useful to track disease progression and screen for hepatocellular carcinoma or cholangiocarcinoma.^15,16

New noninvasive methods. Noninvasive tools for evaluating the presence and severity of liver fibrosis and for differentiating cirrhosis from noncirrhotic conditions have positive predictive values >85% to 90% for some chronic liver diseases.¹⁷ Transient elastography, which assesses liver stiffness, is one such method. Although it is often used successfully, morbid obesity, small intercostal spaces, and ascites limit its diagnostic capability.¹⁸ Recently, some questions about the validity of elastography to assess the extent of fibrosis in patients with chronic cholestatic conditions have been reported.^19,20

Suspect intrahepatic cholestasis? Your next steps

If imaging techniques do not show bile duct obstruction and you suspect the intrahepatic form, second-level tests could have strategic importance. This is where antimitochondrial antibodies (AMAs) come in. AMAs are immunoglobulins (IgG and IgM) directed against mitochondrial antigens. They are important markers for PBC, which is a T-lymphocyte-mediated attack on small intralobular bile ducts resulting in their gradual destruction and eventual disappearance. The sustained loss of intralobular bile ducts leads to signs and symptoms of cholestasis and eventually results in cirrhosis and liver failure.

AMA serum levels show high sensitivity and specificity (90% and 95%, respectively) for PBC.²¹ Some PBC patients (<5%) show histologic confirmation of the disease, but have negative AMA tests (AMA negative PBC or autoimmune cholangitis).²² Therefore, according to the American Association for the Study of Liver Diseases, diagnosis of PBC is guided by the combination of serologic, biochemical, and histologic criteria.²³ Many PBC patients with or without a positive AMA (≥1:40) also have positive circulating antinuclear antibodies (ANA; ≥1:80). The recent availability of lab tests for antibodies (anti-M2, anti-gp120, anti-sp100) has allowed identification of subgroups of patients who have a more aggressive form of PBC. Patients with PBC often have elevated levels of circulating IgM (>280 mg/dL).

Continue to: Other circulating antibodies

Other circulating antibodies can help discriminate among cholestatic disorders. In particular, positive tests for perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are found in 25% to 95% of patients with primary sclerosing cholangitis (PSC), a chronic progressive disorder of unknown etiology that is characterized by inflammation, fibrosis, and stricturing of medium and large ducts of the intrahepatic and extrahepatic biliary tree.²⁴ Anti-smooth muscle antibodies (SMA) can be observed in both PSC and autoimmune hepatitis.

Alkaline phosphatase levels are useful for monitoring evolution of primary biliary cholangitis disease.

Finally, there are syndromes with serologic and histologic overlap that are characterized by the simultaneous presence of PBC with autoimmune hepatitis or PSC or overlap of PSC with autoimmune hepatitis.

Liver biopsy fills in the rest of the diagnostic picture

Unfortunately, blood tests reveal little about organ integrity and are not useful for disease staging. The decision to perform a liver biopsy should be based on several factors, including the patient’s age, serum parameters, the need to stage the disease, therapy choices, and prognosis.¹² One should also consider that biopsy is a costly procedure with potentially serious adverse effects; it should not be repeated frequently. However, when a biopsy is done, it provides critical information, including damage to medium-sized intrahepatic bile ducts with neoductular formation or bile duct scars and strictures.

Treating intrahepatic cholestasis

Although FPs often can provide most—or even all—of the care for patients with stable conditions, a specialist consultation might recommend further testing to identify the underlying disease, which is essential to establish the most appropriate treatment.

Treatment of patients with PBC is based on administering hydrophilic secondary bile salt ursodeoxycholic acid (UDCA) 15 mg/kg/d, which is used to equilibrate the ratio between hydrophilic and hydrophobic bile salts in the liver and bile,²⁵ and is the only treatment approved by the US Food and Drug Administration (FDA) for PBC.⁴ Tauroursodeoxycholate is better absorbed than UDCA, and, although partially deconjugated and reconjugated with glycine, it undergoes reduced biotransformation to more hydrophobic metabolites and has benefits, including antioxidant, immunomodulation, and neuroprotective effects over UDCA—especially for long-term therapy in PBC.²⁶ However, it is not used often in clinical practice.

Continue to: Bile acid administration counters the cytotoxic effect...

Bile acid administration counters the cytotoxic effect of hydrophobic bile salts. Although it seems that UDCA might improve biochemical and histologic features of the disease at earlier stages (I-II), it fails in patients with more advanced disease.²⁷ In addition, monitoring and defining response to UDCA is inconsistent, partly because of variations in guideline criteria.^28,29

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor.

Recently a new molecule, obeticholic acid (OCA), has been approved by the FDA. A farnesoid X receptor agonist, OCA is indicated for treating patients who do not tolerate UDCA or as an adjunct to UDCA in those with a partial response to UDCA, defined as lowering ALP levels by <1.5 times the baseline value after 12 months of treatment.

Treating PSC is more complex. Combination therapy with prednisone and azathioprine is recommended only when there is an overlap syndrome between PSC and autoimmune hepatitis.⁴ UDCA at a high dosage (15-20 mg/kg/d) is used to facilitate long-lasting biochemical remission. These patients also need to be monitored for inflammatory bowel diseases, which affect up to 75% of patients,³⁰ and for cholangiocarcinoma, which is a life-limiting complication because of a lack of therapy options. Finally, these patients might need endoscopic-guided dilatation of the biliary tree when they have evidence of dominant fibrotic strictures of the greater bile ducts.^14,31

Addressing the systemic effects of intrahepatic cholestasis

Pruritus. A number of potential pruritogens, including bile salts, endogenous opioids, histamine, serotonin, and lisophosphatidic acid (LPA), can be targeted to relieve pruritus.

• Bile acid resin binders such as cholestyramine are the first step for treating pruritus. UDCA also can be useful, mainly for intrahepatic cholestasis during pregnancy. Rifampicin, 300 mg/d, improves cholestatic pruritus, but is associated with hepatotoxicity and a number of severe reactions, such as nausea, loss of appetite, hemolytic anemia, and thrombocytopenia.³¹
• Most evidence favors a role for opioids in relieving itch, and micro-opioid receptor antagonists (naltrexone, naloxone, nalmefene) that exert an antipruritic effect can be effective.
• Sertraline (a selective serotonin reuptake inhibitor), 50 to 75 mg/d, usually is well tolerated in patients with chronic cholestasis and exerts a beneficial effect on pruritus in approximately 40% of patients.³²
• Extracorporeal albumin dialysis removes albumin-bound pruritogens and has been found to be effective in patients with liver failure. Steroids and UV light also can be used in select patients.
• The potent neuronal activator LPA and its converting enzyme autotaxin have been identified in the serum of patients with cholestatic pruritus; experimental modalities using LPA antagonists are ongoing for treating pruritus in patients who do not respond to other medications.³³

Continue to: Malnutrition

Malnutrition. Many patients with cholestasis are at risk for malnutrition, which can be exacerbated in those with cirrhosis. Causes of malnutrition include poor oral intake, malabsorption, or dental problems that prevent the patient from chewing. Assess the nutritional status of every patient with chronic cholestasis, and stress the importance of multivitamin supplementation to reverse systemic alterations caused by malnutrition.³⁴

When the patient has advanced disease

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor. Patients routinely experience fatigue, pruritus, and complications of cirrhosis including ascites, encephalopathy, and bleeding. Cholestasis also carries the risk of life-threatening complications, partly because of comorbidities such as osteoporosis and malabsorption.

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications.

Liver transplantation can improve the life expectancy of patients with advanced disease, but because of long waiting lists, candidates for transplant often die before an organ becomes available. For many patients who are not in end-stage condition, targeted therapy is crucial to slow disease progression and is recommended along with hepatitis A and B vaccinations and nutritional counseling.³⁵

Extrahepatic cholestasis is suspected? How to proceed

Computer tomography (CT) is recommended for better identification of neoplastic causes of biliary obstruction and for staging purposes. MRCP is an excellent noninvasive imaging technique for evaluating biliary ducts.³⁶

MRCP has 92% to 93% sensitivity and 97% to 98% specificity for diagnosing biliary duct stones.³⁷ MRCP also is the first-choice modality for evaluating bile ducts in patients with suspected PSC. If performed in expert centers, the diagnostic accuracy reaches that of ERCP. A meta-analysis of studies from 2000 to 2006 has shown a sensitivity of 86% and specificity of 94% for diagnosing PSC.³⁸

Endoscopic ultrasonography, which uses an ultrasonographic probe, allows clinicians to evaluate the integrity of the biliary and pancreatic ducts and is effective for diagnosing and staging cancer of the ampulla of Vater (sensitivity 93% vs 7% for abdominal ultrasonography and 29% for CT), and identifying biliary stones and biliary tree strictures.

Continue to: ERCP

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications. ERCP is nearly exclusively used as a therapeutic procedure for pancreatic sphincterotomy, biliary dilatations, and removing biliary stones. It also has a diagnostic role in dominant stenosis or suspected biliary malignancy using brushing cytology and sampling biopsies of the bile ducts.

Treating extrahepatic cholestasis

Treatment of the different underlying conditions that cause extrahepatic cholestasis is surgical. Thus, the potential surgical techniques that can resolve or improve an extrahepatic cholestatic condition are guided by the surgeon and beyond the scope of this article.

Treating osteopenia: A concern for intra- and extrahepatic cholestasis

Vitamin D deficiency as a consequence of reduced intestinal absorption (poor availability of bile salts) or decreased hepatic activation to 25,OH-cholecalcipherol in both intrahepatic and extrahepatic cholestasis can lead to reduced bone formation.³⁹ However, osteopenia can occur even in early stages of the disease. Prescribing bisphosphonates, in combination with calcium and vitamin D3_, to improve bone mineral density is a good practice.⁴⁰

CASE

Blood tests and ultrasound imaging suggest the presence of a chronic liver disease. Other lab tests indicate that the patient has an ALP level 3 times normal. This finding, together with the other tests, points to a likely diagnosis of intrahepatic cholestatic liver disease. Serology confirms positivity for ANA (1:160) and AMA (1:640). The clinician suspects PBC, so the patient is referred to a liver specialist for further evaluation and to determine whether a liver biopsy is needed.

The liver specialist confirms the diagnosis of PBC, performs a transient elastographym, which indicates a low-grade liver fibrosis (F1 out of 4), and starts therapy with UDCA.

CORRESPONDENCE
Ignazio Grattagliano, MD, Italian College of General Practitioners and Primary Care, Via del Sansovino 179, 50142, Florence, Italy; [email protected].

CASE

A 44-year-old nurse describes persistent fatigue and itching over the last 2 months. She is taking ramipril 5 mg/d for hypertension and has a family history of rheumatic disease. Lab tests reveal a recurrent moderate elevation of gamma glutamyl-transpeptidase (gGT; 75 U/L) associated with, on some occasions, mild elevation of alanine aminotransferase (ALT) levels (100 U/L) of unknown origin. She has no history of hepatitis virus infection, hepatotoxic medications, or alcohol intake. She is overweight with a body mass index of 28.5 kg/m² and a waist circumference of 99 cm (39 inches). Liver ultrasonography detects an enlarged liver with diffuse echostructure dishomogeneity, but no signs of cirrhosis or portal hypertension. The patient’s biliary tree is not dilated.

How would you proceed with the care of this patient?

Cholestasis is characterized by the alteration of bile flow through any part of the biliary system, from the hepatocyte basocellular membrane to the duodenum. The condition is classified as intrahepatic when the cause is a defect of hepatocellular function or obstruction of the biliary tree within the liver. The extrahepatic form includes all conditions obstructing bile flow in the main biliary tract (choledochus, common bile duct).

Suspect intrahepatic cholestasis in a patient with chronic itching, normal transaminases, and mildly elevated gamma glutamyl-transpeptidase.

The key to successfully managing cholestasis lies in the early identification of subtle signs and symptoms before serious complications can arise. In the review that follows, we provide guidance for evaluating laboratory and imaging results that are vital to the accurate diagnosis of intrahepatic and extrahepatic cholestasis. We also detail treatment recommendations.

Clues—subtle and otherwise—of cholestasis

Clinical features of cholestasis include fatigue and itching all over the skin. The latter likely is caused by induction of the enzyme autotaxin, which produces the neuronal activator lysophosphatidic acid. Retention of pruritogenic substances that normally are excreted into bile might contribute to pruritus as well.¹ Jaundice, dark urine, and pale and fatty stools occur with advanced disease. However, a cholestatic condition can be detected in asymptomatic patients with elevated biochemical markers.

Continue to: Mildly elevated gGT and/or alkaline phosphatase (ALP)

Mildly elevated gGT and/or alkaline phosphatase (ALP) (0.5-2.5 times the upper normal limit [UNL] or 19-95 U/L and 60-300 U/L, respectively²) in the presence of normal transaminase levels (<20 U/L) in an asymptomatic patient can indicate chronic liver disease. Signs suggestive of significant liver disease have been reported in many patients with gGT or ALP elevation with good sensitivity (65%) and specificity (83%) for a diagnosis of intrahepatic cholestasis.³ However, because abnormal gGT values are common and often resolve spontaneously, family physicians (FPs) may pay little attention to this finding, thus missing an opportunity for early identification and treatment.

Patient’s history can provide important clues

A thorough patient history is especially important when cholestasis is suspected. Details about the patient’s occupation, environment, and lifestyle are key, as are the specifics of prescribed or over-the-counter medications and supplements that could be hepatotoxic (TABLE 4¹⁰). A number of exogenous substances can cause liver injury, and the use of some herbal products (senna, black cohosh, greater celandine, kava) have been linked to hepatitis and cholestasis.¹¹ Ask patients about alcohol use and history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders.

Continue to: Indicators pointing to cholestasis? It's time for ultrasonography

Abdominal ultrasonography is a first-line diagnostic tool for cholestasis.

While biopsy is considered the gold standard for diagnosing and staging chronic cholestatic liver disease and can exclude an extrahepatic obstruction, it should be employed only if blood tests have been confirmed, second-level tests have been performed, and ultrasound is inconclusive.¹² (More on biopsy in a bit.)

Ultrasonography is a low-cost, widely available, noninvasive test that allows easy identification of extrahepatic dilatation of the biliary tree and sometimes the underlying cause, as well. Ultrasonography identifies extrahepatic cholestasis by allowing visualization of an enlarged choledochus (>7 mm) or common hepatic duct (>5 mm) and an intrahepatic bile duct diameter that is more than 40% larger than adjacent branches of the portal vein.¹³ However, ultrasonography has a low diagnostic sensitivity for many conditions (eg, 15% to 89% for detecting common bile duct stones),¹⁴ requiring other diagnostic procedures, such as endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP), before reaching a diagnosis.

For asymptomatic patients with cirrhosis or those at an early stage of liver disease, ultrasound at 6-month intervals combined with serum liver function tests can be useful to track disease progression and screen for hepatocellular carcinoma or cholangiocarcinoma.^15,16

New noninvasive methods. Noninvasive tools for evaluating the presence and severity of liver fibrosis and for differentiating cirrhosis from noncirrhotic conditions have positive predictive values >85% to 90% for some chronic liver diseases.¹⁷ Transient elastography, which assesses liver stiffness, is one such method. Although it is often used successfully, morbid obesity, small intercostal spaces, and ascites limit its diagnostic capability.¹⁸ Recently, some questions about the validity of elastography to assess the extent of fibrosis in patients with chronic cholestatic conditions have been reported.^19,20

Suspect intrahepatic cholestasis? Your next steps

If imaging techniques do not show bile duct obstruction and you suspect the intrahepatic form, second-level tests could have strategic importance. This is where antimitochondrial antibodies (AMAs) come in. AMAs are immunoglobulins (IgG and IgM) directed against mitochondrial antigens. They are important markers for PBC, which is a T-lymphocyte-mediated attack on small intralobular bile ducts resulting in their gradual destruction and eventual disappearance. The sustained loss of intralobular bile ducts leads to signs and symptoms of cholestasis and eventually results in cirrhosis and liver failure.

AMA serum levels show high sensitivity and specificity (90% and 95%, respectively) for PBC.²¹ Some PBC patients (<5%) show histologic confirmation of the disease, but have negative AMA tests (AMA negative PBC or autoimmune cholangitis).²² Therefore, according to the American Association for the Study of Liver Diseases, diagnosis of PBC is guided by the combination of serologic, biochemical, and histologic criteria.²³ Many PBC patients with or without a positive AMA (≥1:40) also have positive circulating antinuclear antibodies (ANA; ≥1:80). The recent availability of lab tests for antibodies (anti-M2, anti-gp120, anti-sp100) has allowed identification of subgroups of patients who have a more aggressive form of PBC. Patients with PBC often have elevated levels of circulating IgM (>280 mg/dL).

Continue to: Other circulating antibodies

Other circulating antibodies can help discriminate among cholestatic disorders. In particular, positive tests for perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are found in 25% to 95% of patients with primary sclerosing cholangitis (PSC), a chronic progressive disorder of unknown etiology that is characterized by inflammation, fibrosis, and stricturing of medium and large ducts of the intrahepatic and extrahepatic biliary tree.²⁴ Anti-smooth muscle antibodies (SMA) can be observed in both PSC and autoimmune hepatitis.

Alkaline phosphatase levels are useful for monitoring evolution of primary biliary cholangitis disease.

Finally, there are syndromes with serologic and histologic overlap that are characterized by the simultaneous presence of PBC with autoimmune hepatitis or PSC or overlap of PSC with autoimmune hepatitis.

Liver biopsy fills in the rest of the diagnostic picture

Unfortunately, blood tests reveal little about organ integrity and are not useful for disease staging. The decision to perform a liver biopsy should be based on several factors, including the patient’s age, serum parameters, the need to stage the disease, therapy choices, and prognosis.¹² One should also consider that biopsy is a costly procedure with potentially serious adverse effects; it should not be repeated frequently. However, when a biopsy is done, it provides critical information, including damage to medium-sized intrahepatic bile ducts with neoductular formation or bile duct scars and strictures.

Treating intrahepatic cholestasis

Although FPs often can provide most—or even all—of the care for patients with stable conditions, a specialist consultation might recommend further testing to identify the underlying disease, which is essential to establish the most appropriate treatment.

Treatment of patients with PBC is based on administering hydrophilic secondary bile salt ursodeoxycholic acid (UDCA) 15 mg/kg/d, which is used to equilibrate the ratio between hydrophilic and hydrophobic bile salts in the liver and bile,²⁵ and is the only treatment approved by the US Food and Drug Administration (FDA) for PBC.⁴ Tauroursodeoxycholate is better absorbed than UDCA, and, although partially deconjugated and reconjugated with glycine, it undergoes reduced biotransformation to more hydrophobic metabolites and has benefits, including antioxidant, immunomodulation, and neuroprotective effects over UDCA—especially for long-term therapy in PBC.²⁶ However, it is not used often in clinical practice.

Continue to: Bile acid administration counters the cytotoxic effect...

Bile acid administration counters the cytotoxic effect of hydrophobic bile salts. Although it seems that UDCA might improve biochemical and histologic features of the disease at earlier stages (I-II), it fails in patients with more advanced disease.²⁷ In addition, monitoring and defining response to UDCA is inconsistent, partly because of variations in guideline criteria.^28,29

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor.

Recently a new molecule, obeticholic acid (OCA), has been approved by the FDA. A farnesoid X receptor agonist, OCA is indicated for treating patients who do not tolerate UDCA or as an adjunct to UDCA in those with a partial response to UDCA, defined as lowering ALP levels by <1.5 times the baseline value after 12 months of treatment.

Treating PSC is more complex. Combination therapy with prednisone and azathioprine is recommended only when there is an overlap syndrome between PSC and autoimmune hepatitis.⁴ UDCA at a high dosage (15-20 mg/kg/d) is used to facilitate long-lasting biochemical remission. These patients also need to be monitored for inflammatory bowel diseases, which affect up to 75% of patients,³⁰ and for cholangiocarcinoma, which is a life-limiting complication because of a lack of therapy options. Finally, these patients might need endoscopic-guided dilatation of the biliary tree when they have evidence of dominant fibrotic strictures of the greater bile ducts.^14,31

Addressing the systemic effects of intrahepatic cholestasis

Pruritus. A number of potential pruritogens, including bile salts, endogenous opioids, histamine, serotonin, and lisophosphatidic acid (LPA), can be targeted to relieve pruritus.

• Bile acid resin binders such as cholestyramine are the first step for treating pruritus. UDCA also can be useful, mainly for intrahepatic cholestasis during pregnancy. Rifampicin, 300 mg/d, improves cholestatic pruritus, but is associated with hepatotoxicity and a number of severe reactions, such as nausea, loss of appetite, hemolytic anemia, and thrombocytopenia.³¹
• Most evidence favors a role for opioids in relieving itch, and micro-opioid receptor antagonists (naltrexone, naloxone, nalmefene) that exert an antipruritic effect can be effective.
• Sertraline (a selective serotonin reuptake inhibitor), 50 to 75 mg/d, usually is well tolerated in patients with chronic cholestasis and exerts a beneficial effect on pruritus in approximately 40% of patients.³²
• Extracorporeal albumin dialysis removes albumin-bound pruritogens and has been found to be effective in patients with liver failure. Steroids and UV light also can be used in select patients.
• The potent neuronal activator LPA and its converting enzyme autotaxin have been identified in the serum of patients with cholestatic pruritus; experimental modalities using LPA antagonists are ongoing for treating pruritus in patients who do not respond to other medications.³³

Continue to: Malnutrition

Malnutrition. Many patients with cholestasis are at risk for malnutrition, which can be exacerbated in those with cirrhosis. Causes of malnutrition include poor oral intake, malabsorption, or dental problems that prevent the patient from chewing. Assess the nutritional status of every patient with chronic cholestasis, and stress the importance of multivitamin supplementation to reverse systemic alterations caused by malnutrition.³⁴

When the patient has advanced disease

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor. Patients routinely experience fatigue, pruritus, and complications of cirrhosis including ascites, encephalopathy, and bleeding. Cholestasis also carries the risk of life-threatening complications, partly because of comorbidities such as osteoporosis and malabsorption.

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications.

Liver transplantation can improve the life expectancy of patients with advanced disease, but because of long waiting lists, candidates for transplant often die before an organ becomes available. For many patients who are not in end-stage condition, targeted therapy is crucial to slow disease progression and is recommended along with hepatitis A and B vaccinations and nutritional counseling.³⁵

Extrahepatic cholestasis is suspected? How to proceed

Computer tomography (CT) is recommended for better identification of neoplastic causes of biliary obstruction and for staging purposes. MRCP is an excellent noninvasive imaging technique for evaluating biliary ducts.³⁶

MRCP has 92% to 93% sensitivity and 97% to 98% specificity for diagnosing biliary duct stones.³⁷ MRCP also is the first-choice modality for evaluating bile ducts in patients with suspected PSC. If performed in expert centers, the diagnostic accuracy reaches that of ERCP. A meta-analysis of studies from 2000 to 2006 has shown a sensitivity of 86% and specificity of 94% for diagnosing PSC.³⁸

Endoscopic ultrasonography, which uses an ultrasonographic probe, allows clinicians to evaluate the integrity of the biliary and pancreatic ducts and is effective for diagnosing and staging cancer of the ampulla of Vater (sensitivity 93% vs 7% for abdominal ultrasonography and 29% for CT), and identifying biliary stones and biliary tree strictures.

Continue to: ERCP

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications. ERCP is nearly exclusively used as a therapeutic procedure for pancreatic sphincterotomy, biliary dilatations, and removing biliary stones. It also has a diagnostic role in dominant stenosis or suspected biliary malignancy using brushing cytology and sampling biopsies of the bile ducts.

Treating extrahepatic cholestasis

Treatment of the different underlying conditions that cause extrahepatic cholestasis is surgical. Thus, the potential surgical techniques that can resolve or improve an extrahepatic cholestatic condition are guided by the surgeon and beyond the scope of this article.

Treating osteopenia: A concern for intra- and extrahepatic cholestasis

Vitamin D deficiency as a consequence of reduced intestinal absorption (poor availability of bile salts) or decreased hepatic activation to 25,OH-cholecalcipherol in both intrahepatic and extrahepatic cholestasis can lead to reduced bone formation.³⁹ However, osteopenia can occur even in early stages of the disease. Prescribing bisphosphonates, in combination with calcium and vitamin D3_, to improve bone mineral density is a good practice.⁴⁰

CASE

Blood tests and ultrasound imaging suggest the presence of a chronic liver disease. Other lab tests indicate that the patient has an ALP level 3 times normal. This finding, together with the other tests, points to a likely diagnosis of intrahepatic cholestatic liver disease. Serology confirms positivity for ANA (1:160) and AMA (1:640). The clinician suspects PBC, so the patient is referred to a liver specialist for further evaluation and to determine whether a liver biopsy is needed.

The liver specialist confirms the diagnosis of PBC, performs a transient elastographym, which indicates a low-grade liver fibrosis (F1 out of 4), and starts therapy with UDCA.

CORRESPONDENCE
Ignazio Grattagliano, MD, Italian College of General Practitioners and Primary Care, Via del Sansovino 179, 50142, Florence, Italy; [email protected].

CASE

A 44-year-old nurse describes persistent fatigue and itching over the last 2 months. She is taking ramipril 5 mg/d for hypertension and has a family history of rheumatic disease. Lab tests reveal a recurrent moderate elevation of gamma glutamyl-transpeptidase (gGT; 75 U/L) associated with, on some occasions, mild elevation of alanine aminotransferase (ALT) levels (100 U/L) of unknown origin. She has no history of hepatitis virus infection, hepatotoxic medications, or alcohol intake. She is overweight with a body mass index of 28.5 kg/m² and a waist circumference of 99 cm (39 inches). Liver ultrasonography detects an enlarged liver with diffuse echostructure dishomogeneity, but no signs of cirrhosis or portal hypertension. The patient’s biliary tree is not dilated.

How would you proceed with the care of this patient?

Cholestasis is characterized by the alteration of bile flow through any part of the biliary system, from the hepatocyte basocellular membrane to the duodenum. The condition is classified as intrahepatic when the cause is a defect of hepatocellular function or obstruction of the biliary tree within the liver. The extrahepatic form includes all conditions obstructing bile flow in the main biliary tract (choledochus, common bile duct).

Suspect intrahepatic cholestasis in a patient with chronic itching, normal transaminases, and mildly elevated gamma glutamyl-transpeptidase.

The key to successfully managing cholestasis lies in the early identification of subtle signs and symptoms before serious complications can arise. In the review that follows, we provide guidance for evaluating laboratory and imaging results that are vital to the accurate diagnosis of intrahepatic and extrahepatic cholestasis. We also detail treatment recommendations.

Clues—subtle and otherwise—of cholestasis

Clinical features of cholestasis include fatigue and itching all over the skin. The latter likely is caused by induction of the enzyme autotaxin, which produces the neuronal activator lysophosphatidic acid. Retention of pruritogenic substances that normally are excreted into bile might contribute to pruritus as well.¹ Jaundice, dark urine, and pale and fatty stools occur with advanced disease. However, a cholestatic condition can be detected in asymptomatic patients with elevated biochemical markers.

Continue to: Mildly elevated gGT and/or alkaline phosphatase (ALP)

Mildly elevated gGT and/or alkaline phosphatase (ALP) (0.5-2.5 times the upper normal limit [UNL] or 19-95 U/L and 60-300 U/L, respectively²) in the presence of normal transaminase levels (<20 U/L) in an asymptomatic patient can indicate chronic liver disease. Signs suggestive of significant liver disease have been reported in many patients with gGT or ALP elevation with good sensitivity (65%) and specificity (83%) for a diagnosis of intrahepatic cholestasis.³ However, because abnormal gGT values are common and often resolve spontaneously, family physicians (FPs) may pay little attention to this finding, thus missing an opportunity for early identification and treatment.

Patient’s history can provide important clues

A thorough patient history is especially important when cholestasis is suspected. Details about the patient’s occupation, environment, and lifestyle are key, as are the specifics of prescribed or over-the-counter medications and supplements that could be hepatotoxic (TABLE 4¹⁰). A number of exogenous substances can cause liver injury, and the use of some herbal products (senna, black cohosh, greater celandine, kava) have been linked to hepatitis and cholestasis.¹¹ Ask patients about alcohol use and history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders.

Continue to: Indicators pointing to cholestasis? It's time for ultrasonography

Abdominal ultrasonography is a first-line diagnostic tool for cholestasis.

While biopsy is considered the gold standard for diagnosing and staging chronic cholestatic liver disease and can exclude an extrahepatic obstruction, it should be employed only if blood tests have been confirmed, second-level tests have been performed, and ultrasound is inconclusive.¹² (More on biopsy in a bit.)

Ultrasonography is a low-cost, widely available, noninvasive test that allows easy identification of extrahepatic dilatation of the biliary tree and sometimes the underlying cause, as well. Ultrasonography identifies extrahepatic cholestasis by allowing visualization of an enlarged choledochus (>7 mm) or common hepatic duct (>5 mm) and an intrahepatic bile duct diameter that is more than 40% larger than adjacent branches of the portal vein.¹³ However, ultrasonography has a low diagnostic sensitivity for many conditions (eg, 15% to 89% for detecting common bile duct stones),¹⁴ requiring other diagnostic procedures, such as endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP), before reaching a diagnosis.

For asymptomatic patients with cirrhosis or those at an early stage of liver disease, ultrasound at 6-month intervals combined with serum liver function tests can be useful to track disease progression and screen for hepatocellular carcinoma or cholangiocarcinoma.^15,16

New noninvasive methods. Noninvasive tools for evaluating the presence and severity of liver fibrosis and for differentiating cirrhosis from noncirrhotic conditions have positive predictive values >85% to 90% for some chronic liver diseases.¹⁷ Transient elastography, which assesses liver stiffness, is one such method. Although it is often used successfully, morbid obesity, small intercostal spaces, and ascites limit its diagnostic capability.¹⁸ Recently, some questions about the validity of elastography to assess the extent of fibrosis in patients with chronic cholestatic conditions have been reported.^19,20

Suspect intrahepatic cholestasis? Your next steps

If imaging techniques do not show bile duct obstruction and you suspect the intrahepatic form, second-level tests could have strategic importance. This is where antimitochondrial antibodies (AMAs) come in. AMAs are immunoglobulins (IgG and IgM) directed against mitochondrial antigens. They are important markers for PBC, which is a T-lymphocyte-mediated attack on small intralobular bile ducts resulting in their gradual destruction and eventual disappearance. The sustained loss of intralobular bile ducts leads to signs and symptoms of cholestasis and eventually results in cirrhosis and liver failure.

AMA serum levels show high sensitivity and specificity (90% and 95%, respectively) for PBC.²¹ Some PBC patients (<5%) show histologic confirmation of the disease, but have negative AMA tests (AMA negative PBC or autoimmune cholangitis).²² Therefore, according to the American Association for the Study of Liver Diseases, diagnosis of PBC is guided by the combination of serologic, biochemical, and histologic criteria.²³ Many PBC patients with or without a positive AMA (≥1:40) also have positive circulating antinuclear antibodies (ANA; ≥1:80). The recent availability of lab tests for antibodies (anti-M2, anti-gp120, anti-sp100) has allowed identification of subgroups of patients who have a more aggressive form of PBC. Patients with PBC often have elevated levels of circulating IgM (>280 mg/dL).

Continue to: Other circulating antibodies

Other circulating antibodies can help discriminate among cholestatic disorders. In particular, positive tests for perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are found in 25% to 95% of patients with primary sclerosing cholangitis (PSC), a chronic progressive disorder of unknown etiology that is characterized by inflammation, fibrosis, and stricturing of medium and large ducts of the intrahepatic and extrahepatic biliary tree.²⁴ Anti-smooth muscle antibodies (SMA) can be observed in both PSC and autoimmune hepatitis.

Alkaline phosphatase levels are useful for monitoring evolution of primary biliary cholangitis disease.

Finally, there are syndromes with serologic and histologic overlap that are characterized by the simultaneous presence of PBC with autoimmune hepatitis or PSC or overlap of PSC with autoimmune hepatitis.

Liver biopsy fills in the rest of the diagnostic picture

Unfortunately, blood tests reveal little about organ integrity and are not useful for disease staging. The decision to perform a liver biopsy should be based on several factors, including the patient’s age, serum parameters, the need to stage the disease, therapy choices, and prognosis.¹² One should also consider that biopsy is a costly procedure with potentially serious adverse effects; it should not be repeated frequently. However, when a biopsy is done, it provides critical information, including damage to medium-sized intrahepatic bile ducts with neoductular formation or bile duct scars and strictures.

Treating intrahepatic cholestasis

Although FPs often can provide most—or even all—of the care for patients with stable conditions, a specialist consultation might recommend further testing to identify the underlying disease, which is essential to establish the most appropriate treatment.

Treatment of patients with PBC is based on administering hydrophilic secondary bile salt ursodeoxycholic acid (UDCA) 15 mg/kg/d, which is used to equilibrate the ratio between hydrophilic and hydrophobic bile salts in the liver and bile,²⁵ and is the only treatment approved by the US Food and Drug Administration (FDA) for PBC.⁴ Tauroursodeoxycholate is better absorbed than UDCA, and, although partially deconjugated and reconjugated with glycine, it undergoes reduced biotransformation to more hydrophobic metabolites and has benefits, including antioxidant, immunomodulation, and neuroprotective effects over UDCA—especially for long-term therapy in PBC.²⁶ However, it is not used often in clinical practice.

Continue to: Bile acid administration counters the cytotoxic effect...

Bile acid administration counters the cytotoxic effect of hydrophobic bile salts. Although it seems that UDCA might improve biochemical and histologic features of the disease at earlier stages (I-II), it fails in patients with more advanced disease.²⁷ In addition, monitoring and defining response to UDCA is inconsistent, partly because of variations in guideline criteria.^28,29

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor.

Recently a new molecule, obeticholic acid (OCA), has been approved by the FDA. A farnesoid X receptor agonist, OCA is indicated for treating patients who do not tolerate UDCA or as an adjunct to UDCA in those with a partial response to UDCA, defined as lowering ALP levels by <1.5 times the baseline value after 12 months of treatment.

Treating PSC is more complex. Combination therapy with prednisone and azathioprine is recommended only when there is an overlap syndrome between PSC and autoimmune hepatitis.⁴ UDCA at a high dosage (15-20 mg/kg/d) is used to facilitate long-lasting biochemical remission. These patients also need to be monitored for inflammatory bowel diseases, which affect up to 75% of patients,³⁰ and for cholangiocarcinoma, which is a life-limiting complication because of a lack of therapy options. Finally, these patients might need endoscopic-guided dilatation of the biliary tree when they have evidence of dominant fibrotic strictures of the greater bile ducts.^14,31

Addressing the systemic effects of intrahepatic cholestasis

Pruritus. A number of potential pruritogens, including bile salts, endogenous opioids, histamine, serotonin, and lisophosphatidic acid (LPA), can be targeted to relieve pruritus.

• Bile acid resin binders such as cholestyramine are the first step for treating pruritus. UDCA also can be useful, mainly for intrahepatic cholestasis during pregnancy. Rifampicin, 300 mg/d, improves cholestatic pruritus, but is associated with hepatotoxicity and a number of severe reactions, such as nausea, loss of appetite, hemolytic anemia, and thrombocytopenia.³¹
• Most evidence favors a role for opioids in relieving itch, and micro-opioid receptor antagonists (naltrexone, naloxone, nalmefene) that exert an antipruritic effect can be effective.
• Sertraline (a selective serotonin reuptake inhibitor), 50 to 75 mg/d, usually is well tolerated in patients with chronic cholestasis and exerts a beneficial effect on pruritus in approximately 40% of patients.³²
• Extracorporeal albumin dialysis removes albumin-bound pruritogens and has been found to be effective in patients with liver failure. Steroids and UV light also can be used in select patients.
• The potent neuronal activator LPA and its converting enzyme autotaxin have been identified in the serum of patients with cholestatic pruritus; experimental modalities using LPA antagonists are ongoing for treating pruritus in patients who do not respond to other medications.³³

Continue to: Malnutrition

Malnutrition. Many patients with cholestasis are at risk for malnutrition, which can be exacerbated in those with cirrhosis. Causes of malnutrition include poor oral intake, malabsorption, or dental problems that prevent the patient from chewing. Assess the nutritional status of every patient with chronic cholestasis, and stress the importance of multivitamin supplementation to reverse systemic alterations caused by malnutrition.³⁴

When the patient has advanced disease

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor. Patients routinely experience fatigue, pruritus, and complications of cirrhosis including ascites, encephalopathy, and bleeding. Cholestasis also carries the risk of life-threatening complications, partly because of comorbidities such as osteoporosis and malabsorption.

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications.

Liver transplantation can improve the life expectancy of patients with advanced disease, but because of long waiting lists, candidates for transplant often die before an organ becomes available. For many patients who are not in end-stage condition, targeted therapy is crucial to slow disease progression and is recommended along with hepatitis A and B vaccinations and nutritional counseling.³⁵

Extrahepatic cholestasis is suspected? How to proceed

Computer tomography (CT) is recommended for better identification of neoplastic causes of biliary obstruction and for staging purposes. MRCP is an excellent noninvasive imaging technique for evaluating biliary ducts.³⁶

MRCP has 92% to 93% sensitivity and 97% to 98% specificity for diagnosing biliary duct stones.³⁷ MRCP also is the first-choice modality for evaluating bile ducts in patients with suspected PSC. If performed in expert centers, the diagnostic accuracy reaches that of ERCP. A meta-analysis of studies from 2000 to 2006 has shown a sensitivity of 86% and specificity of 94% for diagnosing PSC.³⁸

Endoscopic ultrasonography, which uses an ultrasonographic probe, allows clinicians to evaluate the integrity of the biliary and pancreatic ducts and is effective for diagnosing and staging cancer of the ampulla of Vater (sensitivity 93% vs 7% for abdominal ultrasonography and 29% for CT), and identifying biliary stones and biliary tree strictures.

Continue to: ERCP

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications. ERCP is nearly exclusively used as a therapeutic procedure for pancreatic sphincterotomy, biliary dilatations, and removing biliary stones. It also has a diagnostic role in dominant stenosis or suspected biliary malignancy using brushing cytology and sampling biopsies of the bile ducts.

Treating extrahepatic cholestasis

Treatment of the different underlying conditions that cause extrahepatic cholestasis is surgical. Thus, the potential surgical techniques that can resolve or improve an extrahepatic cholestatic condition are guided by the surgeon and beyond the scope of this article.

Treating osteopenia: A concern for intra- and extrahepatic cholestasis

Vitamin D deficiency as a consequence of reduced intestinal absorption (poor availability of bile salts) or decreased hepatic activation to 25,OH-cholecalcipherol in both intrahepatic and extrahepatic cholestasis can lead to reduced bone formation.³⁹ However, osteopenia can occur even in early stages of the disease. Prescribing bisphosphonates, in combination with calcium and vitamin D3_, to improve bone mineral density is a good practice.⁴⁰

CASE

Blood tests and ultrasound imaging suggest the presence of a chronic liver disease. Other lab tests indicate that the patient has an ALP level 3 times normal. This finding, together with the other tests, points to a likely diagnosis of intrahepatic cholestatic liver disease. Serology confirms positivity for ANA (1:160) and AMA (1:640). The clinician suspects PBC, so the patient is referred to a liver specialist for further evaluation and to determine whether a liver biopsy is needed.

The liver specialist confirms the diagnosis of PBC, performs a transient elastographym, which indicates a low-grade liver fibrosis (F1 out of 4), and starts therapy with UDCA.

CORRESPONDENCE
Ignazio Grattagliano, MD, Italian College of General Practitioners and Primary Care, Via del Sansovino 179, 50142, Florence, Italy; [email protected].

ILLUSTRATIVE CASE

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with over-the-counter medications. You suspect diverticulitis and obtain an abdominal computed tomography (CT) scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis.

How would you treat him?

Diverticulitis is common; about 200,000 people per year are admitted to the hospital because of diverticulitis in the United States.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized control trial (RCT; N=623) found that antibiotic treatment (compared with no antibiotic treatment) for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by a lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, non-uniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

RCT finds that watchful waiting is just as effective as antibiotic Tx

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adult patients in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomized to receive IV administration of amoxicillin-clavulanate 1200 mg 4 times daily for at least 48 hours followed by 625 mg PO 3 times daily for 10 total days of antibiotic treatment (n=266) or to be observed (n=262). Computerized randomization, with a random varying block size and stratified by Hinchey classification and center, was performed, and allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic treatment adverse effects; and all-cause mortality.

Continue to: Results

This study is the first to look at functional return to work and the only study to gauge long-term outcomes with observational treatment.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 days vs 12 days; P=.15; hazard ratio [HR] for functional recovery=0.91; lower limit of 1-sided 95% confidence interval, 0.78). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up (complicated diverticulitis, 3.8% vs 2.6%, respectively; P=.377), recurrent diverticulitis (3.4% vs 3%; P=.494), readmission (17.6% vs 12%; P=.148), or adverse events (48.5% vs 54.5%; P=.221). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 days; P=.006). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

WHAT’S NEW

A study that looks at a true patient-oriented outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate, or requirement for percutaneous drainage.^7,8 This study is the first one to look at functional return to work (a true patient-oriented outcome). And it is the only study to look out to 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize findings to patients with worse forms of diverticulitis

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease), and is not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis maybe more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

Continuet to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with over-the-counter medications. You suspect diverticulitis and obtain an abdominal computed tomography (CT) scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis.

How would you treat him?

Diverticulitis is common; about 200,000 people per year are admitted to the hospital because of diverticulitis in the United States.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized control trial (RCT; N=623) found that antibiotic treatment (compared with no antibiotic treatment) for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by a lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, non-uniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

RCT finds that watchful waiting is just as effective as antibiotic Tx

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adult patients in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomized to receive IV administration of amoxicillin-clavulanate 1200 mg 4 times daily for at least 48 hours followed by 625 mg PO 3 times daily for 10 total days of antibiotic treatment (n=266) or to be observed (n=262). Computerized randomization, with a random varying block size and stratified by Hinchey classification and center, was performed, and allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic treatment adverse effects; and all-cause mortality.

Continue to: Results

This study is the first to look at functional return to work and the only study to gauge long-term outcomes with observational treatment.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 days vs 12 days; P=.15; hazard ratio [HR] for functional recovery=0.91; lower limit of 1-sided 95% confidence interval, 0.78). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up (complicated diverticulitis, 3.8% vs 2.6%, respectively; P=.377), recurrent diverticulitis (3.4% vs 3%; P=.494), readmission (17.6% vs 12%; P=.148), or adverse events (48.5% vs 54.5%; P=.221). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 days; P=.006). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

WHAT’S NEW

A study that looks at a true patient-oriented outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate, or requirement for percutaneous drainage.^7,8 This study is the first one to look at functional return to work (a true patient-oriented outcome). And it is the only study to look out to 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize findings to patients with worse forms of diverticulitis

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease), and is not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis maybe more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

Continuet to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with over-the-counter medications. You suspect diverticulitis and obtain an abdominal computed tomography (CT) scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis.

How would you treat him?

Diverticulitis is common; about 200,000 people per year are admitted to the hospital because of diverticulitis in the United States.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized control trial (RCT; N=623) found that antibiotic treatment (compared with no antibiotic treatment) for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by a lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, non-uniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

RCT finds that watchful waiting is just as effective as antibiotic Tx

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adult patients in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomized to receive IV administration of amoxicillin-clavulanate 1200 mg 4 times daily for at least 48 hours followed by 625 mg PO 3 times daily for 10 total days of antibiotic treatment (n=266) or to be observed (n=262). Computerized randomization, with a random varying block size and stratified by Hinchey classification and center, was performed, and allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic treatment adverse effects; and all-cause mortality.

Continue to: Results

This study is the first to look at functional return to work and the only study to gauge long-term outcomes with observational treatment.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 days vs 12 days; P=.15; hazard ratio [HR] for functional recovery=0.91; lower limit of 1-sided 95% confidence interval, 0.78). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up (complicated diverticulitis, 3.8% vs 2.6%, respectively; P=.377), recurrent diverticulitis (3.4% vs 3%; P=.494), readmission (17.6% vs 12%; P=.148), or adverse events (48.5% vs 54.5%; P=.221). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 days; P=.006). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

WHAT’S NEW

A study that looks at a true patient-oriented outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate, or requirement for percutaneous drainage.^7,8 This study is the first one to look at functional return to work (a true patient-oriented outcome). And it is the only study to look out to 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize findings to patients with worse forms of diverticulitis

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease), and is not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis maybe more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

Continuet to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

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

THE CASE

A 7-year-old boy presented with a one-week history of a pruritic rash, which first appeared on his back and continued to spread across his entire body. The patient’s medical history was significant for a scalp lesion (FIGURE 1) that was being treated with oral griseofulvin (started 3 days earlier). He had no history of seasonal allergies, asthma, recent illness, or recent immunizations.

The physical exam was significant for a body-wide, nonerythematous, papular rash (FIGURE 2). There was evidence of excoriation due to itching. No mucosal involvement was appreciated. The remainder of the examination was unremarkable.

QUESTION

Based on the patient’s history and physical exam, which of the following is the most likely diagnosis?

A. Gianotti-Crosti syndrome

B. Atopic dermatitis

C. Dermatophytid reaction

D. Morbilliform drug eruption.

Continue to: THE DIAGNOSIS

The answer is C, dermatophytid reaction.

DISCUSSION

A dermatophytid reaction is a type of id reaction, or autoeczematization. An id reaction is when a localized dermatitis becomes a generalized pruritic eruption.¹ In this case, the patient’s dermatitis was the result of a dermatophyte infection (tinea capitis), but an id reaction can also occur in response to noninfectious dermatitides and may be of an atopic, contact, or seborrheic nature.¹

Dermatophytid reactions occur in up to 5% of all dermatophyte infections (most commonly tinea pedis) and are proposed to be type IV hypersensitivity reactions to the release of fungal antigens.¹ These reactions can occur either before or after the initiation of antifungal treatment. They manifest as symmetric, pruritic, papulovesicular eruptions with fine scaling and commonly affect the face, trunk, extremities, palms, and interdigital spaces.¹

What about other possible diagnoses?

Gianotti-Crosti syndrome is an asymptomatic, symmetric, papulovesicular dermatosis that involves the face, limbs, and buttocks of children 2 to 6 years of age.² The lesions develop in response to a respiratory or gastrointestinal illness.² They are typically associated with Epstein-Barr virus, hepatitis B, cytomegalovirus, respiratory syncytial virus, and coxsackievirus, but can occur with bacterial infections or following administration of routine immunizations.²

While the initial impulse may be to discontinue oral antifungals, these treatments help resolve the underlying dermatophyte infection and should be continued.

The lesions are self-limited and resolve within 2 months.² Symptomatic lesions may be treated with oral antihistamines or steroids (topical or systemic).²

Continue to: Atopic dermatitis

Atopic dermatitis is characterized by symmetric involvement of the flexural sur­faces of the body with a pruritic, erythematous rash that may have a fine scale.³ It usually manifests prior to 2 years of age, is recurrent, and is commonly associated with allergic rhinitis and asthma.³ Treatment involves trigger avoidance, topical emollients, topical corticosteroids, dilute bleach baths, and topical calcineurin inhibitors.^3,4 For patients with significant nocturnal symptoms and sleep loss, oral antihistamines may be helpful.⁴

Morbilliform drug eruptions are the most common type of dermatologic drug reaction.⁵ These rashes occur approximately one to 2 weeks after exposure to a causative drug; they consist of pruritic, erythematous papules or macules that start centrally and may spread to the proximal extremities.⁵ Treatment involves discontinuation of the offending agent. Symptomatic relief may be achieved with oral antihistamines or topical or systemic corticosteroids.⁵

Treatment of dermatophytid reactions

While the initial impulse in the treatment of a dermatophytid reaction may be to discon­tinue oral antifungals, these treatments actually help resolve the underlying dermatophyte infection and should be continued. For children with tinea capitis, at least 6 weeks of treatment with an oral antifungal agent is warranted. Medications approved by the US Food and Drug Administration include terbinafine (for patients >4 years of age) and griseofulvin (for patients >2 years of age). Dosages are weight-based. (Fluconazole and itraconazole are not approved for this indication.) Lubricants, topical corticosteroids, and oral antihistamines can be used for acute management of pruritus.¹

Our patient was treated successfully with griseofulvin and an oral antihistamine. However, he experienced headaches attrib­uted to griseofulvin and was switched to terbinafine 5 mg/kg/d for 4 weeks. His tinea capitis was resolved at 8 weeks.

CORRESPONDENCE
Richard Temple, MD, CAPT, MC, USN. Department of Family Medicine, Naval Medical Center Camp Lejeune, 100 Brewster Blvd, Camp Lejeune, NC 28547; [email protected].

THE CASE

A 7-year-old boy presented with a one-week history of a pruritic rash, which first appeared on his back and continued to spread across his entire body. The patient’s medical history was significant for a scalp lesion (FIGURE 1) that was being treated with oral griseofulvin (started 3 days earlier). He had no history of seasonal allergies, asthma, recent illness, or recent immunizations.

The physical exam was significant for a body-wide, nonerythematous, papular rash (FIGURE 2). There was evidence of excoriation due to itching. No mucosal involvement was appreciated. The remainder of the examination was unremarkable.

QUESTION

Based on the patient’s history and physical exam, which of the following is the most likely diagnosis?

A. Gianotti-Crosti syndrome

B. Atopic dermatitis

C. Dermatophytid reaction

D. Morbilliform drug eruption.

Continue to: THE DIAGNOSIS

The answer is C, dermatophytid reaction.

DISCUSSION

A dermatophytid reaction is a type of id reaction, or autoeczematization. An id reaction is when a localized dermatitis becomes a generalized pruritic eruption.¹ In this case, the patient’s dermatitis was the result of a dermatophyte infection (tinea capitis), but an id reaction can also occur in response to noninfectious dermatitides and may be of an atopic, contact, or seborrheic nature.¹

Dermatophytid reactions occur in up to 5% of all dermatophyte infections (most commonly tinea pedis) and are proposed to be type IV hypersensitivity reactions to the release of fungal antigens.¹ These reactions can occur either before or after the initiation of antifungal treatment. They manifest as symmetric, pruritic, papulovesicular eruptions with fine scaling and commonly affect the face, trunk, extremities, palms, and interdigital spaces.¹

What about other possible diagnoses?

Gianotti-Crosti syndrome is an asymptomatic, symmetric, papulovesicular dermatosis that involves the face, limbs, and buttocks of children 2 to 6 years of age.² The lesions develop in response to a respiratory or gastrointestinal illness.² They are typically associated with Epstein-Barr virus, hepatitis B, cytomegalovirus, respiratory syncytial virus, and coxsackievirus, but can occur with bacterial infections or following administration of routine immunizations.²

While the initial impulse may be to discontinue oral antifungals, these treatments help resolve the underlying dermatophyte infection and should be continued.

The lesions are self-limited and resolve within 2 months.² Symptomatic lesions may be treated with oral antihistamines or steroids (topical or systemic).²

Continue to: Atopic dermatitis

Atopic dermatitis is characterized by symmetric involvement of the flexural sur­faces of the body with a pruritic, erythematous rash that may have a fine scale.³ It usually manifests prior to 2 years of age, is recurrent, and is commonly associated with allergic rhinitis and asthma.³ Treatment involves trigger avoidance, topical emollients, topical corticosteroids, dilute bleach baths, and topical calcineurin inhibitors.^3,4 For patients with significant nocturnal symptoms and sleep loss, oral antihistamines may be helpful.⁴

Morbilliform drug eruptions are the most common type of dermatologic drug reaction.⁵ These rashes occur approximately one to 2 weeks after exposure to a causative drug; they consist of pruritic, erythematous papules or macules that start centrally and may spread to the proximal extremities.⁵ Treatment involves discontinuation of the offending agent. Symptomatic relief may be achieved with oral antihistamines or topical or systemic corticosteroids.⁵

Treatment of dermatophytid reactions

While the initial impulse in the treatment of a dermatophytid reaction may be to discon­tinue oral antifungals, these treatments actually help resolve the underlying dermatophyte infection and should be continued. For children with tinea capitis, at least 6 weeks of treatment with an oral antifungal agent is warranted. Medications approved by the US Food and Drug Administration include terbinafine (for patients >4 years of age) and griseofulvin (for patients >2 years of age). Dosages are weight-based. (Fluconazole and itraconazole are not approved for this indication.) Lubricants, topical corticosteroids, and oral antihistamines can be used for acute management of pruritus.¹

Our patient was treated successfully with griseofulvin and an oral antihistamine. However, he experienced headaches attrib­uted to griseofulvin and was switched to terbinafine 5 mg/kg/d for 4 weeks. His tinea capitis was resolved at 8 weeks.

CORRESPONDENCE
Richard Temple, MD, CAPT, MC, USN. Department of Family Medicine, Naval Medical Center Camp Lejeune, 100 Brewster Blvd, Camp Lejeune, NC 28547; [email protected].

THE CASE

A 7-year-old boy presented with a one-week history of a pruritic rash, which first appeared on his back and continued to spread across his entire body. The patient’s medical history was significant for a scalp lesion (FIGURE 1) that was being treated with oral griseofulvin (started 3 days earlier). He had no history of seasonal allergies, asthma, recent illness, or recent immunizations.

The physical exam was significant for a body-wide, nonerythematous, papular rash (FIGURE 2). There was evidence of excoriation due to itching. No mucosal involvement was appreciated. The remainder of the examination was unremarkable.

QUESTION

Based on the patient’s history and physical exam, which of the following is the most likely diagnosis?

A. Gianotti-Crosti syndrome

B. Atopic dermatitis

C. Dermatophytid reaction

D. Morbilliform drug eruption.

Continue to: THE DIAGNOSIS

The answer is C, dermatophytid reaction.

DISCUSSION

A dermatophytid reaction is a type of id reaction, or autoeczematization. An id reaction is when a localized dermatitis becomes a generalized pruritic eruption.¹ In this case, the patient’s dermatitis was the result of a dermatophyte infection (tinea capitis), but an id reaction can also occur in response to noninfectious dermatitides and may be of an atopic, contact, or seborrheic nature.¹

Dermatophytid reactions occur in up to 5% of all dermatophyte infections (most commonly tinea pedis) and are proposed to be type IV hypersensitivity reactions to the release of fungal antigens.¹ These reactions can occur either before or after the initiation of antifungal treatment. They manifest as symmetric, pruritic, papulovesicular eruptions with fine scaling and commonly affect the face, trunk, extremities, palms, and interdigital spaces.¹

What about other possible diagnoses?

Gianotti-Crosti syndrome is an asymptomatic, symmetric, papulovesicular dermatosis that involves the face, limbs, and buttocks of children 2 to 6 years of age.² The lesions develop in response to a respiratory or gastrointestinal illness.² They are typically associated with Epstein-Barr virus, hepatitis B, cytomegalovirus, respiratory syncytial virus, and coxsackievirus, but can occur with bacterial infections or following administration of routine immunizations.²

While the initial impulse may be to discontinue oral antifungals, these treatments help resolve the underlying dermatophyte infection and should be continued.

The lesions are self-limited and resolve within 2 months.² Symptomatic lesions may be treated with oral antihistamines or steroids (topical or systemic).²

Continue to: Atopic dermatitis

Atopic dermatitis is characterized by symmetric involvement of the flexural sur­faces of the body with a pruritic, erythematous rash that may have a fine scale.³ It usually manifests prior to 2 years of age, is recurrent, and is commonly associated with allergic rhinitis and asthma.³ Treatment involves trigger avoidance, topical emollients, topical corticosteroids, dilute bleach baths, and topical calcineurin inhibitors.^3,4 For patients with significant nocturnal symptoms and sleep loss, oral antihistamines may be helpful.⁴

Morbilliform drug eruptions are the most common type of dermatologic drug reaction.⁵ These rashes occur approximately one to 2 weeks after exposure to a causative drug; they consist of pruritic, erythematous papules or macules that start centrally and may spread to the proximal extremities.⁵ Treatment involves discontinuation of the offending agent. Symptomatic relief may be achieved with oral antihistamines or topical or systemic corticosteroids.⁵

Treatment of dermatophytid reactions

While the initial impulse in the treatment of a dermatophytid reaction may be to discon­tinue oral antifungals, these treatments actually help resolve the underlying dermatophyte infection and should be continued. For children with tinea capitis, at least 6 weeks of treatment with an oral antifungal agent is warranted. Medications approved by the US Food and Drug Administration include terbinafine (for patients >4 years of age) and griseofulvin (for patients >2 years of age). Dosages are weight-based. (Fluconazole and itraconazole are not approved for this indication.) Lubricants, topical corticosteroids, and oral antihistamines can be used for acute management of pruritus.¹

Our patient was treated successfully with griseofulvin and an oral antihistamine. However, he experienced headaches attrib­uted to griseofulvin and was switched to terbinafine 5 mg/kg/d for 4 weeks. His tinea capitis was resolved at 8 weeks.

CORRESPONDENCE
Richard Temple, MD, CAPT, MC, USN. Department of Family Medicine, Naval Medical Center Camp Lejeune, 100 Brewster Blvd, Camp Lejeune, NC 28547; [email protected].

Diabetes affects approximately 9.4% of the US population (more than 30 million people),¹ and it is one of the most common conditions treated by family physicians. Additionally, more than 80 million Americans meet the criteria for prediabetes.¹ The prevalence of diabetes has increased in adults between the time periods 1988-1994 and 2011-2014, and it varies by race and ethnicity, with the highest prevalence, 18%, among African Americans and Mexican Americans, and the lowest, 9.6%, among non-Hispanic whites (FIGURE).²

Diet is the cornerstone of diabetes treatment

The foundation of a comprehensive management plan for type 2 diabetes mellitus (T2DM) is an appropriate diet. A growing body of evidence shows that a well-structured diet is important in controlling diabetes, delaying or preventing the onset of diabetes, and, in some instances, contributing to its remission. Diabetes UK, the United Kingdom’s equivalent of the American Diabetes Association (ADA), recently updated its clinical guideline for physicians and patients on the role of nutrition in managing and preventing diabetes, and it is consistent with one published by the ADA in 2013.^3,4

The Diabetes UK guideline is the result of an evidence-based process that meets the standards recommended by the National Academy of Medicine (previously the Institute of Medicine): a systematic review and formal assessment of the quality of the evidence, and recommendations based on the highest quality evidence available, with the level of evidence stated for each recommendation.⁵ Assessing the level of evidence and determining the strengths of recommendations were done using the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) system, which uses an approach similar to that of the Strength of Recommendation Taxonomy (SORT).

What, and what not, to focus on. The first set of recommendations states that everyone with, or at risk for, diabetes should receive structured, personalized, and ongoing nutritional advice from a dietician who is coordinated with their clinical care. Nutritional advice should focus on the quality and quantity of food, not on specific nutrients (fat and carbohydrates), since there is no good evidence on what proportion of such nutrients is optimal. And it should be tailored to the culture and eating preferences of the patient.

The type of diet with the strongest evidence base for preventing T2DM is a Mediterranean diet, which is supported by level-4, high-quality evidence. Important aspects of a Mediterranean diet are the regular consumption of nuts, whole grains, fruits, and vegetables; use of olive oil instead of butter; and favoring fish over red meat.⁶ Other dietary patterns associated with reduced risk but supported only by level-2, low-quality evidence, include Dietary Approaches to Stop Hypertension (DASH), vegetarian, vegan, and Nordic healthy diets. Moderate carbohydrate restriction is supported only by level-1, very low-quality evidence.

The UK guideline, too, recommends preferentially eating whole grains, fruits, and green leafy vegetables, as well as yogurt, cheese, tea, and coffee. And it advises reducing consumption of red processed meats, potatoes (especially French fries), sugar-sweetened beverages, and refined carbohydrates. However, these specific food preferences are supported only by low-level evidence. Both Diabetes UK and the ADA recommend minimizing consumption of free sugars and added fructose, in addition to sugar-sweetened drinks, but conclude that artificial sweeteners are safe and can be recommended. Both organizations also recommend against the use of vitamins and minerals to manage or prevent diabetes and against protein restriction for those with diabetic nephropathy.

Plant stanols and plant sterols are found in a variety of plant foods such as cereals, vegetable oils, seeds, and nuts, and are now being added to some food products. (For more on plant stanols and plant sterols.) They have a chemical structure similar to cholesterol and reduce the intestinal absorption of cholesterol, thereby lowering total serum cholesterol and LDL-cholesterol. Both Diabetes UK and the ADA recommend 2 to 3 grams of stanols/sterols per day.

Continue to: Alcohol intake

Alcohol intake. And what about alcohol intake in those with T2DM? Once again, both guidelines are in concert by stating that alcohol use in those with diabetes should be moderate, defined by the ADA as one or fewer drinks/d for women and 2 or fewer for men.

Weight loss and exercise are important, too. Those who are overweight or obese with T2DM can improve glycemic control with a 5% weight loss achieved by reducing caloric intake and by increasing energy expenditure with 150 minutes of moderate physical activity per week over at least 3 days.³ This recommendation is supported by high-quality evidence.

A 15-kg weight loss is recommended for those attempting diabetes remission (supported by moderate-level evidence).³ One small study in the United Kingdom found that more than half of those with T2DM could achieve remission with weight loss of 10 kg or more; 86% with weight loss of 15 kg or more.⁷ The Diabetes UK guideline panel rated this as having moderate-level evidence.

The bottom line. Diet and exercise are key interventions for the prevention and treatment of diabetes and can lead to remission if sufficient weight loss is achieved. To achieve and maintain an optimal diet, patients need individualized professional advice and followup. The evidence base for nutritional advice is growing and can be used to improve the quality of these patient-provider interactions.

Diabetes affects approximately 9.4% of the US population (more than 30 million people),¹ and it is one of the most common conditions treated by family physicians. Additionally, more than 80 million Americans meet the criteria for prediabetes.¹ The prevalence of diabetes has increased in adults between the time periods 1988-1994 and 2011-2014, and it varies by race and ethnicity, with the highest prevalence, 18%, among African Americans and Mexican Americans, and the lowest, 9.6%, among non-Hispanic whites (FIGURE).²

Diet is the cornerstone of diabetes treatment

The foundation of a comprehensive management plan for type 2 diabetes mellitus (T2DM) is an appropriate diet. A growing body of evidence shows that a well-structured diet is important in controlling diabetes, delaying or preventing the onset of diabetes, and, in some instances, contributing to its remission. Diabetes UK, the United Kingdom’s equivalent of the American Diabetes Association (ADA), recently updated its clinical guideline for physicians and patients on the role of nutrition in managing and preventing diabetes, and it is consistent with one published by the ADA in 2013.^3,4

The Diabetes UK guideline is the result of an evidence-based process that meets the standards recommended by the National Academy of Medicine (previously the Institute of Medicine): a systematic review and formal assessment of the quality of the evidence, and recommendations based on the highest quality evidence available, with the level of evidence stated for each recommendation.⁵ Assessing the level of evidence and determining the strengths of recommendations were done using the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) system, which uses an approach similar to that of the Strength of Recommendation Taxonomy (SORT).

What, and what not, to focus on. The first set of recommendations states that everyone with, or at risk for, diabetes should receive structured, personalized, and ongoing nutritional advice from a dietician who is coordinated with their clinical care. Nutritional advice should focus on the quality and quantity of food, not on specific nutrients (fat and carbohydrates), since there is no good evidence on what proportion of such nutrients is optimal. And it should be tailored to the culture and eating preferences of the patient.

The type of diet with the strongest evidence base for preventing T2DM is a Mediterranean diet, which is supported by level-4, high-quality evidence. Important aspects of a Mediterranean diet are the regular consumption of nuts, whole grains, fruits, and vegetables; use of olive oil instead of butter; and favoring fish over red meat.⁶ Other dietary patterns associated with reduced risk but supported only by level-2, low-quality evidence, include Dietary Approaches to Stop Hypertension (DASH), vegetarian, vegan, and Nordic healthy diets. Moderate carbohydrate restriction is supported only by level-1, very low-quality evidence.

The UK guideline, too, recommends preferentially eating whole grains, fruits, and green leafy vegetables, as well as yogurt, cheese, tea, and coffee. And it advises reducing consumption of red processed meats, potatoes (especially French fries), sugar-sweetened beverages, and refined carbohydrates. However, these specific food preferences are supported only by low-level evidence. Both Diabetes UK and the ADA recommend minimizing consumption of free sugars and added fructose, in addition to sugar-sweetened drinks, but conclude that artificial sweeteners are safe and can be recommended. Both organizations also recommend against the use of vitamins and minerals to manage or prevent diabetes and against protein restriction for those with diabetic nephropathy.

Plant stanols and plant sterols are found in a variety of plant foods such as cereals, vegetable oils, seeds, and nuts, and are now being added to some food products. (For more on plant stanols and plant sterols.) They have a chemical structure similar to cholesterol and reduce the intestinal absorption of cholesterol, thereby lowering total serum cholesterol and LDL-cholesterol. Both Diabetes UK and the ADA recommend 2 to 3 grams of stanols/sterols per day.

Continue to: Alcohol intake

Alcohol intake. And what about alcohol intake in those with T2DM? Once again, both guidelines are in concert by stating that alcohol use in those with diabetes should be moderate, defined by the ADA as one or fewer drinks/d for women and 2 or fewer for men.

Weight loss and exercise are important, too. Those who are overweight or obese with T2DM can improve glycemic control with a 5% weight loss achieved by reducing caloric intake and by increasing energy expenditure with 150 minutes of moderate physical activity per week over at least 3 days.³ This recommendation is supported by high-quality evidence.

A 15-kg weight loss is recommended for those attempting diabetes remission (supported by moderate-level evidence).³ One small study in the United Kingdom found that more than half of those with T2DM could achieve remission with weight loss of 10 kg or more; 86% with weight loss of 15 kg or more.⁷ The Diabetes UK guideline panel rated this as having moderate-level evidence.

The bottom line. Diet and exercise are key interventions for the prevention and treatment of diabetes and can lead to remission if sufficient weight loss is achieved. To achieve and maintain an optimal diet, patients need individualized professional advice and followup. The evidence base for nutritional advice is growing and can be used to improve the quality of these patient-provider interactions.

Diabetes affects approximately 9.4% of the US population (more than 30 million people),¹ and it is one of the most common conditions treated by family physicians. Additionally, more than 80 million Americans meet the criteria for prediabetes.¹ The prevalence of diabetes has increased in adults between the time periods 1988-1994 and 2011-2014, and it varies by race and ethnicity, with the highest prevalence, 18%, among African Americans and Mexican Americans, and the lowest, 9.6%, among non-Hispanic whites (FIGURE).²

Diet is the cornerstone of diabetes treatment

The foundation of a comprehensive management plan for type 2 diabetes mellitus (T2DM) is an appropriate diet. A growing body of evidence shows that a well-structured diet is important in controlling diabetes, delaying or preventing the onset of diabetes, and, in some instances, contributing to its remission. Diabetes UK, the United Kingdom’s equivalent of the American Diabetes Association (ADA), recently updated its clinical guideline for physicians and patients on the role of nutrition in managing and preventing diabetes, and it is consistent with one published by the ADA in 2013.^3,4

The Diabetes UK guideline is the result of an evidence-based process that meets the standards recommended by the National Academy of Medicine (previously the Institute of Medicine): a systematic review and formal assessment of the quality of the evidence, and recommendations based on the highest quality evidence available, with the level of evidence stated for each recommendation.⁵ Assessing the level of evidence and determining the strengths of recommendations were done using the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) system, which uses an approach similar to that of the Strength of Recommendation Taxonomy (SORT).

What, and what not, to focus on. The first set of recommendations states that everyone with, or at risk for, diabetes should receive structured, personalized, and ongoing nutritional advice from a dietician who is coordinated with their clinical care. Nutritional advice should focus on the quality and quantity of food, not on specific nutrients (fat and carbohydrates), since there is no good evidence on what proportion of such nutrients is optimal. And it should be tailored to the culture and eating preferences of the patient.

The type of diet with the strongest evidence base for preventing T2DM is a Mediterranean diet, which is supported by level-4, high-quality evidence. Important aspects of a Mediterranean diet are the regular consumption of nuts, whole grains, fruits, and vegetables; use of olive oil instead of butter; and favoring fish over red meat.⁶ Other dietary patterns associated with reduced risk but supported only by level-2, low-quality evidence, include Dietary Approaches to Stop Hypertension (DASH), vegetarian, vegan, and Nordic healthy diets. Moderate carbohydrate restriction is supported only by level-1, very low-quality evidence.

The UK guideline, too, recommends preferentially eating whole grains, fruits, and green leafy vegetables, as well as yogurt, cheese, tea, and coffee. And it advises reducing consumption of red processed meats, potatoes (especially French fries), sugar-sweetened beverages, and refined carbohydrates. However, these specific food preferences are supported only by low-level evidence. Both Diabetes UK and the ADA recommend minimizing consumption of free sugars and added fructose, in addition to sugar-sweetened drinks, but conclude that artificial sweeteners are safe and can be recommended. Both organizations also recommend against the use of vitamins and minerals to manage or prevent diabetes and against protein restriction for those with diabetic nephropathy.

Plant stanols and plant sterols are found in a variety of plant foods such as cereals, vegetable oils, seeds, and nuts, and are now being added to some food products. (For more on plant stanols and plant sterols.) They have a chemical structure similar to cholesterol and reduce the intestinal absorption of cholesterol, thereby lowering total serum cholesterol and LDL-cholesterol. Both Diabetes UK and the ADA recommend 2 to 3 grams of stanols/sterols per day.

Continue to: Alcohol intake

Alcohol intake. And what about alcohol intake in those with T2DM? Once again, both guidelines are in concert by stating that alcohol use in those with diabetes should be moderate, defined by the ADA as one or fewer drinks/d for women and 2 or fewer for men.

Weight loss and exercise are important, too. Those who are overweight or obese with T2DM can improve glycemic control with a 5% weight loss achieved by reducing caloric intake and by increasing energy expenditure with 150 minutes of moderate physical activity per week over at least 3 days.³ This recommendation is supported by high-quality evidence.

A 15-kg weight loss is recommended for those attempting diabetes remission (supported by moderate-level evidence).³ One small study in the United Kingdom found that more than half of those with T2DM could achieve remission with weight loss of 10 kg or more; 86% with weight loss of 15 kg or more.⁷ The Diabetes UK guideline panel rated this as having moderate-level evidence.

The bottom line. Diet and exercise are key interventions for the prevention and treatment of diabetes and can lead to remission if sufficient weight loss is achieved. To achieve and maintain an optimal diet, patients need individualized professional advice and followup. The evidence base for nutritional advice is growing and can be used to improve the quality of these patient-provider interactions.