Reviews

As do women from a wide range of cultures, South Asian (SA) women frequently report feelings of shame associated with receiving a psychiatric diagnosis during the postpartum period because they fear it may reflect poorly on their ability to be good mothers or negatively impact their family’s reputation. To improve outcomes for these patients, clinicians should strive to provide culturally competent care. Based on our experience caring for SA women, we review several social and cultural barriers these women face when seeking psychiatric treatment, and provide approaches to incorporate into your therapeutic interactions with them.

Be aware of psychosomatic presentations. SA mothers who develop postpartum psychiatric symptoms might not present with complaints of dysphoria, crying, low energy, or suicidal thoughts. They may instead describe psychosomatic symptoms such as headaches and body pains.

Consider their hesitation to use psychiatric terms. SA women may not be comfortable using psychiatric terms such as depression or anxiety. Instead, they might respond more positively when their preferred descriptive terms (ie, sadness, worry, stress) are used by the clinicians who treat them.

Engage the partner and/or family. SA women may emphasize that they are part of a family unit, rather than regarding themselves as individuals. Thus, including family members in the treatment plan may help improve adherence.

Screen for suicide risk. Evidence suggests that young SA women have a higher rate of suicide and suicide attempts than young SA men or non-SA women.^1,2 Further, they may be less willing to speak openly about it.

Ask questions about cultural or traditional forms of treatment. SA mothers, particularly those who are breastfeeding, might be wary of Western medicine and may be familiar with traditional Indian medicine practices such as herbal, homeopathic, or Ayurvedic approaches.³ These interventions may include a specified diet, use of herbal treatments, exercise, and lifestyle recommendations.When taking the patient’s history, find out which treatments she is currently using, and discuss whether she can safely continue to use them.

Do not mistake poor eye contact for lack of engagement. Because SA patients may view a physician as a source of authority, they might regard direct eye contact with a physician as being somewhat disrespectful, and they may avoid eye contact altogether.

Continue to: Maintain an active approach

Maintain an active approach. SA women may prefer to view the physician as an expert, rather than a partner with whom to develop a collaborative relationship. Thus, they may feel more comfortable with direct feedback rather than a passive or reflective approach.

Suggest a postpartum support group. In a U.K. study of 17 SA postpartum women, age 20 to 45, group therapy improved health outcomes and overall satisfaction.⁴ It may be particularly helpful to SA patients if group therapy is facilitated by a culturally sensitive moderator.

Help patients overcome logistical barriers. Lack of transportation, childcare difficulties, and financial limitations are common deterrents to treatment. These barriers may be particularly challenging for SA women of lower socioeconomic status. Postpartum mothers who feel overtasked with caring for their children and undertaking household duties may feel less able to complete therapy.

Screen for adherence. Although SA patients may view clinicians as authority figures, adherence with medications or treatment plans should not be assumed. Many patients may quietly avoid treatments or recommendations instead of discussing their ambivalence with their clinicians.

As do women from a wide range of cultures, South Asian (SA) women frequently report feelings of shame associated with receiving a psychiatric diagnosis during the postpartum period because they fear it may reflect poorly on their ability to be good mothers or negatively impact their family’s reputation. To improve outcomes for these patients, clinicians should strive to provide culturally competent care. Based on our experience caring for SA women, we review several social and cultural barriers these women face when seeking psychiatric treatment, and provide approaches to incorporate into your therapeutic interactions with them.

Be aware of psychosomatic presentations. SA mothers who develop postpartum psychiatric symptoms might not present with complaints of dysphoria, crying, low energy, or suicidal thoughts. They may instead describe psychosomatic symptoms such as headaches and body pains.

Consider their hesitation to use psychiatric terms. SA women may not be comfortable using psychiatric terms such as depression or anxiety. Instead, they might respond more positively when their preferred descriptive terms (ie, sadness, worry, stress) are used by the clinicians who treat them.

Engage the partner and/or family. SA women may emphasize that they are part of a family unit, rather than regarding themselves as individuals. Thus, including family members in the treatment plan may help improve adherence.

Screen for suicide risk. Evidence suggests that young SA women have a higher rate of suicide and suicide attempts than young SA men or non-SA women.^1,2 Further, they may be less willing to speak openly about it.

Ask questions about cultural or traditional forms of treatment. SA mothers, particularly those who are breastfeeding, might be wary of Western medicine and may be familiar with traditional Indian medicine practices such as herbal, homeopathic, or Ayurvedic approaches.³ These interventions may include a specified diet, use of herbal treatments, exercise, and lifestyle recommendations.When taking the patient’s history, find out which treatments she is currently using, and discuss whether she can safely continue to use them.

Do not mistake poor eye contact for lack of engagement. Because SA patients may view a physician as a source of authority, they might regard direct eye contact with a physician as being somewhat disrespectful, and they may avoid eye contact altogether.

Continue to: Maintain an active approach

Maintain an active approach. SA women may prefer to view the physician as an expert, rather than a partner with whom to develop a collaborative relationship. Thus, they may feel more comfortable with direct feedback rather than a passive or reflective approach.

Suggest a postpartum support group. In a U.K. study of 17 SA postpartum women, age 20 to 45, group therapy improved health outcomes and overall satisfaction.⁴ It may be particularly helpful to SA patients if group therapy is facilitated by a culturally sensitive moderator.

Help patients overcome logistical barriers. Lack of transportation, childcare difficulties, and financial limitations are common deterrents to treatment. These barriers may be particularly challenging for SA women of lower socioeconomic status. Postpartum mothers who feel overtasked with caring for their children and undertaking household duties may feel less able to complete therapy.

Screen for adherence. Although SA patients may view clinicians as authority figures, adherence with medications or treatment plans should not be assumed. Many patients may quietly avoid treatments or recommendations instead of discussing their ambivalence with their clinicians.

As do women from a wide range of cultures, South Asian (SA) women frequently report feelings of shame associated with receiving a psychiatric diagnosis during the postpartum period because they fear it may reflect poorly on their ability to be good mothers or negatively impact their family’s reputation. To improve outcomes for these patients, clinicians should strive to provide culturally competent care. Based on our experience caring for SA women, we review several social and cultural barriers these women face when seeking psychiatric treatment, and provide approaches to incorporate into your therapeutic interactions with them.

Be aware of psychosomatic presentations. SA mothers who develop postpartum psychiatric symptoms might not present with complaints of dysphoria, crying, low energy, or suicidal thoughts. They may instead describe psychosomatic symptoms such as headaches and body pains.

Consider their hesitation to use psychiatric terms. SA women may not be comfortable using psychiatric terms such as depression or anxiety. Instead, they might respond more positively when their preferred descriptive terms (ie, sadness, worry, stress) are used by the clinicians who treat them.

Engage the partner and/or family. SA women may emphasize that they are part of a family unit, rather than regarding themselves as individuals. Thus, including family members in the treatment plan may help improve adherence.

Screen for suicide risk. Evidence suggests that young SA women have a higher rate of suicide and suicide attempts than young SA men or non-SA women.^1,2 Further, they may be less willing to speak openly about it.

Ask questions about cultural or traditional forms of treatment. SA mothers, particularly those who are breastfeeding, might be wary of Western medicine and may be familiar with traditional Indian medicine practices such as herbal, homeopathic, or Ayurvedic approaches.³ These interventions may include a specified diet, use of herbal treatments, exercise, and lifestyle recommendations.When taking the patient’s history, find out which treatments she is currently using, and discuss whether she can safely continue to use them.

Do not mistake poor eye contact for lack of engagement. Because SA patients may view a physician as a source of authority, they might regard direct eye contact with a physician as being somewhat disrespectful, and they may avoid eye contact altogether.

Continue to: Maintain an active approach

Maintain an active approach. SA women may prefer to view the physician as an expert, rather than a partner with whom to develop a collaborative relationship. Thus, they may feel more comfortable with direct feedback rather than a passive or reflective approach.

Suggest a postpartum support group. In a U.K. study of 17 SA postpartum women, age 20 to 45, group therapy improved health outcomes and overall satisfaction.⁴ It may be particularly helpful to SA patients if group therapy is facilitated by a culturally sensitive moderator.

Help patients overcome logistical barriers. Lack of transportation, childcare difficulties, and financial limitations are common deterrents to treatment. These barriers may be particularly challenging for SA women of lower socioeconomic status. Postpartum mothers who feel overtasked with caring for their children and undertaking household duties may feel less able to complete therapy.

Screen for adherence. Although SA patients may view clinicians as authority figures, adherence with medications or treatment plans should not be assumed. Many patients may quietly avoid treatments or recommendations instead of discussing their ambivalence with their clinicians.

The loss of a loved one to suicide is often experienced as “devastating.”¹ While survivors of suicide loss may be able to move through the grief process without clinical support,² the traumatic and stigmatizing nature of suicide is likely to make its aftermath more challenging to navigate than other types of loss. Sanford et al³ found that more than two-thirds of suicide loss survivors sought therapy after their loss. Further, when individuals facing these challenges present for treatment, clinicians often face challenges of their own.

Very few clinicians are trained in general grief processes,⁴ and even those specifically trained in grief and loss have been shown to “miss” several of the common clinical features that are unique to suicide loss.³ In my professional experience, the intensity and duration of suicide grief are often greater than they are for other losses, and many survivors of suicide loss have reported that others, including clinicians, have “pathologized” this, rather than having understood it as normative under the circumstances.

Although there is extensive literature on the aftermath of suicide for surviving loved ones, very few controlled studies have assessed interventions specifically for this population. Yet the U.S. Guidelines for Suicide Postvention⁵ explicitly call for improved training for those who work with suicide loss survivors, as well as research on these interventions. Jordan and McGann⁶ noted, “Without a full knowledge of suicide and its aftermath, it is very possible to make clinical errors which can hamper treatment.” This article summarizes what is currently known about the general experience of suicide bereavement and optimal interventions in treatment.

What makes suicide loss unique?

Suicide bereavement is distinct from other types of loss in 3 significant ways⁷:

• the thematic content of the grief
• the social processes surrounding the survivor
• the impact that suicide has on family systems.

Additionally, the perceived intentionality and preventability of a suicide death, as well as its stigmatized and traumatic nature, differentiate it from other types of traumatic loss.⁷ These elements are all likely to affect the nature, intensity, and duration of the grief.

Stigma and suicide. Stigma associated with suicide is well documented.⁸ Former U.S. Surgeon General David Satcher⁹ specifically described stigma toward suicide as one of the biggest barriers to prevention. In addition, researchers have found that the stigma associated with suicide “spills over” to the bereaved family members. Doka^10,11 refers to “disenfranchised grief,” in which bereaved individuals receive the message that their grief is not legitimate, and as a result, they are likely to internalize this view. Studies have shown that individuals bereaved by suicide are also stigmatized, and are believed to be more psychologically disturbed, less likable, more blameworthy, more ashamed, and more in need of professional help than other bereaved individuals.^8,12-20

These judgments often mirror suicide loss survivors’ self-punitive assessments, which then become exacerbated by and intertwined with both externally imposed and internalized stigma. Thus, it is not uncommon for survivors of suicide loss to question their own right to grieve, to report low expectations of social support, and to feel compelled to deny or hide the mode of death. To the extent that they are actively grieving, survivors of suicide loss often feel that they must do so in isolation. Thus, the perception of stigma, whether external or internalized, can have a profound effect on decisions about disclosure, requesting support, and ultimately on one’s ability to integrate the loss. Indeed, Feigelman et al²¹ found that stigmatization after suicide was specifically associated with ongoing grief difficulties, depression, and suicidal ideation.

Continue to: Traumatic nature of suicide

Traumatic nature of suicide. Suicide loss is also quite traumatic, and posttraumatic stress disorder (PTSD) symptoms such as shock, horror, disbelief, and intrusive/perseverative thoughts and questions, particularly in the earlier stages of grief, are common. Sanford et al³ found that the higher the level of “perceived closeness” to the deceased, the more likely that survivors of suicide loss would experience PTSD symptoms. In addition, the dramatic loss of social support following a suicide loss may itself be traumatic, which can serve to compound these difficulties. Notably, Sanford et al³ found that even for those survivors of suicide loss in treatment who endorsed PTSD symptoms, many of their treating clinicians did not assess or diagnose this disorder, thus missing an important component for treatment.

Increased risk for suicidality. Studies have shown that individuals who have lost a loved one to suicide are themselves at heightened risk for suicidal ideation and behaviors.^22-27 Therefore, an assessment for suicide risk is always advisable. However, it is important to note that suicidal ideation is not uncommon and can serve different functions for survivors of suicide loss without necessarily progressing to a plan for acting on such ideations. Survivors of suicide loss may wish to “join” their loved one; to understand or identify with the mental state of the deceased; to punish themselves for failing to prevent the suicide; or to end their own pain through death. Therefore, it is crucial to assess the nature and function of expressed ideation (in addition to the presence or absence of plans) before assigning the level of risk.

Elements of suicide grief

After the loss of a loved one to suicide, the path to healing is often complex, with survivors of suicide loss enduring the following challenges:

Existential assumptions are shattered. Several authors^28-30 have found that suicide loss is also likely to shatter survivors’ existential assumptions regarding their worldviews, roles, and identities, as well as religious and spiritual beliefs. As one survivor of suicide loss in my practice noted, “The world is gone, nothing is predictable anymore, and it’s no longer safe to assume anything.” Others have described feeling “fragmented” in ways they had never before experienced, and many have reported difficulties in “trusting” their own judgment, the stability of the world, and relationships. “Why?” becomes an emergent and insistent question in the survivor’s efforts to understand the suicide and (ideally) reassemble a coherent narrative around the loss.

Increased duration and intensity of grief. The duration of the grief process is likely to be affected by the traumatic nature of suicide loss, the differential social support accorded to its survivors, and the difficulty in finding systems that can validate and normalize the unique elements in suicide bereavement. The stigmatized reactions of others, particularly when internalized, can present barriers to the processing of grief. In addition, the intensity of the trauma and existential impact, as well as the perseverative nature of several of the unique themes (Box 1), can also prolong the processing and increase the intensity of suicide grief. Clinicians would do well to recognize the relatively “normative” nature of the increased duration and intensity, rather than seeing it as immediately indicative of a DSM diagnosis of complicated/prolonged grief disorder.

Box 1
Common themes in the suicide grief process

Continue to: Family disruption

Family disruption. It is not uncommon for a suicide loss to result in family disruption.^6,31-32 This may manifest in the blaming of family members for “sins of omission or commission,”⁶ conflicts around the disclosure of the suicide both within and outside of the family, discordant grieving styles, and difficulties in understanding and attending to the needs of one’s children while grieving oneself.

Despite the common elements often seen in suicide grief, it is crucial to recognize that this process is not “one size fits all.” Not only are there individual variants, but Grad et al³³ found gender-based differences in grieving styles, and cultural issues such as the “meanings” assigned to suicide, and culturally sanctioned grief rituals and behaviors that are also likely to affect how grief is experienced and expressed. In addition, personal variants such as closeness/conflicts with the deceased, histories of previous trauma or loss, pre-existing psychiatric disorders, and attachment orientation³⁴ are likely to impact the grief process.

Losing close friends and colleagues may be similarly traumatic, but these survivors of suicide loss often receive even less social support than those who have kinship losses. Finally, when a suicide loss occurs in a professional capacity (such as the loss of a patient), this is likely to have many additional implications for one’s professional functions and identity.³⁵

Interventions to help survivors

Several goals and “tasks” are involved in the suicide bereavement process (Box 2^1,6,30,36-40). These can be achieved through the following interventions: Support groups. Many survivors find that support groups that focus on suicide loss are extremely helpful, and research has supported this.^1,4,41-44 Interactions with other suicide loss survivors provide hope, connection, and an “antidote” to stigma and shame. Optimally, group facilitators provide education, validation and normalization of the grief trajectory, and facilitate the sharing of both loss experiences and current functioning between group members. As a result, group participants often report renewed connections, increased efficacy in giving and accepting support, and decreased distress (including reductions in PTSD and depressive symptoms). The American Association of Suicidology (www.suicidology.org) and American Foundation of Suicide Prevention (www.afsp.org) provide contact information for suicide loss survivor groups (by geographical area) as well as information about online support groups.

Box 2
Goals and 'tasks' in suicide bereavement

Individual treatment. The limited research on individual treatment for suicide loss survivors suggests that while most participants find it generally helpful, a significant number of others report that their therapists lack knowledge of suicide grief and endorse stigmatizing attitudes toward suicide and suicide loss survivors.^45-46 In addition, Sanford et al³ found that survivors of suicide loss who endorsed PTSD symptoms were not assessed, diagnosed, or treated for these symptoms.

Continue to: This speaks to the importance of understanding what is...

This speaks to the importance of understanding what is “normative” for survivors of suicide loss. In general, “normalization” and psychoeducation about the suicide grief trajectory can play an important role in work with survivors of suicide loss, even in the presence of diagnosable disorders. While PTSD, depressive symptoms, and suicidal ideation are not uncommon in suicide loss survivors, and certainly may warrant clinical assessment and treatment, it can be helpful (and less stigmatizing) for your patients to know that these diagnoses are relatively common and understandable in the context of this devastating experience. For instance, survivors of suicide loss often report feeling relieved when clinicians explain the connections between traumatic loss and PTSD and/or depressive symptoms, and this can also help to relieve secondary anxiety about “going crazy.” Many survivors of suicide loss also describe feeling as though they are functioning on “autopilot” in the earlier stages of grief; it can help them understand the “function” of compartmentalization as potentially adaptive in the short run.

Suicide loss survivors may also find it helpful to learn about suicidal states of mind and their relationships to any types of mental illness their loved ones had struggled with.⁴⁷

Your role: Help survivors integrate the loss

Before beginning treatment with an individual who has lost a loved one to suicide, clinicians should thoroughly explore their own understanding of and experience with suicide, including assumptions around causation, internalized stigma about suicidal individuals and survivors of suicide loss, their own history of suicide loss or suicidality, cultural/religious attitudes, and anxiety/defenses associated with the topic of suicide. These factors, particularly when unexamined, are likely to impact the treatment relationship and one’s clinical efficacy.

In concert with the existing literature, consider the potential goals and tasks involved in the integration of the individual’s suicide loss, along with any individual factors/variants that may impact the grief trajectory. Kosminsky and Jordon³⁴ described the role of the clinician in this situation as a “transitional attachment figure” who facilitates the management and integration of the loss into the creation of what survivors of suicide loss have termed a “new normal.”

Because suicide loss is often associated with PTSD and other psychiatric illnesses (eg, depression, suicidality, substance abuse), it is essential to balance the assessment and treatment of these issues with attention to grief issues as needed. Again, to the extent that such issues have arisen primarily in the wake of the suicide loss, it can be helpful for patients to understand their connection to the context of the loss.

Continue to: Ideally, the clinician should...

Ideally, the clinician should be “present” with the patient’s pain, normative guilt, and rumination, without attempting to quickly eliminate or “fix” it or provide premature reassurance that the survivor of suicide loss “did nothing wrong.” Rather, as Jordan⁶ suggests, the clinician should act to promote a “fair trial” with respect to the patient’s guilt and blame, with an understanding of the “tyranny of hindsight.” The promotion of ambiguity tolerance should also play a role in coming to terms with many questions that may remain unanswered.

Optimally, clinicians should encourage patients to attend to their ongoing relationship with the deceased, particularly in the service of resolving “unfinished business,” ultimately integrating the loss into memories of the whole person. In line with this, survivors of suicide loss may be encouraged to create a narrative of the loss that incorporates both complexity and ambiguity. In the service of supporting the suicide loss survivor’s reinvestment in life, it is often helpful to facilitate their ability to anticipate and cope with triggers, such as anniversaries, birthdays, or holidays, as well as to develop and use skills for managing difficult or stigmatizing social or cultural reactions.

Any disruptions in family functioning should also be addressed. Psychoeducation about discordant grieving styles (particularly around gender) and the support of children’s grief may be helpful, and referrals to family or couples therapists should be considered as needed. Finally, the facilitation of suicide loss survivors’ creation of memorializations or rituals can help promote healing and make their loss meaningful.

Bottom Line

Losing a loved one to suicide is often a devastating and traumatic experience, but with optimal support, most survivors are ultimately able to integrate the loss and grow as a result. Understanding the suicide grief trajectory, as well as general guidelines for treatment, will facilitate healing and growth in the aftermath of suicide loss.

Related Resources

• Jordan JR, McIntosh JL. Grief after suicide: understanding the consequences and caring for the survivors. New York, NY: Routledge/Taylor & Francis Group; 2011.
• American Association of Suicidology. http://www.suicidology.org/. 
• American Foundation for Suicide Prevention. https://afsp.org/.

The loss of a loved one to suicide is often experienced as “devastating.”¹ While survivors of suicide loss may be able to move through the grief process without clinical support,² the traumatic and stigmatizing nature of suicide is likely to make its aftermath more challenging to navigate than other types of loss. Sanford et al³ found that more than two-thirds of suicide loss survivors sought therapy after their loss. Further, when individuals facing these challenges present for treatment, clinicians often face challenges of their own.

Very few clinicians are trained in general grief processes,⁴ and even those specifically trained in grief and loss have been shown to “miss” several of the common clinical features that are unique to suicide loss.³ In my professional experience, the intensity and duration of suicide grief are often greater than they are for other losses, and many survivors of suicide loss have reported that others, including clinicians, have “pathologized” this, rather than having understood it as normative under the circumstances.

Although there is extensive literature on the aftermath of suicide for surviving loved ones, very few controlled studies have assessed interventions specifically for this population. Yet the U.S. Guidelines for Suicide Postvention⁵ explicitly call for improved training for those who work with suicide loss survivors, as well as research on these interventions. Jordan and McGann⁶ noted, “Without a full knowledge of suicide and its aftermath, it is very possible to make clinical errors which can hamper treatment.” This article summarizes what is currently known about the general experience of suicide bereavement and optimal interventions in treatment.

What makes suicide loss unique?

Suicide bereavement is distinct from other types of loss in 3 significant ways⁷:

• the thematic content of the grief
• the social processes surrounding the survivor
• the impact that suicide has on family systems.

Additionally, the perceived intentionality and preventability of a suicide death, as well as its stigmatized and traumatic nature, differentiate it from other types of traumatic loss.⁷ These elements are all likely to affect the nature, intensity, and duration of the grief.

Stigma and suicide. Stigma associated with suicide is well documented.⁸ Former U.S. Surgeon General David Satcher⁹ specifically described stigma toward suicide as one of the biggest barriers to prevention. In addition, researchers have found that the stigma associated with suicide “spills over” to the bereaved family members. Doka^10,11 refers to “disenfranchised grief,” in which bereaved individuals receive the message that their grief is not legitimate, and as a result, they are likely to internalize this view. Studies have shown that individuals bereaved by suicide are also stigmatized, and are believed to be more psychologically disturbed, less likable, more blameworthy, more ashamed, and more in need of professional help than other bereaved individuals.^8,12-20

These judgments often mirror suicide loss survivors’ self-punitive assessments, which then become exacerbated by and intertwined with both externally imposed and internalized stigma. Thus, it is not uncommon for survivors of suicide loss to question their own right to grieve, to report low expectations of social support, and to feel compelled to deny or hide the mode of death. To the extent that they are actively grieving, survivors of suicide loss often feel that they must do so in isolation. Thus, the perception of stigma, whether external or internalized, can have a profound effect on decisions about disclosure, requesting support, and ultimately on one’s ability to integrate the loss. Indeed, Feigelman et al²¹ found that stigmatization after suicide was specifically associated with ongoing grief difficulties, depression, and suicidal ideation.

Continue to: Traumatic nature of suicide

Traumatic nature of suicide. Suicide loss is also quite traumatic, and posttraumatic stress disorder (PTSD) symptoms such as shock, horror, disbelief, and intrusive/perseverative thoughts and questions, particularly in the earlier stages of grief, are common. Sanford et al³ found that the higher the level of “perceived closeness” to the deceased, the more likely that survivors of suicide loss would experience PTSD symptoms. In addition, the dramatic loss of social support following a suicide loss may itself be traumatic, which can serve to compound these difficulties. Notably, Sanford et al³ found that even for those survivors of suicide loss in treatment who endorsed PTSD symptoms, many of their treating clinicians did not assess or diagnose this disorder, thus missing an important component for treatment.

Increased risk for suicidality. Studies have shown that individuals who have lost a loved one to suicide are themselves at heightened risk for suicidal ideation and behaviors.^22-27 Therefore, an assessment for suicide risk is always advisable. However, it is important to note that suicidal ideation is not uncommon and can serve different functions for survivors of suicide loss without necessarily progressing to a plan for acting on such ideations. Survivors of suicide loss may wish to “join” their loved one; to understand or identify with the mental state of the deceased; to punish themselves for failing to prevent the suicide; or to end their own pain through death. Therefore, it is crucial to assess the nature and function of expressed ideation (in addition to the presence or absence of plans) before assigning the level of risk.

Elements of suicide grief

After the loss of a loved one to suicide, the path to healing is often complex, with survivors of suicide loss enduring the following challenges:

Existential assumptions are shattered. Several authors^28-30 have found that suicide loss is also likely to shatter survivors’ existential assumptions regarding their worldviews, roles, and identities, as well as religious and spiritual beliefs. As one survivor of suicide loss in my practice noted, “The world is gone, nothing is predictable anymore, and it’s no longer safe to assume anything.” Others have described feeling “fragmented” in ways they had never before experienced, and many have reported difficulties in “trusting” their own judgment, the stability of the world, and relationships. “Why?” becomes an emergent and insistent question in the survivor’s efforts to understand the suicide and (ideally) reassemble a coherent narrative around the loss.

Increased duration and intensity of grief. The duration of the grief process is likely to be affected by the traumatic nature of suicide loss, the differential social support accorded to its survivors, and the difficulty in finding systems that can validate and normalize the unique elements in suicide bereavement. The stigmatized reactions of others, particularly when internalized, can present barriers to the processing of grief. In addition, the intensity of the trauma and existential impact, as well as the perseverative nature of several of the unique themes (Box 1), can also prolong the processing and increase the intensity of suicide grief. Clinicians would do well to recognize the relatively “normative” nature of the increased duration and intensity, rather than seeing it as immediately indicative of a DSM diagnosis of complicated/prolonged grief disorder.

Box 1
Common themes in the suicide grief process

Continue to: Family disruption

Family disruption. It is not uncommon for a suicide loss to result in family disruption.^6,31-32 This may manifest in the blaming of family members for “sins of omission or commission,”⁶ conflicts around the disclosure of the suicide both within and outside of the family, discordant grieving styles, and difficulties in understanding and attending to the needs of one’s children while grieving oneself.

Despite the common elements often seen in suicide grief, it is crucial to recognize that this process is not “one size fits all.” Not only are there individual variants, but Grad et al³³ found gender-based differences in grieving styles, and cultural issues such as the “meanings” assigned to suicide, and culturally sanctioned grief rituals and behaviors that are also likely to affect how grief is experienced and expressed. In addition, personal variants such as closeness/conflicts with the deceased, histories of previous trauma or loss, pre-existing psychiatric disorders, and attachment orientation³⁴ are likely to impact the grief process.

Losing close friends and colleagues may be similarly traumatic, but these survivors of suicide loss often receive even less social support than those who have kinship losses. Finally, when a suicide loss occurs in a professional capacity (such as the loss of a patient), this is likely to have many additional implications for one’s professional functions and identity.³⁵

Interventions to help survivors

Several goals and “tasks” are involved in the suicide bereavement process (Box 2^1,6,30,36-40). These can be achieved through the following interventions: Support groups. Many survivors find that support groups that focus on suicide loss are extremely helpful, and research has supported this.^1,4,41-44 Interactions with other suicide loss survivors provide hope, connection, and an “antidote” to stigma and shame. Optimally, group facilitators provide education, validation and normalization of the grief trajectory, and facilitate the sharing of both loss experiences and current functioning between group members. As a result, group participants often report renewed connections, increased efficacy in giving and accepting support, and decreased distress (including reductions in PTSD and depressive symptoms). The American Association of Suicidology (www.suicidology.org) and American Foundation of Suicide Prevention (www.afsp.org) provide contact information for suicide loss survivor groups (by geographical area) as well as information about online support groups.

Box 2
Goals and 'tasks' in suicide bereavement

Individual treatment. The limited research on individual treatment for suicide loss survivors suggests that while most participants find it generally helpful, a significant number of others report that their therapists lack knowledge of suicide grief and endorse stigmatizing attitudes toward suicide and suicide loss survivors.^45-46 In addition, Sanford et al³ found that survivors of suicide loss who endorsed PTSD symptoms were not assessed, diagnosed, or treated for these symptoms.

Continue to: This speaks to the importance of understanding what is...

This speaks to the importance of understanding what is “normative” for survivors of suicide loss. In general, “normalization” and psychoeducation about the suicide grief trajectory can play an important role in work with survivors of suicide loss, even in the presence of diagnosable disorders. While PTSD, depressive symptoms, and suicidal ideation are not uncommon in suicide loss survivors, and certainly may warrant clinical assessment and treatment, it can be helpful (and less stigmatizing) for your patients to know that these diagnoses are relatively common and understandable in the context of this devastating experience. For instance, survivors of suicide loss often report feeling relieved when clinicians explain the connections between traumatic loss and PTSD and/or depressive symptoms, and this can also help to relieve secondary anxiety about “going crazy.” Many survivors of suicide loss also describe feeling as though they are functioning on “autopilot” in the earlier stages of grief; it can help them understand the “function” of compartmentalization as potentially adaptive in the short run.

Suicide loss survivors may also find it helpful to learn about suicidal states of mind and their relationships to any types of mental illness their loved ones had struggled with.⁴⁷

Your role: Help survivors integrate the loss

Before beginning treatment with an individual who has lost a loved one to suicide, clinicians should thoroughly explore their own understanding of and experience with suicide, including assumptions around causation, internalized stigma about suicidal individuals and survivors of suicide loss, their own history of suicide loss or suicidality, cultural/religious attitudes, and anxiety/defenses associated with the topic of suicide. These factors, particularly when unexamined, are likely to impact the treatment relationship and one’s clinical efficacy.

In concert with the existing literature, consider the potential goals and tasks involved in the integration of the individual’s suicide loss, along with any individual factors/variants that may impact the grief trajectory. Kosminsky and Jordon³⁴ described the role of the clinician in this situation as a “transitional attachment figure” who facilitates the management and integration of the loss into the creation of what survivors of suicide loss have termed a “new normal.”

Because suicide loss is often associated with PTSD and other psychiatric illnesses (eg, depression, suicidality, substance abuse), it is essential to balance the assessment and treatment of these issues with attention to grief issues as needed. Again, to the extent that such issues have arisen primarily in the wake of the suicide loss, it can be helpful for patients to understand their connection to the context of the loss.

Continue to: Ideally, the clinician should...

Ideally, the clinician should be “present” with the patient’s pain, normative guilt, and rumination, without attempting to quickly eliminate or “fix” it or provide premature reassurance that the survivor of suicide loss “did nothing wrong.” Rather, as Jordan⁶ suggests, the clinician should act to promote a “fair trial” with respect to the patient’s guilt and blame, with an understanding of the “tyranny of hindsight.” The promotion of ambiguity tolerance should also play a role in coming to terms with many questions that may remain unanswered.

Optimally, clinicians should encourage patients to attend to their ongoing relationship with the deceased, particularly in the service of resolving “unfinished business,” ultimately integrating the loss into memories of the whole person. In line with this, survivors of suicide loss may be encouraged to create a narrative of the loss that incorporates both complexity and ambiguity. In the service of supporting the suicide loss survivor’s reinvestment in life, it is often helpful to facilitate their ability to anticipate and cope with triggers, such as anniversaries, birthdays, or holidays, as well as to develop and use skills for managing difficult or stigmatizing social or cultural reactions.

Any disruptions in family functioning should also be addressed. Psychoeducation about discordant grieving styles (particularly around gender) and the support of children’s grief may be helpful, and referrals to family or couples therapists should be considered as needed. Finally, the facilitation of suicide loss survivors’ creation of memorializations or rituals can help promote healing and make their loss meaningful.

Bottom Line

Losing a loved one to suicide is often a devastating and traumatic experience, but with optimal support, most survivors are ultimately able to integrate the loss and grow as a result. Understanding the suicide grief trajectory, as well as general guidelines for treatment, will facilitate healing and growth in the aftermath of suicide loss.

Related Resources

• Jordan JR, McIntosh JL. Grief after suicide: understanding the consequences and caring for the survivors. New York, NY: Routledge/Taylor & Francis Group; 2011.
• American Association of Suicidology. http://www.suicidology.org/. 
• American Foundation for Suicide Prevention. https://afsp.org/.

The loss of a loved one to suicide is often experienced as “devastating.”¹ While survivors of suicide loss may be able to move through the grief process without clinical support,² the traumatic and stigmatizing nature of suicide is likely to make its aftermath more challenging to navigate than other types of loss. Sanford et al³ found that more than two-thirds of suicide loss survivors sought therapy after their loss. Further, when individuals facing these challenges present for treatment, clinicians often face challenges of their own.

Very few clinicians are trained in general grief processes,⁴ and even those specifically trained in grief and loss have been shown to “miss” several of the common clinical features that are unique to suicide loss.³ In my professional experience, the intensity and duration of suicide grief are often greater than they are for other losses, and many survivors of suicide loss have reported that others, including clinicians, have “pathologized” this, rather than having understood it as normative under the circumstances.

Although there is extensive literature on the aftermath of suicide for surviving loved ones, very few controlled studies have assessed interventions specifically for this population. Yet the U.S. Guidelines for Suicide Postvention⁵ explicitly call for improved training for those who work with suicide loss survivors, as well as research on these interventions. Jordan and McGann⁶ noted, “Without a full knowledge of suicide and its aftermath, it is very possible to make clinical errors which can hamper treatment.” This article summarizes what is currently known about the general experience of suicide bereavement and optimal interventions in treatment.

What makes suicide loss unique?

Suicide bereavement is distinct from other types of loss in 3 significant ways⁷:

• the thematic content of the grief
• the social processes surrounding the survivor
• the impact that suicide has on family systems.

Additionally, the perceived intentionality and preventability of a suicide death, as well as its stigmatized and traumatic nature, differentiate it from other types of traumatic loss.⁷ These elements are all likely to affect the nature, intensity, and duration of the grief.

Stigma and suicide. Stigma associated with suicide is well documented.⁸ Former U.S. Surgeon General David Satcher⁹ specifically described stigma toward suicide as one of the biggest barriers to prevention. In addition, researchers have found that the stigma associated with suicide “spills over” to the bereaved family members. Doka^10,11 refers to “disenfranchised grief,” in which bereaved individuals receive the message that their grief is not legitimate, and as a result, they are likely to internalize this view. Studies have shown that individuals bereaved by suicide are also stigmatized, and are believed to be more psychologically disturbed, less likable, more blameworthy, more ashamed, and more in need of professional help than other bereaved individuals.^8,12-20

These judgments often mirror suicide loss survivors’ self-punitive assessments, which then become exacerbated by and intertwined with both externally imposed and internalized stigma. Thus, it is not uncommon for survivors of suicide loss to question their own right to grieve, to report low expectations of social support, and to feel compelled to deny or hide the mode of death. To the extent that they are actively grieving, survivors of suicide loss often feel that they must do so in isolation. Thus, the perception of stigma, whether external or internalized, can have a profound effect on decisions about disclosure, requesting support, and ultimately on one’s ability to integrate the loss. Indeed, Feigelman et al²¹ found that stigmatization after suicide was specifically associated with ongoing grief difficulties, depression, and suicidal ideation.

Continue to: Traumatic nature of suicide

Traumatic nature of suicide. Suicide loss is also quite traumatic, and posttraumatic stress disorder (PTSD) symptoms such as shock, horror, disbelief, and intrusive/perseverative thoughts and questions, particularly in the earlier stages of grief, are common. Sanford et al³ found that the higher the level of “perceived closeness” to the deceased, the more likely that survivors of suicide loss would experience PTSD symptoms. In addition, the dramatic loss of social support following a suicide loss may itself be traumatic, which can serve to compound these difficulties. Notably, Sanford et al³ found that even for those survivors of suicide loss in treatment who endorsed PTSD symptoms, many of their treating clinicians did not assess or diagnose this disorder, thus missing an important component for treatment.

Increased risk for suicidality. Studies have shown that individuals who have lost a loved one to suicide are themselves at heightened risk for suicidal ideation and behaviors.^22-27 Therefore, an assessment for suicide risk is always advisable. However, it is important to note that suicidal ideation is not uncommon and can serve different functions for survivors of suicide loss without necessarily progressing to a plan for acting on such ideations. Survivors of suicide loss may wish to “join” their loved one; to understand or identify with the mental state of the deceased; to punish themselves for failing to prevent the suicide; or to end their own pain through death. Therefore, it is crucial to assess the nature and function of expressed ideation (in addition to the presence or absence of plans) before assigning the level of risk.

Elements of suicide grief

After the loss of a loved one to suicide, the path to healing is often complex, with survivors of suicide loss enduring the following challenges:

Existential assumptions are shattered. Several authors^28-30 have found that suicide loss is also likely to shatter survivors’ existential assumptions regarding their worldviews, roles, and identities, as well as religious and spiritual beliefs. As one survivor of suicide loss in my practice noted, “The world is gone, nothing is predictable anymore, and it’s no longer safe to assume anything.” Others have described feeling “fragmented” in ways they had never before experienced, and many have reported difficulties in “trusting” their own judgment, the stability of the world, and relationships. “Why?” becomes an emergent and insistent question in the survivor’s efforts to understand the suicide and (ideally) reassemble a coherent narrative around the loss.

Increased duration and intensity of grief. The duration of the grief process is likely to be affected by the traumatic nature of suicide loss, the differential social support accorded to its survivors, and the difficulty in finding systems that can validate and normalize the unique elements in suicide bereavement. The stigmatized reactions of others, particularly when internalized, can present barriers to the processing of grief. In addition, the intensity of the trauma and existential impact, as well as the perseverative nature of several of the unique themes (Box 1), can also prolong the processing and increase the intensity of suicide grief. Clinicians would do well to recognize the relatively “normative” nature of the increased duration and intensity, rather than seeing it as immediately indicative of a DSM diagnosis of complicated/prolonged grief disorder.

Box 1
Common themes in the suicide grief process

Continue to: Family disruption

Family disruption. It is not uncommon for a suicide loss to result in family disruption.^6,31-32 This may manifest in the blaming of family members for “sins of omission or commission,”⁶ conflicts around the disclosure of the suicide both within and outside of the family, discordant grieving styles, and difficulties in understanding and attending to the needs of one’s children while grieving oneself.

Despite the common elements often seen in suicide grief, it is crucial to recognize that this process is not “one size fits all.” Not only are there individual variants, but Grad et al³³ found gender-based differences in grieving styles, and cultural issues such as the “meanings” assigned to suicide, and culturally sanctioned grief rituals and behaviors that are also likely to affect how grief is experienced and expressed. In addition, personal variants such as closeness/conflicts with the deceased, histories of previous trauma or loss, pre-existing psychiatric disorders, and attachment orientation³⁴ are likely to impact the grief process.

Losing close friends and colleagues may be similarly traumatic, but these survivors of suicide loss often receive even less social support than those who have kinship losses. Finally, when a suicide loss occurs in a professional capacity (such as the loss of a patient), this is likely to have many additional implications for one’s professional functions and identity.³⁵

Interventions to help survivors

Several goals and “tasks” are involved in the suicide bereavement process (Box 2^1,6,30,36-40). These can be achieved through the following interventions: Support groups. Many survivors find that support groups that focus on suicide loss are extremely helpful, and research has supported this.^1,4,41-44 Interactions with other suicide loss survivors provide hope, connection, and an “antidote” to stigma and shame. Optimally, group facilitators provide education, validation and normalization of the grief trajectory, and facilitate the sharing of both loss experiences and current functioning between group members. As a result, group participants often report renewed connections, increased efficacy in giving and accepting support, and decreased distress (including reductions in PTSD and depressive symptoms). The American Association of Suicidology (www.suicidology.org) and American Foundation of Suicide Prevention (www.afsp.org) provide contact information for suicide loss survivor groups (by geographical area) as well as information about online support groups.

Box 2
Goals and 'tasks' in suicide bereavement

Individual treatment. The limited research on individual treatment for suicide loss survivors suggests that while most participants find it generally helpful, a significant number of others report that their therapists lack knowledge of suicide grief and endorse stigmatizing attitudes toward suicide and suicide loss survivors.^45-46 In addition, Sanford et al³ found that survivors of suicide loss who endorsed PTSD symptoms were not assessed, diagnosed, or treated for these symptoms.

Continue to: This speaks to the importance of understanding what is...

This speaks to the importance of understanding what is “normative” for survivors of suicide loss. In general, “normalization” and psychoeducation about the suicide grief trajectory can play an important role in work with survivors of suicide loss, even in the presence of diagnosable disorders. While PTSD, depressive symptoms, and suicidal ideation are not uncommon in suicide loss survivors, and certainly may warrant clinical assessment and treatment, it can be helpful (and less stigmatizing) for your patients to know that these diagnoses are relatively common and understandable in the context of this devastating experience. For instance, survivors of suicide loss often report feeling relieved when clinicians explain the connections between traumatic loss and PTSD and/or depressive symptoms, and this can also help to relieve secondary anxiety about “going crazy.” Many survivors of suicide loss also describe feeling as though they are functioning on “autopilot” in the earlier stages of grief; it can help them understand the “function” of compartmentalization as potentially adaptive in the short run.

Suicide loss survivors may also find it helpful to learn about suicidal states of mind and their relationships to any types of mental illness their loved ones had struggled with.⁴⁷

Your role: Help survivors integrate the loss

Before beginning treatment with an individual who has lost a loved one to suicide, clinicians should thoroughly explore their own understanding of and experience with suicide, including assumptions around causation, internalized stigma about suicidal individuals and survivors of suicide loss, their own history of suicide loss or suicidality, cultural/religious attitudes, and anxiety/defenses associated with the topic of suicide. These factors, particularly when unexamined, are likely to impact the treatment relationship and one’s clinical efficacy.

In concert with the existing literature, consider the potential goals and tasks involved in the integration of the individual’s suicide loss, along with any individual factors/variants that may impact the grief trajectory. Kosminsky and Jordon³⁴ described the role of the clinician in this situation as a “transitional attachment figure” who facilitates the management and integration of the loss into the creation of what survivors of suicide loss have termed a “new normal.”

Because suicide loss is often associated with PTSD and other psychiatric illnesses (eg, depression, suicidality, substance abuse), it is essential to balance the assessment and treatment of these issues with attention to grief issues as needed. Again, to the extent that such issues have arisen primarily in the wake of the suicide loss, it can be helpful for patients to understand their connection to the context of the loss.

Continue to: Ideally, the clinician should...

Ideally, the clinician should be “present” with the patient’s pain, normative guilt, and rumination, without attempting to quickly eliminate or “fix” it or provide premature reassurance that the survivor of suicide loss “did nothing wrong.” Rather, as Jordan⁶ suggests, the clinician should act to promote a “fair trial” with respect to the patient’s guilt and blame, with an understanding of the “tyranny of hindsight.” The promotion of ambiguity tolerance should also play a role in coming to terms with many questions that may remain unanswered.

Optimally, clinicians should encourage patients to attend to their ongoing relationship with the deceased, particularly in the service of resolving “unfinished business,” ultimately integrating the loss into memories of the whole person. In line with this, survivors of suicide loss may be encouraged to create a narrative of the loss that incorporates both complexity and ambiguity. In the service of supporting the suicide loss survivor’s reinvestment in life, it is often helpful to facilitate their ability to anticipate and cope with triggers, such as anniversaries, birthdays, or holidays, as well as to develop and use skills for managing difficult or stigmatizing social or cultural reactions.

Any disruptions in family functioning should also be addressed. Psychoeducation about discordant grieving styles (particularly around gender) and the support of children’s grief may be helpful, and referrals to family or couples therapists should be considered as needed. Finally, the facilitation of suicide loss survivors’ creation of memorializations or rituals can help promote healing and make their loss meaningful.

Bottom Line

Losing a loved one to suicide is often a devastating and traumatic experience, but with optimal support, most survivors are ultimately able to integrate the loss and grow as a result. Understanding the suicide grief trajectory, as well as general guidelines for treatment, will facilitate healing and growth in the aftermath of suicide loss.

Related Resources

• Jordan JR, McIntosh JL. Grief after suicide: understanding the consequences and caring for the survivors. New York, NY: Routledge/Taylor & Francis Group; 2011.
• American Association of Suicidology. http://www.suicidology.org/. 
• American Foundation for Suicide Prevention. https://afsp.org/.

Unless your practice is cash-only, reimbursements from your patients’ health insurance companies are necessary to ensure its survival. Although the reimbursement process appears straightforward (provide a service, submit a claim, and receive a payment), it is actually quite complex, and, if not properly managed, a claim can be denied at any stage of the process.¹ In its 2013 National Health Insurer Report Card, the American Medical Association reported that major payers returned 11% to 29% of claim lines with $0 for payment.^1,2 This often is the case because patients are responsible for the balance, but it also occurs as the result of claim edits (up to 7%) and other denials (up to 5%).^1,2

Claims can be denied for various reasons, including¹:

• missed filing deadlines
• billing for non-covered services
• discrepancies between diagnostic codes, procedures codes, modifiers, and clinician documentation
• missing pre-authorization documentation or a signed Advanced Beneficiary Notice of Non-Coverage.

Strategies for avoiding denials

A psychiatric practice requires a practical system to prevent the occurrence of denials, starting from the point of referral. Working through denials is more costly and time­consuming than preventing them from occurring in the first place. For every 15 denials prevented each month, your practice can save approximately $4,500 per year in costs associated with correcting those claims; by preventing denials, the practice also receives reimbursement sooner.¹ You can be guaranteed to leave significant amounts of money on the table if you are not able to prevent or reduce denials.

The following methods can be used to help reduce the likelihood of having a claim denied.^1,3

Obtain the patient’s health insurance information at first contact and confirm his or her coverage benefits, deductibles, copay requirements, and exclusions before scheduling the first appointment. Verify this information at each of the patient’s subsequent visits to reduce the chances of having a claim denied due to invalid subscriber information. Also, keep in mind that Medicaid eligibility can change daily.

Employ a digital record system, such as electronic medical records, to track authorizations.

Know the filing deadlines for each of your payers. If you miss a deadline, there is no recourse.

Continue to: Check each claim

Check each claim for accurate coding, diagnosis, and payment (eg, copay, co-insurance, and/or deductible, depending on the health insurance plan) taken before the claim is submitted. If your practice size permits, assign a staff member to confirm this information and keep track of deadlines for submissions, resubmissions, and appeals of denied claims. Using a single gatekeeper can help decrease the chances that a denial will “slip through the cracks.”

Confirm that diagnostic codes, procedures codes, and modifiers are justified by the clinician’s documentation. Have a medical coder compare notes with the clinician to determine if any critical information needed to justify the codes used has been omitted.

Implement an electronic system that can automatically identify any changes and updates to the Centers for Medicare and Medicaid Services (CMS) regulations and guidance, International Classification of Diseases (ICD) versions and codes, and Current Procedural Terminology (CPT) codes and guidelines. To help reduce denied claims, educate all staff (schedulers, coders, billers, nursing staff, and other clinicians) frequently about these changes, and provide regular feedback to those involved in correcting denials.

Unless your practice is cash-only, reimbursements from your patients’ health insurance companies are necessary to ensure its survival. Although the reimbursement process appears straightforward (provide a service, submit a claim, and receive a payment), it is actually quite complex, and, if not properly managed, a claim can be denied at any stage of the process.¹ In its 2013 National Health Insurer Report Card, the American Medical Association reported that major payers returned 11% to 29% of claim lines with $0 for payment.^1,2 This often is the case because patients are responsible for the balance, but it also occurs as the result of claim edits (up to 7%) and other denials (up to 5%).^1,2

Claims can be denied for various reasons, including¹:

• missed filing deadlines
• billing for non-covered services
• discrepancies between diagnostic codes, procedures codes, modifiers, and clinician documentation
• missing pre-authorization documentation or a signed Advanced Beneficiary Notice of Non-Coverage.

Strategies for avoiding denials

A psychiatric practice requires a practical system to prevent the occurrence of denials, starting from the point of referral. Working through denials is more costly and time­consuming than preventing them from occurring in the first place. For every 15 denials prevented each month, your practice can save approximately $4,500 per year in costs associated with correcting those claims; by preventing denials, the practice also receives reimbursement sooner.¹ You can be guaranteed to leave significant amounts of money on the table if you are not able to prevent or reduce denials.

The following methods can be used to help reduce the likelihood of having a claim denied.^1,3

Obtain the patient’s health insurance information at first contact and confirm his or her coverage benefits, deductibles, copay requirements, and exclusions before scheduling the first appointment. Verify this information at each of the patient’s subsequent visits to reduce the chances of having a claim denied due to invalid subscriber information. Also, keep in mind that Medicaid eligibility can change daily.

Employ a digital record system, such as electronic medical records, to track authorizations.

Know the filing deadlines for each of your payers. If you miss a deadline, there is no recourse.

Continue to: Check each claim

Check each claim for accurate coding, diagnosis, and payment (eg, copay, co-insurance, and/or deductible, depending on the health insurance plan) taken before the claim is submitted. If your practice size permits, assign a staff member to confirm this information and keep track of deadlines for submissions, resubmissions, and appeals of denied claims. Using a single gatekeeper can help decrease the chances that a denial will “slip through the cracks.”

Confirm that diagnostic codes, procedures codes, and modifiers are justified by the clinician’s documentation. Have a medical coder compare notes with the clinician to determine if any critical information needed to justify the codes used has been omitted.

Implement an electronic system that can automatically identify any changes and updates to the Centers for Medicare and Medicaid Services (CMS) regulations and guidance, International Classification of Diseases (ICD) versions and codes, and Current Procedural Terminology (CPT) codes and guidelines. To help reduce denied claims, educate all staff (schedulers, coders, billers, nursing staff, and other clinicians) frequently about these changes, and provide regular feedback to those involved in correcting denials.

Unless your practice is cash-only, reimbursements from your patients’ health insurance companies are necessary to ensure its survival. Although the reimbursement process appears straightforward (provide a service, submit a claim, and receive a payment), it is actually quite complex, and, if not properly managed, a claim can be denied at any stage of the process.¹ In its 2013 National Health Insurer Report Card, the American Medical Association reported that major payers returned 11% to 29% of claim lines with $0 for payment.^1,2 This often is the case because patients are responsible for the balance, but it also occurs as the result of claim edits (up to 7%) and other denials (up to 5%).^1,2

Claims can be denied for various reasons, including¹:

• missed filing deadlines
• billing for non-covered services
• discrepancies between diagnostic codes, procedures codes, modifiers, and clinician documentation
• missing pre-authorization documentation or a signed Advanced Beneficiary Notice of Non-Coverage.

Strategies for avoiding denials

A psychiatric practice requires a practical system to prevent the occurrence of denials, starting from the point of referral. Working through denials is more costly and time­consuming than preventing them from occurring in the first place. For every 15 denials prevented each month, your practice can save approximately $4,500 per year in costs associated with correcting those claims; by preventing denials, the practice also receives reimbursement sooner.¹ You can be guaranteed to leave significant amounts of money on the table if you are not able to prevent or reduce denials.

The following methods can be used to help reduce the likelihood of having a claim denied.^1,3

Obtain the patient’s health insurance information at first contact and confirm his or her coverage benefits, deductibles, copay requirements, and exclusions before scheduling the first appointment. Verify this information at each of the patient’s subsequent visits to reduce the chances of having a claim denied due to invalid subscriber information. Also, keep in mind that Medicaid eligibility can change daily.

Employ a digital record system, such as electronic medical records, to track authorizations.

Know the filing deadlines for each of your payers. If you miss a deadline, there is no recourse.

Continue to: Check each claim

Check each claim for accurate coding, diagnosis, and payment (eg, copay, co-insurance, and/or deductible, depending on the health insurance plan) taken before the claim is submitted. If your practice size permits, assign a staff member to confirm this information and keep track of deadlines for submissions, resubmissions, and appeals of denied claims. Using a single gatekeeper can help decrease the chances that a denial will “slip through the cracks.”

Confirm that diagnostic codes, procedures codes, and modifiers are justified by the clinician’s documentation. Have a medical coder compare notes with the clinician to determine if any critical information needed to justify the codes used has been omitted.

Implement an electronic system that can automatically identify any changes and updates to the Centers for Medicare and Medicaid Services (CMS) regulations and guidance, International Classification of Diseases (ICD) versions and codes, and Current Procedural Terminology (CPT) codes and guidelines. To help reduce denied claims, educate all staff (schedulers, coders, billers, nursing staff, and other clinicians) frequently about these changes, and provide regular feedback to those involved in correcting denials.

Patients who are treated with clozapine—a second-generation antipsychotic approved for treatment-resistant schizophrenia—require monitoring for serious adverse effects. Many of these adverse effects, such as agranulocytosis or seizures, are familiar to clinicians; however, gastrointestinal (GI) hypomotility is not always recognized as a potentially serious adverse effect, even though it is one of the most common causes for hospital admission.¹Its manifestations range from being relatively benign (nausea, vomiting, constipation) to potentially severe (fecal impaction) or even life-threatening (bowel obstruction, ileus, toxic megacolon).²

GI hypomotility is caused by clozapine’s strong anticholinergic properties, which lead to slowed smooth muscle contractions and delayed bowel transit time. It is further compounded by clozapine’s 5-HT3 antagonism, which is also known to slow bowel transit time. To avoid the potentially serious risks associated with GI hypomotility, we offer simple approaches for clinicians to follow when treating patients with clozapine.

Teach patients to watch for GI symptoms

Before starting a patient on clozapine, and at all subsequent visits, ask him or her about bowel habits and GI symptoms. Because the onset of GI hypomotility can be subtle, ask patients to pay close attention to their bowel habits and keep a diary to document GI symptoms and bowel movements. Signs of bowel obstruction can include an inability to pass stool, nausea, vomiting, abdominal pain, and a bloated abdomen. Staff who care for patients taking clozapine who live in a supervised setting should be educated about the relevance of a patient’s changing bowel habits or GI complaints. Also, teach patients about simple lifestyle modifications they can make to counteract constipation, including increased physical activity, adequate hydration, and consuming a fiber-rich diet.

Avoid anticholinergics, consider a bowel regimen

If possible, avoid prescribing anticholinergic medications to a patient receiving clozapine because such agents may add to clozapine’s anticholinergic load. Some patients may require medical management of chronic constipation with stool softeners and stimulant laxatives. The Table outlines a typical bowel regimen we use for patients at our clinic. Some clinicians may prefer earlier and more regular use of senna glycoside. Also, patients might need a referral to their primary care physician if prevention has failed and fecal impaction requires enemas or mechanical disimpaction. An urgent referral to the emergency department is needed if a patient has a suspected bowel obstruction.

Acknowledgment

The authors thank Travis Baggett, MD, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, for reviewing the medical management of constipation.

Patients who are treated with clozapine—a second-generation antipsychotic approved for treatment-resistant schizophrenia—require monitoring for serious adverse effects. Many of these adverse effects, such as agranulocytosis or seizures, are familiar to clinicians; however, gastrointestinal (GI) hypomotility is not always recognized as a potentially serious adverse effect, even though it is one of the most common causes for hospital admission.¹Its manifestations range from being relatively benign (nausea, vomiting, constipation) to potentially severe (fecal impaction) or even life-threatening (bowel obstruction, ileus, toxic megacolon).²

GI hypomotility is caused by clozapine’s strong anticholinergic properties, which lead to slowed smooth muscle contractions and delayed bowel transit time. It is further compounded by clozapine’s 5-HT3 antagonism, which is also known to slow bowel transit time. To avoid the potentially serious risks associated with GI hypomotility, we offer simple approaches for clinicians to follow when treating patients with clozapine.

Teach patients to watch for GI symptoms

Before starting a patient on clozapine, and at all subsequent visits, ask him or her about bowel habits and GI symptoms. Because the onset of GI hypomotility can be subtle, ask patients to pay close attention to their bowel habits and keep a diary to document GI symptoms and bowel movements. Signs of bowel obstruction can include an inability to pass stool, nausea, vomiting, abdominal pain, and a bloated abdomen. Staff who care for patients taking clozapine who live in a supervised setting should be educated about the relevance of a patient’s changing bowel habits or GI complaints. Also, teach patients about simple lifestyle modifications they can make to counteract constipation, including increased physical activity, adequate hydration, and consuming a fiber-rich diet.

Avoid anticholinergics, consider a bowel regimen

If possible, avoid prescribing anticholinergic medications to a patient receiving clozapine because such agents may add to clozapine’s anticholinergic load. Some patients may require medical management of chronic constipation with stool softeners and stimulant laxatives. The Table outlines a typical bowel regimen we use for patients at our clinic. Some clinicians may prefer earlier and more regular use of senna glycoside. Also, patients might need a referral to their primary care physician if prevention has failed and fecal impaction requires enemas or mechanical disimpaction. An urgent referral to the emergency department is needed if a patient has a suspected bowel obstruction.

Acknowledgment

The authors thank Travis Baggett, MD, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, for reviewing the medical management of constipation.

Patients who are treated with clozapine—a second-generation antipsychotic approved for treatment-resistant schizophrenia—require monitoring for serious adverse effects. Many of these adverse effects, such as agranulocytosis or seizures, are familiar to clinicians; however, gastrointestinal (GI) hypomotility is not always recognized as a potentially serious adverse effect, even though it is one of the most common causes for hospital admission.¹Its manifestations range from being relatively benign (nausea, vomiting, constipation) to potentially severe (fecal impaction) or even life-threatening (bowel obstruction, ileus, toxic megacolon).²

GI hypomotility is caused by clozapine’s strong anticholinergic properties, which lead to slowed smooth muscle contractions and delayed bowel transit time. It is further compounded by clozapine’s 5-HT3 antagonism, which is also known to slow bowel transit time. To avoid the potentially serious risks associated with GI hypomotility, we offer simple approaches for clinicians to follow when treating patients with clozapine.

Teach patients to watch for GI symptoms

Before starting a patient on clozapine, and at all subsequent visits, ask him or her about bowel habits and GI symptoms. Because the onset of GI hypomotility can be subtle, ask patients to pay close attention to their bowel habits and keep a diary to document GI symptoms and bowel movements. Signs of bowel obstruction can include an inability to pass stool, nausea, vomiting, abdominal pain, and a bloated abdomen. Staff who care for patients taking clozapine who live in a supervised setting should be educated about the relevance of a patient’s changing bowel habits or GI complaints. Also, teach patients about simple lifestyle modifications they can make to counteract constipation, including increased physical activity, adequate hydration, and consuming a fiber-rich diet.

Avoid anticholinergics, consider a bowel regimen

If possible, avoid prescribing anticholinergic medications to a patient receiving clozapine because such agents may add to clozapine’s anticholinergic load. Some patients may require medical management of chronic constipation with stool softeners and stimulant laxatives. The Table outlines a typical bowel regimen we use for patients at our clinic. Some clinicians may prefer earlier and more regular use of senna glycoside. Also, patients might need a referral to their primary care physician if prevention has failed and fecal impaction requires enemas or mechanical disimpaction. An urgent referral to the emergency department is needed if a patient has a suspected bowel obstruction.

Acknowledgment

The authors thank Travis Baggett, MD, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, for reviewing the medical management of constipation.

Xenomelia, literally meaning “foreign limb,” is a neuropsychiatric condition in which nonpsychotic individuals have an intense, persistent belief that one or more of their limbs does not belong to their body; instead they regard it as an alien appendage that should be discarded.¹ This unwavering, fixed belief resembles a delusion and is often debilitating to the point where the affected person strongly desires amputation of the unwanted limb. Traditionally, such requests often are denied by the medical community, which may cause an individual who has xenomelia to attempt risky self-amputation, or to injure the limb in a manner that makes subsequent amputation medically necessary.¹

The name for this condition has evolved over the years, depending on the emphasis given to specific characteristics. It was once called apotemnophilia, meaning “love of amputation,” when the condition was believed to be a fetish involving sexual gratification derived from being an amputee.^2,3 The term “body integrity identity disorder” (BIID) was introduced several decades later to incorporate the condition into a broader spectrum of accepted psychiatric pathologies, reasoning that it was the cause of a mismatch between objective and subjective body schema, similar to anorexia nervosa or body dysmorphic disorder.^4,5 This name also served to draw parallels between this condition and gender identity disorder. However, unlike these other disorders, individuals with this condition have sufficient factual insight to know they appear “normal” to others. The newest term, xenomelia, was established to acknowledge the neurologic component of the condition after neuroimaging studies showed structural changes to the right parietal lobe in individuals who desired amputation of their left lower limb, thus linking the part of the brain that processes sensory input from the affected limb.⁶

While particular nuances in symptomatology were modified in formulating these older names, certain hallmark features of xenomelia have remained the same.⁷ The condition starts in early childhood, prior to puberty. Those who have it feel intense distress, and are resigned to the notion that nothing but amputation can alleviate their distress. Xenomelia is overwhelmingly more common in males than females. It is accompanied by nontraditional attitudes about disability, including admiration of amputees and complete apathy and disregard toward the impairment that amputation would cause.

While the data are insufficient to draw a definitive conclusion, the trend in the published literature suggests in xenomelia, the lower left leg is predominantly the limb implicated in the condition, in right-handed individuals.¹

Here, we describe the case of a young man, Mr. H, with xenomelia who contacted us after reading about this condition in a review we recently published.¹ He agreed to allow us to anonymously describe his history and symptoms so that clinicians can recognize and help other individuals with xenomelia. His history may also help stimulate exploration of etiological factors and novel treatment strategies for xenomelia, other than amputation of a healthy limb.

CASE

‘I have this limb that should not be’

Mr. H, age 31, is a white male of Eastern European descent who was born, raised, and resides in a major metropolitan area in the western United States. He is married, college-educated, and currently works as a computer programmer for a prominent technology company. During our conversation via telephone, he exhibits above-average intelligence, appears to be in euthymic mood, and speaks with broad affect. Mr. H displays no psychotic symptoms such as overt delusions, hallucinations, reality distortion, or response to internal stimuli. His past psychiatric history includes attention-deficit/hyperactivity disorder (ADHD), which was diagnosed at age 6 and treated with appropriate medication under the care of a psychiatrist until age 18, when Mr. H decided to discontinue treatment. He no longer endorses symptoms of ADHD. He has no chronic medical conditions other than season allergies, for which he sometimes takes antihistamines, and occasional exacerbation of sciatica, for which he takes an over-the-counter nonsteroidal anti-inflammatory medication. Mr. H also has episodic insomnia, which he attributes to job-related stress and working odd hours. He was treated for meningitis as an infant, and underwent a bilateral myringotomy as a young child to treat recurrent ear infections. He has no other surgical history. He was raised in a middle-class Christian household that included both parents, who are still alive, still together, and have no significant psychiatric or medical history. He has no siblings.

Although he lives an ostensibly normal life, Mr. H suffers in silence and secrecy with xenomelia. According to him, there was never a time in his life when he didn’t feel that his left leg was “too long” and he was “walking on a stilt.” He says, “It takes a daily toll on my health and well-being.” He can clearly recall being 4 years old and playing games in which he would pretend to injure his left leg. He says, “When we played ‘make believe,’ the game would always end with something ‘happening’ to [my left leg].” He enjoys outdoor sports like snowboarding and mountain biking, and although he denies self-injurious behavior, he says in the event of an accident, he would prefer to land on his left leg, because it is the part of his body that he considers most “expendable.” One of his most vivid memories of childhood was going shopping with his parents and seeing an older man with only one leg standing on crutches in the parking lot outside the entrance. He remembers feeling “jealous” of this man.

Continue to: Although his parents were not particularly wealthy...

Although his parents were not particularly wealthy, they sent him to a private Christian school for most of his childhood. Mr. H admits that while there he didn’t fit in and felt like an outcast, in part because he didn’t come from the level of wealth of his classmates, and because having ADHD left him isolative and avoidant. “I was always the one going away to take medication,” he explains, and he also developed a hostile attitude. He was suspended from school multiple times for fighting. These years left him tremendously anxious and depressed, and he would often find it therapeutic to sit with his left leg bent underneath him, so as to hide its undesired portion. It was common for him to tie his leg up and stare at himself in the mirror for minutes to hours as a form of stress reduction.

Most of Mr. H’s social circle is composed of friends he has known since childhood, none of whom are aware of his condition. He acknowledges that his feelings are “bizarre in nature” and so he has kept this secret on a “need-to-know” basis out of “fear of rejection, mockery, and damage to my reputation.” Through the years, he has sought out and encountered others with this condition, first anonymously on the internet, then in-person once he gets to know and trust them. He claims to know and be friendly with several people with xenomelia in his own city, some of whom have undergone amputation and are extremely happy with the results. According to Mr. H, there is a community aspect to xenomelia in his city, and people with the condition often meet each other socially. He has revealed his secret to 2 women he dated, including his present wife, who he told 3 years into their relationship. “I was prepared for her to leave me,” he recalls. Although he has never connected the desire for amputation with sexuality, he certainly believes that amputating his left leg would enhance his sex life. “Do I find amputees sexy?” he asks, “I would say yes.” On a 10-point scale, he considers his sex life to be a “7 or 8,” and it would reach 10 if he underwent amputation.

Mr. H has a calendar on which he keeps track of the days when he feels “impaired” by his xenomelia. He marks each day as either “red” or “green.” So far, he does not recognize a pattern of exacerbation. “I have my good days, then I have my bad days,” he laments. “On good days, I think about amputation and where my leg should actually end, but it is something I can quickly push off. On my bad days, I am constantly reminded in one way or another that, yes, I have this limb that should not be.” While he has never sought treatment for this condition from a health care professional, he developed his own therapeutic regimen that includes yoga, hiking, and daily use of cannabis, which “helps take the edge off.” He used alcohol in the past as self-medication, but stopped drinking to excess when it started to disrupt other aspects of his life. According to Mr. H, the goal is to distract himself from the condition, which provides temporary relief. “I find if my mind is more engaged, the amputation thoughts are fewer and less in intensity.” He reports that the months leading up to his wedding were particularly therapeutic because wedding planning provided an excellent distraction.

Overall, his current desire for amputation is steadily increasing. “Lately it has become more of a roller coaster,” he says. “If there’s a safe way to do it, I’ll do it.” An amputation would allow him to “feel good, complete, grounded, and content.” If he were to undergo amputation, he would use a prosthetic in order to retain mobility and keep his physique as discreet as possible. He has made initial inquiries into getting an amputation, saying, “I have heard of rumors of surgeons willing to perform the surgery, for a price. However, I have not completed the ‘vetting process’ to actually come into contact with the surgeons themselves.” Similar to others with xenomelia, he is easily able to draw a line on his leg, exactly where the desired amputation should occur.⁸ For most of his life, that line would have been 2 inches above his knee, but in recent years, the line has drifted lower, to 2 inches below the knee. However, he “wouldn’t mind either” line of amputation. He indicates the area below the desired line is less sensitive to pain than the corresponding part of his right leg, particularly his toes.

Mr. H’s wife is extremely supportive and understanding of her husband’s condition, but is opposed to the possibility of amputation (Box).

Box
Xenomelia: A spouse's perspective

Continue to: Much left to be learned about xenomelia

Much left to be learned about xenomelia

What remains to be discovered about xenomelia falls into 2 areas:

• the possible usefulness of various neuroimaging modalities (morphological MRI, functional MRI, magnetic resonance spectroscopy, and diffusion tensor imaging) to identify and localize anomalous neural pathways or neuroanatomical foci associated with this condition, such as an aberrantly developed or poorly myelinated right parietal lobe, which houses the limb’s physical proprioception
• a biopsychosocial inquiry into whether there exists a specific combination of a given individual’s organic brain, mind, and environmental interactions that may give rise to this condition, and whether we might detect a prodrome that arises in early childhood. The objective of any research into this condition would be to minimize its effects, if not prevent them altogether.¹

As this case illustrates, xenomelia begins in early childhood, with symptoms being reported in children as young as age 3.⁷ However, no published literature has investigated these early stages. We’ve learned that individuals with xenomelia often can point to key childhood experiences or memories related to seeing people with amputated limbs. They remember feeling a sense of wonder, fascination, or other strong emotion. It may be in this memory that xenomelia is permanently imprinted. This was definitely true for Mr. H, who never knew a time when he didn’t endure some level of debilitation from xenomelia, and distinctly remembers feeling jealous upon seeing a man with the amputated leg standing on crutches in a store parking lot. Although he has come across many amputees in his life, Mr. H says he vividly remembers everything about that particular man in that particular moment, adding “I can still see the clothes he was wearing. I can still see the cars in the parking lot.” That was likely his moment of vivid and powerful imprinting.

Particularly influential changes occur in adolescence, not just in the course of physical development, but in the formulation of self-identity, which involves the inevitable comparison of one’s own appearance to that of others, with heightened awareness of what others might perceive. This phenomenon is known as “the imaginary audience,” and it is often overemphasized in the minds of individuals with xenomelia.⁷ Mr. H is a textbook example of someone acutely aware of his “audience,” suffering from the embarrassment that came from being less wealthy than others at his school, and having to manage his ADHD in plain sight of his classmates, who knew that he required medication. It is no surprise that he felt like an outcast and got suspended for fighting. He would relieve anxiety by tying his leg up and staring at himself in the mirror, finding refuge in front of an audience of one that understood and sympathized with his suffering.

Among the most notorious aspects of this condition is investigation into the possibility of there being a sexual component to the desire for amputation. The notion that the desire is a fetish employed for the purpose of sexual arousal was first propagated by Penthouse magazine in the 1970s.⁹ Learning that xenomelia exists in a child long before sexual maturation—and in an older adult long after sexual drive peaks—suggests the condition is independent of sexuality. However, this aspect of xenomelia continues to be investigated. A recent study found that >70% of individuals with xenomelia are at least partially motivated by the perceived enhancement in sexual gratification.¹⁰ Individuals with this motivation are predominantly male, homosexual, come from a religious background, and are far more likely to self-amputate.¹⁰ Mr. H admitted that he is sexually attracted to amputees, and while he had no complaints about his sex life, he felt it could only reach the highest levels of gratification if he were an amputee.

It is reasonable to posit that there is a genetic mechanism that creates a cortical template of one’s body, and this template connects with the limbic system, encoding a visual preference for and attraction to one’s own idealized and preferred body morphology that includes an amputated limb.¹¹ Therefore, if Mr. H sees himself as an amputee, it would be reasonable for him to identify with and be attracted to other amputees. However, Mr. H is clearly not preoccupied with sexuality, and believes that heightened sexual gratification would be an ancillary bonus, and not the main objective, of amputation.

Continue to: Most individuals who have particpated in research studies about xenomelia tend to...

Most individuals who have participated in research studies about xenomelia tend to be older, mainly in their 60s. This is particularly true of individuals who go through with amputation. At some point, the need for a person to invoke their autonomy, alleviate their debilitation, and fulfill their desire may supersede their aversion to physical disability and social ridicule. At this stage in his life, Mr. H can’t commit to going forward with the amputation. However, he regards the likelihood of undergoing amputation to be quite high. He made initial inquiries to find a surgeon who would be willing to perform the procedure. Given that he has found people with xenomelia who have undergone amputation, he will likely will be able find a surgeon to perform the procedure. Mr. H reports that just about everyone he has ever known with xenomelia who underwent amputation is completely satisfied with their decision, even years later. He has come across only one person who regretted the amputation, and he believes that person was likely suffering from other psychiatric issues, and did not have true xenomelia.

In the mind of an individual with xenomelia, the desire for amputation is separate from a desire to be disabled. Mr. H is mindful of the assumed irrationality of removing a healthy but “alien” limb to replace it with a prosthetic limb that is equally alien. The perceived irony is not lost on him. He values his mobility, and has no desire to use crutches, a wheelchair, or any other ambulatory tool. This is consistent with most individuals with xenomelia, who are neither motived by the desire to flaunt their amputated limb, nor by the sympathy they might receive from others by endorsing impaired mobility. They don’t consider themselves disabled. On the contrary, for them, amputation is a much-desired enhancement to their health and well-being.

Increased opportunities for research

The internet, social media, and even peer-reviewed medical journals offer ever-increasing opportunities for individuals with xenomelia, such as Mr. H, to have their story told, regardless of whether they choose to identify themselves or remain anonymous. There are no published data about the prevalence of xenomelia, but it is almost certainly rare. However, if Mr. H was able to meet multiple people with xeno­melia in his own city and form a supportive community with them, then perhaps it isn’t exactly as rare as one might initially assume. People with xenomelia may tend to look for each other, hoping those with the same condition might show them the greatest empathy.

From Mr. H’s experience, it appears that it would be possible to locate a sufficient number of individuals with xenomelia for the purposes of conducting research, which might allow for results with acceptable statistical power. There are plenty of individual patient stories, and by documenting these stories in published literature, it is likely that patterns would emerge and causality might be determined. Such data might be bolstered by a possible strong neurologic corroboration based on what is found via neuroimaging.

Informed research into xenomelia is still in the early stages, and it is clear that there is much left to discover. It is vital that, moving forward, investigation into this condition be thorough and objective, with the goal of alleviating this secretive and debilitating neuropsychiatric condition.

Continue to: Bottom Line

Individuals with xenomelia have the persistent belief that one or more of their limbs does not belong to their body but is an alien appendage that should be removed. Patients with this condition may resort to self-amputation or self-mutilation that requires subsequent surgical amputation. Xenomelia may be related to anomalous brain development, with a lack of neural representation of a limb in the right parietal lobe.

Related Resources

• Hilti LM, Hänggi J, Vitacco DA, et al. The desire for healthy limb amputation: structural brain correlates and clinical features of xenomelia. Brain. 2013;136(pt 1):318-329.
• Brugger P, Lenggenhager B, Giummarra MJ. Xenomelia: a social neuroscience view of altered bodily self-consciousness. Front Psychol. 2013;4:204. doi:10.3389/fpsyg.2013.00204.

Xenomelia, literally meaning “foreign limb,” is a neuropsychiatric condition in which nonpsychotic individuals have an intense, persistent belief that one or more of their limbs does not belong to their body; instead they regard it as an alien appendage that should be discarded.¹ This unwavering, fixed belief resembles a delusion and is often debilitating to the point where the affected person strongly desires amputation of the unwanted limb. Traditionally, such requests often are denied by the medical community, which may cause an individual who has xenomelia to attempt risky self-amputation, or to injure the limb in a manner that makes subsequent amputation medically necessary.¹

The name for this condition has evolved over the years, depending on the emphasis given to specific characteristics. It was once called apotemnophilia, meaning “love of amputation,” when the condition was believed to be a fetish involving sexual gratification derived from being an amputee.^2,3 The term “body integrity identity disorder” (BIID) was introduced several decades later to incorporate the condition into a broader spectrum of accepted psychiatric pathologies, reasoning that it was the cause of a mismatch between objective and subjective body schema, similar to anorexia nervosa or body dysmorphic disorder.^4,5 This name also served to draw parallels between this condition and gender identity disorder. However, unlike these other disorders, individuals with this condition have sufficient factual insight to know they appear “normal” to others. The newest term, xenomelia, was established to acknowledge the neurologic component of the condition after neuroimaging studies showed structural changes to the right parietal lobe in individuals who desired amputation of their left lower limb, thus linking the part of the brain that processes sensory input from the affected limb.⁶

While particular nuances in symptomatology were modified in formulating these older names, certain hallmark features of xenomelia have remained the same.⁷ The condition starts in early childhood, prior to puberty. Those who have it feel intense distress, and are resigned to the notion that nothing but amputation can alleviate their distress. Xenomelia is overwhelmingly more common in males than females. It is accompanied by nontraditional attitudes about disability, including admiration of amputees and complete apathy and disregard toward the impairment that amputation would cause.

While the data are insufficient to draw a definitive conclusion, the trend in the published literature suggests in xenomelia, the lower left leg is predominantly the limb implicated in the condition, in right-handed individuals.¹

Here, we describe the case of a young man, Mr. H, with xenomelia who contacted us after reading about this condition in a review we recently published.¹ He agreed to allow us to anonymously describe his history and symptoms so that clinicians can recognize and help other individuals with xenomelia. His history may also help stimulate exploration of etiological factors and novel treatment strategies for xenomelia, other than amputation of a healthy limb.

CASE

‘I have this limb that should not be’

Mr. H, age 31, is a white male of Eastern European descent who was born, raised, and resides in a major metropolitan area in the western United States. He is married, college-educated, and currently works as a computer programmer for a prominent technology company. During our conversation via telephone, he exhibits above-average intelligence, appears to be in euthymic mood, and speaks with broad affect. Mr. H displays no psychotic symptoms such as overt delusions, hallucinations, reality distortion, or response to internal stimuli. His past psychiatric history includes attention-deficit/hyperactivity disorder (ADHD), which was diagnosed at age 6 and treated with appropriate medication under the care of a psychiatrist until age 18, when Mr. H decided to discontinue treatment. He no longer endorses symptoms of ADHD. He has no chronic medical conditions other than season allergies, for which he sometimes takes antihistamines, and occasional exacerbation of sciatica, for which he takes an over-the-counter nonsteroidal anti-inflammatory medication. Mr. H also has episodic insomnia, which he attributes to job-related stress and working odd hours. He was treated for meningitis as an infant, and underwent a bilateral myringotomy as a young child to treat recurrent ear infections. He has no other surgical history. He was raised in a middle-class Christian household that included both parents, who are still alive, still together, and have no significant psychiatric or medical history. He has no siblings.

Although he lives an ostensibly normal life, Mr. H suffers in silence and secrecy with xenomelia. According to him, there was never a time in his life when he didn’t feel that his left leg was “too long” and he was “walking on a stilt.” He says, “It takes a daily toll on my health and well-being.” He can clearly recall being 4 years old and playing games in which he would pretend to injure his left leg. He says, “When we played ‘make believe,’ the game would always end with something ‘happening’ to [my left leg].” He enjoys outdoor sports like snowboarding and mountain biking, and although he denies self-injurious behavior, he says in the event of an accident, he would prefer to land on his left leg, because it is the part of his body that he considers most “expendable.” One of his most vivid memories of childhood was going shopping with his parents and seeing an older man with only one leg standing on crutches in the parking lot outside the entrance. He remembers feeling “jealous” of this man.

Continue to: Although his parents were not particularly wealthy...

Although his parents were not particularly wealthy, they sent him to a private Christian school for most of his childhood. Mr. H admits that while there he didn’t fit in and felt like an outcast, in part because he didn’t come from the level of wealth of his classmates, and because having ADHD left him isolative and avoidant. “I was always the one going away to take medication,” he explains, and he also developed a hostile attitude. He was suspended from school multiple times for fighting. These years left him tremendously anxious and depressed, and he would often find it therapeutic to sit with his left leg bent underneath him, so as to hide its undesired portion. It was common for him to tie his leg up and stare at himself in the mirror for minutes to hours as a form of stress reduction.

Most of Mr. H’s social circle is composed of friends he has known since childhood, none of whom are aware of his condition. He acknowledges that his feelings are “bizarre in nature” and so he has kept this secret on a “need-to-know” basis out of “fear of rejection, mockery, and damage to my reputation.” Through the years, he has sought out and encountered others with this condition, first anonymously on the internet, then in-person once he gets to know and trust them. He claims to know and be friendly with several people with xenomelia in his own city, some of whom have undergone amputation and are extremely happy with the results. According to Mr. H, there is a community aspect to xenomelia in his city, and people with the condition often meet each other socially. He has revealed his secret to 2 women he dated, including his present wife, who he told 3 years into their relationship. “I was prepared for her to leave me,” he recalls. Although he has never connected the desire for amputation with sexuality, he certainly believes that amputating his left leg would enhance his sex life. “Do I find amputees sexy?” he asks, “I would say yes.” On a 10-point scale, he considers his sex life to be a “7 or 8,” and it would reach 10 if he underwent amputation.

Mr. H has a calendar on which he keeps track of the days when he feels “impaired” by his xenomelia. He marks each day as either “red” or “green.” So far, he does not recognize a pattern of exacerbation. “I have my good days, then I have my bad days,” he laments. “On good days, I think about amputation and where my leg should actually end, but it is something I can quickly push off. On my bad days, I am constantly reminded in one way or another that, yes, I have this limb that should not be.” While he has never sought treatment for this condition from a health care professional, he developed his own therapeutic regimen that includes yoga, hiking, and daily use of cannabis, which “helps take the edge off.” He used alcohol in the past as self-medication, but stopped drinking to excess when it started to disrupt other aspects of his life. According to Mr. H, the goal is to distract himself from the condition, which provides temporary relief. “I find if my mind is more engaged, the amputation thoughts are fewer and less in intensity.” He reports that the months leading up to his wedding were particularly therapeutic because wedding planning provided an excellent distraction.

Overall, his current desire for amputation is steadily increasing. “Lately it has become more of a roller coaster,” he says. “If there’s a safe way to do it, I’ll do it.” An amputation would allow him to “feel good, complete, grounded, and content.” If he were to undergo amputation, he would use a prosthetic in order to retain mobility and keep his physique as discreet as possible. He has made initial inquiries into getting an amputation, saying, “I have heard of rumors of surgeons willing to perform the surgery, for a price. However, I have not completed the ‘vetting process’ to actually come into contact with the surgeons themselves.” Similar to others with xenomelia, he is easily able to draw a line on his leg, exactly where the desired amputation should occur.⁸ For most of his life, that line would have been 2 inches above his knee, but in recent years, the line has drifted lower, to 2 inches below the knee. However, he “wouldn’t mind either” line of amputation. He indicates the area below the desired line is less sensitive to pain than the corresponding part of his right leg, particularly his toes.

Mr. H’s wife is extremely supportive and understanding of her husband’s condition, but is opposed to the possibility of amputation (Box).

Box
Xenomelia: A spouse's perspective

Continue to: Much left to be learned about xenomelia

Much left to be learned about xenomelia

What remains to be discovered about xenomelia falls into 2 areas:

• the possible usefulness of various neuroimaging modalities (morphological MRI, functional MRI, magnetic resonance spectroscopy, and diffusion tensor imaging) to identify and localize anomalous neural pathways or neuroanatomical foci associated with this condition, such as an aberrantly developed or poorly myelinated right parietal lobe, which houses the limb’s physical proprioception
• a biopsychosocial inquiry into whether there exists a specific combination of a given individual’s organic brain, mind, and environmental interactions that may give rise to this condition, and whether we might detect a prodrome that arises in early childhood. The objective of any research into this condition would be to minimize its effects, if not prevent them altogether.¹

As this case illustrates, xenomelia begins in early childhood, with symptoms being reported in children as young as age 3.⁷ However, no published literature has investigated these early stages. We’ve learned that individuals with xenomelia often can point to key childhood experiences or memories related to seeing people with amputated limbs. They remember feeling a sense of wonder, fascination, or other strong emotion. It may be in this memory that xenomelia is permanently imprinted. This was definitely true for Mr. H, who never knew a time when he didn’t endure some level of debilitation from xenomelia, and distinctly remembers feeling jealous upon seeing a man with the amputated leg standing on crutches in a store parking lot. Although he has come across many amputees in his life, Mr. H says he vividly remembers everything about that particular man in that particular moment, adding “I can still see the clothes he was wearing. I can still see the cars in the parking lot.” That was likely his moment of vivid and powerful imprinting.

Particularly influential changes occur in adolescence, not just in the course of physical development, but in the formulation of self-identity, which involves the inevitable comparison of one’s own appearance to that of others, with heightened awareness of what others might perceive. This phenomenon is known as “the imaginary audience,” and it is often overemphasized in the minds of individuals with xenomelia.⁷ Mr. H is a textbook example of someone acutely aware of his “audience,” suffering from the embarrassment that came from being less wealthy than others at his school, and having to manage his ADHD in plain sight of his classmates, who knew that he required medication. It is no surprise that he felt like an outcast and got suspended for fighting. He would relieve anxiety by tying his leg up and staring at himself in the mirror, finding refuge in front of an audience of one that understood and sympathized with his suffering.

Among the most notorious aspects of this condition is investigation into the possibility of there being a sexual component to the desire for amputation. The notion that the desire is a fetish employed for the purpose of sexual arousal was first propagated by Penthouse magazine in the 1970s.⁹ Learning that xenomelia exists in a child long before sexual maturation—and in an older adult long after sexual drive peaks—suggests the condition is independent of sexuality. However, this aspect of xenomelia continues to be investigated. A recent study found that >70% of individuals with xenomelia are at least partially motivated by the perceived enhancement in sexual gratification.¹⁰ Individuals with this motivation are predominantly male, homosexual, come from a religious background, and are far more likely to self-amputate.¹⁰ Mr. H admitted that he is sexually attracted to amputees, and while he had no complaints about his sex life, he felt it could only reach the highest levels of gratification if he were an amputee.

It is reasonable to posit that there is a genetic mechanism that creates a cortical template of one’s body, and this template connects with the limbic system, encoding a visual preference for and attraction to one’s own idealized and preferred body morphology that includes an amputated limb.¹¹ Therefore, if Mr. H sees himself as an amputee, it would be reasonable for him to identify with and be attracted to other amputees. However, Mr. H is clearly not preoccupied with sexuality, and believes that heightened sexual gratification would be an ancillary bonus, and not the main objective, of amputation.

Continue to: Most individuals who have particpated in research studies about xenomelia tend to...

Most individuals who have participated in research studies about xenomelia tend to be older, mainly in their 60s. This is particularly true of individuals who go through with amputation. At some point, the need for a person to invoke their autonomy, alleviate their debilitation, and fulfill their desire may supersede their aversion to physical disability and social ridicule. At this stage in his life, Mr. H can’t commit to going forward with the amputation. However, he regards the likelihood of undergoing amputation to be quite high. He made initial inquiries to find a surgeon who would be willing to perform the procedure. Given that he has found people with xenomelia who have undergone amputation, he will likely will be able find a surgeon to perform the procedure. Mr. H reports that just about everyone he has ever known with xenomelia who underwent amputation is completely satisfied with their decision, even years later. He has come across only one person who regretted the amputation, and he believes that person was likely suffering from other psychiatric issues, and did not have true xenomelia.

In the mind of an individual with xenomelia, the desire for amputation is separate from a desire to be disabled. Mr. H is mindful of the assumed irrationality of removing a healthy but “alien” limb to replace it with a prosthetic limb that is equally alien. The perceived irony is not lost on him. He values his mobility, and has no desire to use crutches, a wheelchair, or any other ambulatory tool. This is consistent with most individuals with xenomelia, who are neither motived by the desire to flaunt their amputated limb, nor by the sympathy they might receive from others by endorsing impaired mobility. They don’t consider themselves disabled. On the contrary, for them, amputation is a much-desired enhancement to their health and well-being.

Increased opportunities for research

The internet, social media, and even peer-reviewed medical journals offer ever-increasing opportunities for individuals with xenomelia, such as Mr. H, to have their story told, regardless of whether they choose to identify themselves or remain anonymous. There are no published data about the prevalence of xenomelia, but it is almost certainly rare. However, if Mr. H was able to meet multiple people with xeno­melia in his own city and form a supportive community with them, then perhaps it isn’t exactly as rare as one might initially assume. People with xenomelia may tend to look for each other, hoping those with the same condition might show them the greatest empathy.

From Mr. H’s experience, it appears that it would be possible to locate a sufficient number of individuals with xenomelia for the purposes of conducting research, which might allow for results with acceptable statistical power. There are plenty of individual patient stories, and by documenting these stories in published literature, it is likely that patterns would emerge and causality might be determined. Such data might be bolstered by a possible strong neurologic corroboration based on what is found via neuroimaging.

Informed research into xenomelia is still in the early stages, and it is clear that there is much left to discover. It is vital that, moving forward, investigation into this condition be thorough and objective, with the goal of alleviating this secretive and debilitating neuropsychiatric condition.

Continue to: Bottom Line

Individuals with xenomelia have the persistent belief that one or more of their limbs does not belong to their body but is an alien appendage that should be removed. Patients with this condition may resort to self-amputation or self-mutilation that requires subsequent surgical amputation. Xenomelia may be related to anomalous brain development, with a lack of neural representation of a limb in the right parietal lobe.

Related Resources

• Hilti LM, Hänggi J, Vitacco DA, et al. The desire for healthy limb amputation: structural brain correlates and clinical features of xenomelia. Brain. 2013;136(pt 1):318-329.
• Brugger P, Lenggenhager B, Giummarra MJ. Xenomelia: a social neuroscience view of altered bodily self-consciousness. Front Psychol. 2013;4:204. doi:10.3389/fpsyg.2013.00204.

Xenomelia, literally meaning “foreign limb,” is a neuropsychiatric condition in which nonpsychotic individuals have an intense, persistent belief that one or more of their limbs does not belong to their body; instead they regard it as an alien appendage that should be discarded.¹ This unwavering, fixed belief resembles a delusion and is often debilitating to the point where the affected person strongly desires amputation of the unwanted limb. Traditionally, such requests often are denied by the medical community, which may cause an individual who has xenomelia to attempt risky self-amputation, or to injure the limb in a manner that makes subsequent amputation medically necessary.¹

The name for this condition has evolved over the years, depending on the emphasis given to specific characteristics. It was once called apotemnophilia, meaning “love of amputation,” when the condition was believed to be a fetish involving sexual gratification derived from being an amputee.^2,3 The term “body integrity identity disorder” (BIID) was introduced several decades later to incorporate the condition into a broader spectrum of accepted psychiatric pathologies, reasoning that it was the cause of a mismatch between objective and subjective body schema, similar to anorexia nervosa or body dysmorphic disorder.^4,5 This name also served to draw parallels between this condition and gender identity disorder. However, unlike these other disorders, individuals with this condition have sufficient factual insight to know they appear “normal” to others. The newest term, xenomelia, was established to acknowledge the neurologic component of the condition after neuroimaging studies showed structural changes to the right parietal lobe in individuals who desired amputation of their left lower limb, thus linking the part of the brain that processes sensory input from the affected limb.⁶

While particular nuances in symptomatology were modified in formulating these older names, certain hallmark features of xenomelia have remained the same.⁷ The condition starts in early childhood, prior to puberty. Those who have it feel intense distress, and are resigned to the notion that nothing but amputation can alleviate their distress. Xenomelia is overwhelmingly more common in males than females. It is accompanied by nontraditional attitudes about disability, including admiration of amputees and complete apathy and disregard toward the impairment that amputation would cause.

While the data are insufficient to draw a definitive conclusion, the trend in the published literature suggests in xenomelia, the lower left leg is predominantly the limb implicated in the condition, in right-handed individuals.¹

Here, we describe the case of a young man, Mr. H, with xenomelia who contacted us after reading about this condition in a review we recently published.¹ He agreed to allow us to anonymously describe his history and symptoms so that clinicians can recognize and help other individuals with xenomelia. His history may also help stimulate exploration of etiological factors and novel treatment strategies for xenomelia, other than amputation of a healthy limb.

CASE

‘I have this limb that should not be’

Mr. H, age 31, is a white male of Eastern European descent who was born, raised, and resides in a major metropolitan area in the western United States. He is married, college-educated, and currently works as a computer programmer for a prominent technology company. During our conversation via telephone, he exhibits above-average intelligence, appears to be in euthymic mood, and speaks with broad affect. Mr. H displays no psychotic symptoms such as overt delusions, hallucinations, reality distortion, or response to internal stimuli. His past psychiatric history includes attention-deficit/hyperactivity disorder (ADHD), which was diagnosed at age 6 and treated with appropriate medication under the care of a psychiatrist until age 18, when Mr. H decided to discontinue treatment. He no longer endorses symptoms of ADHD. He has no chronic medical conditions other than season allergies, for which he sometimes takes antihistamines, and occasional exacerbation of sciatica, for which he takes an over-the-counter nonsteroidal anti-inflammatory medication. Mr. H also has episodic insomnia, which he attributes to job-related stress and working odd hours. He was treated for meningitis as an infant, and underwent a bilateral myringotomy as a young child to treat recurrent ear infections. He has no other surgical history. He was raised in a middle-class Christian household that included both parents, who are still alive, still together, and have no significant psychiatric or medical history. He has no siblings.

Although he lives an ostensibly normal life, Mr. H suffers in silence and secrecy with xenomelia. According to him, there was never a time in his life when he didn’t feel that his left leg was “too long” and he was “walking on a stilt.” He says, “It takes a daily toll on my health and well-being.” He can clearly recall being 4 years old and playing games in which he would pretend to injure his left leg. He says, “When we played ‘make believe,’ the game would always end with something ‘happening’ to [my left leg].” He enjoys outdoor sports like snowboarding and mountain biking, and although he denies self-injurious behavior, he says in the event of an accident, he would prefer to land on his left leg, because it is the part of his body that he considers most “expendable.” One of his most vivid memories of childhood was going shopping with his parents and seeing an older man with only one leg standing on crutches in the parking lot outside the entrance. He remembers feeling “jealous” of this man.

Continue to: Although his parents were not particularly wealthy...

Although his parents were not particularly wealthy, they sent him to a private Christian school for most of his childhood. Mr. H admits that while there he didn’t fit in and felt like an outcast, in part because he didn’t come from the level of wealth of his classmates, and because having ADHD left him isolative and avoidant. “I was always the one going away to take medication,” he explains, and he also developed a hostile attitude. He was suspended from school multiple times for fighting. These years left him tremendously anxious and depressed, and he would often find it therapeutic to sit with his left leg bent underneath him, so as to hide its undesired portion. It was common for him to tie his leg up and stare at himself in the mirror for minutes to hours as a form of stress reduction.

Most of Mr. H’s social circle is composed of friends he has known since childhood, none of whom are aware of his condition. He acknowledges that his feelings are “bizarre in nature” and so he has kept this secret on a “need-to-know” basis out of “fear of rejection, mockery, and damage to my reputation.” Through the years, he has sought out and encountered others with this condition, first anonymously on the internet, then in-person once he gets to know and trust them. He claims to know and be friendly with several people with xenomelia in his own city, some of whom have undergone amputation and are extremely happy with the results. According to Mr. H, there is a community aspect to xenomelia in his city, and people with the condition often meet each other socially. He has revealed his secret to 2 women he dated, including his present wife, who he told 3 years into their relationship. “I was prepared for her to leave me,” he recalls. Although he has never connected the desire for amputation with sexuality, he certainly believes that amputating his left leg would enhance his sex life. “Do I find amputees sexy?” he asks, “I would say yes.” On a 10-point scale, he considers his sex life to be a “7 or 8,” and it would reach 10 if he underwent amputation.

Mr. H has a calendar on which he keeps track of the days when he feels “impaired” by his xenomelia. He marks each day as either “red” or “green.” So far, he does not recognize a pattern of exacerbation. “I have my good days, then I have my bad days,” he laments. “On good days, I think about amputation and where my leg should actually end, but it is something I can quickly push off. On my bad days, I am constantly reminded in one way or another that, yes, I have this limb that should not be.” While he has never sought treatment for this condition from a health care professional, he developed his own therapeutic regimen that includes yoga, hiking, and daily use of cannabis, which “helps take the edge off.” He used alcohol in the past as self-medication, but stopped drinking to excess when it started to disrupt other aspects of his life. According to Mr. H, the goal is to distract himself from the condition, which provides temporary relief. “I find if my mind is more engaged, the amputation thoughts are fewer and less in intensity.” He reports that the months leading up to his wedding were particularly therapeutic because wedding planning provided an excellent distraction.

Overall, his current desire for amputation is steadily increasing. “Lately it has become more of a roller coaster,” he says. “If there’s a safe way to do it, I’ll do it.” An amputation would allow him to “feel good, complete, grounded, and content.” If he were to undergo amputation, he would use a prosthetic in order to retain mobility and keep his physique as discreet as possible. He has made initial inquiries into getting an amputation, saying, “I have heard of rumors of surgeons willing to perform the surgery, for a price. However, I have not completed the ‘vetting process’ to actually come into contact with the surgeons themselves.” Similar to others with xenomelia, he is easily able to draw a line on his leg, exactly where the desired amputation should occur.⁸ For most of his life, that line would have been 2 inches above his knee, but in recent years, the line has drifted lower, to 2 inches below the knee. However, he “wouldn’t mind either” line of amputation. He indicates the area below the desired line is less sensitive to pain than the corresponding part of his right leg, particularly his toes.

Mr. H’s wife is extremely supportive and understanding of her husband’s condition, but is opposed to the possibility of amputation (Box).

Box
Xenomelia: A spouse's perspective

Continue to: Much left to be learned about xenomelia

Much left to be learned about xenomelia

What remains to be discovered about xenomelia falls into 2 areas:

• the possible usefulness of various neuroimaging modalities (morphological MRI, functional MRI, magnetic resonance spectroscopy, and diffusion tensor imaging) to identify and localize anomalous neural pathways or neuroanatomical foci associated with this condition, such as an aberrantly developed or poorly myelinated right parietal lobe, which houses the limb’s physical proprioception
• a biopsychosocial inquiry into whether there exists a specific combination of a given individual’s organic brain, mind, and environmental interactions that may give rise to this condition, and whether we might detect a prodrome that arises in early childhood. The objective of any research into this condition would be to minimize its effects, if not prevent them altogether.¹

As this case illustrates, xenomelia begins in early childhood, with symptoms being reported in children as young as age 3.⁷ However, no published literature has investigated these early stages. We’ve learned that individuals with xenomelia often can point to key childhood experiences or memories related to seeing people with amputated limbs. They remember feeling a sense of wonder, fascination, or other strong emotion. It may be in this memory that xenomelia is permanently imprinted. This was definitely true for Mr. H, who never knew a time when he didn’t endure some level of debilitation from xenomelia, and distinctly remembers feeling jealous upon seeing a man with the amputated leg standing on crutches in a store parking lot. Although he has come across many amputees in his life, Mr. H says he vividly remembers everything about that particular man in that particular moment, adding “I can still see the clothes he was wearing. I can still see the cars in the parking lot.” That was likely his moment of vivid and powerful imprinting.

Particularly influential changes occur in adolescence, not just in the course of physical development, but in the formulation of self-identity, which involves the inevitable comparison of one’s own appearance to that of others, with heightened awareness of what others might perceive. This phenomenon is known as “the imaginary audience,” and it is often overemphasized in the minds of individuals with xenomelia.⁷ Mr. H is a textbook example of someone acutely aware of his “audience,” suffering from the embarrassment that came from being less wealthy than others at his school, and having to manage his ADHD in plain sight of his classmates, who knew that he required medication. It is no surprise that he felt like an outcast and got suspended for fighting. He would relieve anxiety by tying his leg up and staring at himself in the mirror, finding refuge in front of an audience of one that understood and sympathized with his suffering.

Among the most notorious aspects of this condition is investigation into the possibility of there being a sexual component to the desire for amputation. The notion that the desire is a fetish employed for the purpose of sexual arousal was first propagated by Penthouse magazine in the 1970s.⁹ Learning that xenomelia exists in a child long before sexual maturation—and in an older adult long after sexual drive peaks—suggests the condition is independent of sexuality. However, this aspect of xenomelia continues to be investigated. A recent study found that >70% of individuals with xenomelia are at least partially motivated by the perceived enhancement in sexual gratification.¹⁰ Individuals with this motivation are predominantly male, homosexual, come from a religious background, and are far more likely to self-amputate.¹⁰ Mr. H admitted that he is sexually attracted to amputees, and while he had no complaints about his sex life, he felt it could only reach the highest levels of gratification if he were an amputee.

It is reasonable to posit that there is a genetic mechanism that creates a cortical template of one’s body, and this template connects with the limbic system, encoding a visual preference for and attraction to one’s own idealized and preferred body morphology that includes an amputated limb.¹¹ Therefore, if Mr. H sees himself as an amputee, it would be reasonable for him to identify with and be attracted to other amputees. However, Mr. H is clearly not preoccupied with sexuality, and believes that heightened sexual gratification would be an ancillary bonus, and not the main objective, of amputation.

Continue to: Most individuals who have particpated in research studies about xenomelia tend to...

Most individuals who have participated in research studies about xenomelia tend to be older, mainly in their 60s. This is particularly true of individuals who go through with amputation. At some point, the need for a person to invoke their autonomy, alleviate their debilitation, and fulfill their desire may supersede their aversion to physical disability and social ridicule. At this stage in his life, Mr. H can’t commit to going forward with the amputation. However, he regards the likelihood of undergoing amputation to be quite high. He made initial inquiries to find a surgeon who would be willing to perform the procedure. Given that he has found people with xenomelia who have undergone amputation, he will likely will be able find a surgeon to perform the procedure. Mr. H reports that just about everyone he has ever known with xenomelia who underwent amputation is completely satisfied with their decision, even years later. He has come across only one person who regretted the amputation, and he believes that person was likely suffering from other psychiatric issues, and did not have true xenomelia.

In the mind of an individual with xenomelia, the desire for amputation is separate from a desire to be disabled. Mr. H is mindful of the assumed irrationality of removing a healthy but “alien” limb to replace it with a prosthetic limb that is equally alien. The perceived irony is not lost on him. He values his mobility, and has no desire to use crutches, a wheelchair, or any other ambulatory tool. This is consistent with most individuals with xenomelia, who are neither motived by the desire to flaunt their amputated limb, nor by the sympathy they might receive from others by endorsing impaired mobility. They don’t consider themselves disabled. On the contrary, for them, amputation is a much-desired enhancement to their health and well-being.

Increased opportunities for research

The internet, social media, and even peer-reviewed medical journals offer ever-increasing opportunities for individuals with xenomelia, such as Mr. H, to have their story told, regardless of whether they choose to identify themselves or remain anonymous. There are no published data about the prevalence of xenomelia, but it is almost certainly rare. However, if Mr. H was able to meet multiple people with xeno­melia in his own city and form a supportive community with them, then perhaps it isn’t exactly as rare as one might initially assume. People with xenomelia may tend to look for each other, hoping those with the same condition might show them the greatest empathy.

From Mr. H’s experience, it appears that it would be possible to locate a sufficient number of individuals with xenomelia for the purposes of conducting research, which might allow for results with acceptable statistical power. There are plenty of individual patient stories, and by documenting these stories in published literature, it is likely that patterns would emerge and causality might be determined. Such data might be bolstered by a possible strong neurologic corroboration based on what is found via neuroimaging.

Informed research into xenomelia is still in the early stages, and it is clear that there is much left to discover. It is vital that, moving forward, investigation into this condition be thorough and objective, with the goal of alleviating this secretive and debilitating neuropsychiatric condition.

Continue to: Bottom Line

Individuals with xenomelia have the persistent belief that one or more of their limbs does not belong to their body but is an alien appendage that should be removed. Patients with this condition may resort to self-amputation or self-mutilation that requires subsequent surgical amputation. Xenomelia may be related to anomalous brain development, with a lack of neural representation of a limb in the right parietal lobe.

Related Resources

• Hilti LM, Hänggi J, Vitacco DA, et al. The desire for healthy limb amputation: structural brain correlates and clinical features of xenomelia. Brain. 2013;136(pt 1):318-329.
• Brugger P, Lenggenhager B, Giummarra MJ. Xenomelia: a social neuroscience view of altered bodily self-consciousness. Front Psychol. 2013;4:204. doi:10.3389/fpsyg.2013.00204.

Elevated levels of circulating enzymes that are frequently of hepatic origin (aminotransferases and alkaline phosphatase) and bilirubin in the absence of symptoms are common in clinical practice. A dogmatic but true statement holds that there are no trivial elevations in these substances. All persistent elevations of liver enzymes need a methodical evaluation and an appropriate working diagnosis.¹

Here, we outline a framework for the workup and treatment of common causes of liver enzyme elevations.

PATTERN OF ELEVATION: CHOLESTATIC OR HEPATOCELLULAR

Based on the pattern of elevation, causes of elevated liver enzymes can be sorted into disorders of cholestasis and disorders of hepatocellular injury (Table 1).¹

Cholestatic disorders tend to cause elevations in alkaline phosphatase, bilirubin, and gamma-glutamyl transferase (GGT).

Hepatocellular injury raises levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

HOW SHOULD ABNORMAL RESULTS BE EVALUATED?

When approaching liver enzyme elevations, the clinician should develop a working differential diagnosis based on the medical and social history and physical examination.

Think about alcohol, drugs, and fat

The most common causes of liver enzyme elevation are alcohol toxicity, medication overdose, and fatty liver disease.

Alcohol intake should be ascertained. “Significant” consumption is defined as more than 21 drinks per week in men or more than 14 drinks per week in women, over a period of at least 2 years.²

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

Alcoholic liver disease can be difficult to diagnose, as many people are initially reluctant to fully disclose how much they drink, but it should be suspected when the ratio of AST to ALT is 2 or greater.

In a classic study, a ratio greater than 2 was found in 70% of patients with alcoholic hepatitis and cirrhosis, compared with 26% of patients with postnecrotic cirrhosis, 8% with chronic hepatitis, 4% with viral hepatitis, and none with obstructive jaundice.³ Importantly, the disorder is often correctable if the patient is able to remain abstinent from alcohol over time.

A detailed medication history is important and should focus especially on recently added medications, dosage changes, medication overuse, and use of nonprescription drugs and herbal supplements. Common medications that affect liver enzyme levels include statins, which cause hepatic dysfunction primarily during the first 3 months of therapy, nonsteroidal anti-inflammatory drugs, antiep­ileptic drugs, antibiotics, anabolic steroids, and acetaminophen (Table 2).¹ Use of illicit drugs and herbal remedies should be discussed, as they may cause toxin-mediated hepatitis.

Although inflammation from drug toxicity will resolve if the offending agent is discontinued, complete recovery may take weeks to months.⁴

A pertinent social history includes exposure to environmental hepatotoxins such as amatoxin (contained in some wild mushrooms) and occupational hazards (eg, vinyl chloride). Risk factors for viral hepatitis should be evaluated, including intravenous drug use, blood transfusions, unprotected sexual contact, organ transplant, perinatal transmission, and a history of work in healthcare facilities or travel to regions in which hepatitis A or E is endemic.

The medical and family history should include details of associated conditions, such as:

• Right heart failure (a cause of congestive hepatopathy)
• Metabolic syndrome (associated with fatty liver disease)
• Inflammatory bowel disease and primary sclerosing cholangitis
• Early-onset emphysema and alpha-1 antitrypsin deficiency.

The physical examination should be thorough, with emphasis on the abdomen, and search for stigmata of advanced liver disease such as hepatomegaly, splenomegaly, ascites, edema, spider angiomata, jaundice, and asterixis. Any patient with evidence of chronic liver disease should be referred to a subspecialist for further evaluation.

Abnormal liver enzyme findings or physical examination findings should direct the subsequent diagnostic workup with laboratory testing and imaging.⁵

For cholestasis. If laboratory data are consistent with cholestasis or abnormal bile flow, it should be further characterized as extrahepatic or intrahepatic. Common causes of extrahepatic cholestasis include biliary tree obstruction due to stones or malignancy, often visualized as intraductal biliary dilation on ultrasonography of the right upper quadrant. Common causes of intrahepatic cholestasis include viral and alcoholic hepatitis, nonalcoholic steatohepatitis, certain drugs and toxins such as alkylated steroids and herbal medications, infiltrative diseases such as amyloid, sarcoid, lymphoma, and tuberculosis, and primary biliary cholangitis.

Abnormal findings on ultrasonography should be further pursued with advanced imaging, ie, computed tomography or magnetic resonance cholangiopancreatography (MRCP). The confirmation of a lesion on imaging is often followed by endoscopic retrograde cholangiopancreatography (ERCP) in an attempt to obtain biopsy samples, remove obstructions, and place therapeutic stents. In instances when endoscopic attempts fail to relieve the obstruction, surgical referral may be appropriate.

For nonhepatobiliary problems. Depending on clinical presentation, it may also be important to consider nonhepatobiliary causes of elevated liver enzymes.

Alkaline phosphatase is found in many other tissue types, including bone, kidney, and the placenta, and can be elevated during pregnancy, adolescence, and even after fatty meals due to intestinal release.⁶ After screening for the aforementioned physiologic conditions, isolated elevated alkaline phosphatase should be further evaluated by obtaining GGT or 5-nucleotidase levels, which are more specifically of hepatic origin. If these levels are within normal limits, further evaluation for conditions of bone growth and cellular turnover such as Paget disease, hyperparathyroidism, and malignancy should be considered. Specifically, Stauffer syndrome should be considered when there is a paraneoplastic rise in the alkaline phosphatase level in the setting of renal cell carcinoma without liver metastases.

AST and ALT levels may also be elevated in clinical situations and syndromes unrelated to liver disease. Rhabdomyolysis, for instance, may be associated with elevations of AST in more than 90% of cases, and ALT in more than 75%.⁷ Markers of muscle injury including serum creatine kinase should be obtained in the setting of heat stroke, muscle weakness, strenuous activity, or seizures, as related elevations in AST and ALT may not always be clinically indicative of liver injury.

Given the many conditions that may cause elevated liver enzymes, evaluation and treatment should focus on identifying and removing offending agents and targeting the underlying process with appropriate medical therapy.

FATTY LIVER

With rates of obesity and type 2 diabetes on the rise in the general population, identifying and treating nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) require increased awareness and close coordination between primary care providers and subspecialists.

According to current estimates, up to one-third of the US population (100 million people) may have NAFLD, and 1% to 3% of the population (4–6 million people) likely have NASH, defined as steatosis with inflammation. Development of NASH places patients at a significantly higher risk of fibrosis, hepatocellular injury, and cancer.⁸

NAFLD is more common in men than in women. It is present in around 80% to 90% of obese adults, two-thirds of adults with type 2 diabetes, and many people with hyperlipidemia. It is also becoming more common in children, with 40% to 70% of obese children likely having some element of NAFLD.

Diagnosis of fatty liver

Although liver enzymes are more likely to be abnormal in individuals with NAFLD, many individuals with underlying NAFLD may have normal laboratory evaluations. ALT may be elevated in only up to 20% of cases and does not likely correlate with the level of underlying liver damage, although increasing GGT may serve as a marker of fibrosis over time.^9–11 In contrast to alcohol injury, however, the AST-ALT ratio is usually less than 1.0.

Noninvasive tools for diagnosing NAFLD include the NAFLD fibrosis score, which incorporates age, hyperglycemia, body mass index, platelet count, albumin level, and AST-ALT ratio. This and related scoring algorithms may be useful in differentiating patients with minimal fibrosis from those with advanced fibrosis.^12,13

Ultrasonography is a first-line diagnostic test for steatosis, although it may demonstrate fatty infiltration only around 60% of the time. Computed tomography and magnetic resonance imaging are more sensitive, but costlier. Transient elastography (FibroScan; Echosens, Paris, France) has become more popular and has been shown to correlate with findings on liver biopsy in diagnosing or excluding advanced liver fibrosis.^14,15

The gold standard for diagnosing NAFLD and NASH is identifying fat-laden hepatocytes or portal inflammation on biopsy; however, biopsy is generally reserved for cases in which the diagnosis remains uncertain.

Behavioral treatment

The primary treatment for NAFLD consists of behavioral modification including weight loss, exercise, and adherence to a low-fat diet, in addition to tight glycemic control and treatment of any underlying lipid abnormalities. Studies have shown that a reduction of 7% to 10% of body weight is associated with a decrease in the inflammation of NAFLD, though no strict guidelines have been established.¹⁶

Given the prevalence of NAFLD and the need for longitudinal treatment, primary care physicians will play a significant role in long-term monitoring and management of patients with fatty liver disease.

Hereditary hemochromatosis

Hereditary hemochromatosis is the most common inherited liver disorder in adults of European descent,¹⁷ and can be effectively treated if discovered early. But its clinical diagnosis can be challenging, as many patients have no symptoms at presentation despite abnormal liver enzyme levels. Early symptoms may include severe fatigue, arthralgias, and, in men, impotence, before the appearance of the classic triad of “bronze diabetes” with cirrhosis, diabetes, and darkening of the skin.¹⁸

If hemochromatosis is suspected, laboratory tests should include a calculation of percent transferrin saturation, with saturation greater than 45% warranting serum ferritin measurement to evaluate for iron overload (ferritin > 200–300 ng/mL in men, > 150–200 ng/mL in women).¹⁹ If iron overload is confirmed, referral to a gastroenterologist is recommended.

Genetic evaluation is often pursued, but patients may ultimately require liver biopsy regardless of the findings, as some patients homozygous for the HFE mutation C282Y may not have clinical hemochromatosis, whereas others with hereditary hemochromatosis may not have the HFE mutation.

Therapeutic phlebotomy is the treatment of choice, and most patients tolerate it well.

Chronic hepatitis B virus and hepatitis C virus infections

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common in the United States, with HBV affecting more than 1 million people and HCV affecting an estimated 3.5 million.

Chronic HCV infection. Direct-acting antiviral drugs have revolutionized HCV treatment and have led to a sustained viral response and presumed cure at 12 weeks in more than 95% of cases across all HCV genotypes.²⁰ Given the recent development of effective and well-tolerated treatments, primary care physicians have assumed a pivotal role in screening for HCV.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America²¹ recommend screening for HCV in people who have risk factors for it, ie:

• HCV exposure
• HIV infection
• Behavioral or environmental risks for contracting the virus such as intravenous drug use or incarceration
• Birth between 1945 and 1965 (one-time testing).

If HCV antibody screening is positive, HCV RNA should be obtained to quantify the viral load and confirm active infection, and genotype testing should be performed to guide treatment. Among the 6 most common HCV genotypes, genotype 1 is the most common in North America, accounting for over 70% of cases in the United States.

Although recommendations and therapies are constantly evolving, the selection of a treatment regimen and the duration of therapy are determined by viral genotype, history of prior treatment, stage of liver fibrosis, potential drug interactions, and frequently, medication cost and insurance coverage.

HBV infection. The treatment for acute HBV infection is generally supportive, though viral suppression with tenofovir or entecavir may be required for those who develop coagulopathy, bilirubinemia, or liver failure. Treatment of chronic HBV infection may not be required and is generally considered for those with elevated ALT, high viral load, or evidence of liver fibrosis on noninvasive measurements such as transient elastography.

Autoimmune hepatitis

Autoimmune causes of liver enzyme elevations should also be considered during initial screening. Positive antinuclear antibody and positive antismooth muscle antibody tests are common in cases of autoimmune hepatitis.²² Autoimmune hepatitis affects women more often than men, with a ratio of 4:1. The peaks of incidence occur during adolescence and between ages 30 and 45.²³

Primary biliary cholangitis

Additionally, an elevated alkaline phosphatase level should raise concern for underlying primary biliary cholangitis (formerly called primary biliary cirrhosis), an autoimmune disorder that affects the small and medium intrahepatic bile ducts. Diagnosis of primary biliary cholangitis can be assisted by a positive test for antimitochondrial antibody, present in almost 90% of patients.²⁴

Primary sclerosing cholangitis

Elevated alkaline phosphatase is also the hallmark of primary sclerosing cholangitis, which is associated with inflammatory bowel disease.²⁵ Primary sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, which are visualized on MRCP and confirmed by biopsy if needed.

REFERRAL

Subspecialty referral should be considered if the cause remains ambiguous or unknown, if there is concern for a rare hepatic disorder such as an autoimmune condition, Wilson disease, or alpha-1 antitrypsin deficiency, or if there is evidence of advanced or chronic liver disease.

Primary care physicians are at the forefront of detecting and diagnosing liver disease, and close coordination with subspecialists will remain crucial in delivering patient care.

Elevated levels of circulating enzymes that are frequently of hepatic origin (aminotransferases and alkaline phosphatase) and bilirubin in the absence of symptoms are common in clinical practice. A dogmatic but true statement holds that there are no trivial elevations in these substances. All persistent elevations of liver enzymes need a methodical evaluation and an appropriate working diagnosis.¹

Here, we outline a framework for the workup and treatment of common causes of liver enzyme elevations.

PATTERN OF ELEVATION: CHOLESTATIC OR HEPATOCELLULAR

Based on the pattern of elevation, causes of elevated liver enzymes can be sorted into disorders of cholestasis and disorders of hepatocellular injury (Table 1).¹

Cholestatic disorders tend to cause elevations in alkaline phosphatase, bilirubin, and gamma-glutamyl transferase (GGT).

Hepatocellular injury raises levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

HOW SHOULD ABNORMAL RESULTS BE EVALUATED?

When approaching liver enzyme elevations, the clinician should develop a working differential diagnosis based on the medical and social history and physical examination.

Think about alcohol, drugs, and fat

The most common causes of liver enzyme elevation are alcohol toxicity, medication overdose, and fatty liver disease.

Alcohol intake should be ascertained. “Significant” consumption is defined as more than 21 drinks per week in men or more than 14 drinks per week in women, over a period of at least 2 years.²

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

Alcoholic liver disease can be difficult to diagnose, as many people are initially reluctant to fully disclose how much they drink, but it should be suspected when the ratio of AST to ALT is 2 or greater.

In a classic study, a ratio greater than 2 was found in 70% of patients with alcoholic hepatitis and cirrhosis, compared with 26% of patients with postnecrotic cirrhosis, 8% with chronic hepatitis, 4% with viral hepatitis, and none with obstructive jaundice.³ Importantly, the disorder is often correctable if the patient is able to remain abstinent from alcohol over time.

A detailed medication history is important and should focus especially on recently added medications, dosage changes, medication overuse, and use of nonprescription drugs and herbal supplements. Common medications that affect liver enzyme levels include statins, which cause hepatic dysfunction primarily during the first 3 months of therapy, nonsteroidal anti-inflammatory drugs, antiep­ileptic drugs, antibiotics, anabolic steroids, and acetaminophen (Table 2).¹ Use of illicit drugs and herbal remedies should be discussed, as they may cause toxin-mediated hepatitis.

Although inflammation from drug toxicity will resolve if the offending agent is discontinued, complete recovery may take weeks to months.⁴

A pertinent social history includes exposure to environmental hepatotoxins such as amatoxin (contained in some wild mushrooms) and occupational hazards (eg, vinyl chloride). Risk factors for viral hepatitis should be evaluated, including intravenous drug use, blood transfusions, unprotected sexual contact, organ transplant, perinatal transmission, and a history of work in healthcare facilities or travel to regions in which hepatitis A or E is endemic.

The medical and family history should include details of associated conditions, such as:

• Right heart failure (a cause of congestive hepatopathy)
• Metabolic syndrome (associated with fatty liver disease)
• Inflammatory bowel disease and primary sclerosing cholangitis
• Early-onset emphysema and alpha-1 antitrypsin deficiency.

The physical examination should be thorough, with emphasis on the abdomen, and search for stigmata of advanced liver disease such as hepatomegaly, splenomegaly, ascites, edema, spider angiomata, jaundice, and asterixis. Any patient with evidence of chronic liver disease should be referred to a subspecialist for further evaluation.

Abnormal liver enzyme findings or physical examination findings should direct the subsequent diagnostic workup with laboratory testing and imaging.⁵

For cholestasis. If laboratory data are consistent with cholestasis or abnormal bile flow, it should be further characterized as extrahepatic or intrahepatic. Common causes of extrahepatic cholestasis include biliary tree obstruction due to stones or malignancy, often visualized as intraductal biliary dilation on ultrasonography of the right upper quadrant. Common causes of intrahepatic cholestasis include viral and alcoholic hepatitis, nonalcoholic steatohepatitis, certain drugs and toxins such as alkylated steroids and herbal medications, infiltrative diseases such as amyloid, sarcoid, lymphoma, and tuberculosis, and primary biliary cholangitis.

Abnormal findings on ultrasonography should be further pursued with advanced imaging, ie, computed tomography or magnetic resonance cholangiopancreatography (MRCP). The confirmation of a lesion on imaging is often followed by endoscopic retrograde cholangiopancreatography (ERCP) in an attempt to obtain biopsy samples, remove obstructions, and place therapeutic stents. In instances when endoscopic attempts fail to relieve the obstruction, surgical referral may be appropriate.

For nonhepatobiliary problems. Depending on clinical presentation, it may also be important to consider nonhepatobiliary causes of elevated liver enzymes.

Alkaline phosphatase is found in many other tissue types, including bone, kidney, and the placenta, and can be elevated during pregnancy, adolescence, and even after fatty meals due to intestinal release.⁶ After screening for the aforementioned physiologic conditions, isolated elevated alkaline phosphatase should be further evaluated by obtaining GGT or 5-nucleotidase levels, which are more specifically of hepatic origin. If these levels are within normal limits, further evaluation for conditions of bone growth and cellular turnover such as Paget disease, hyperparathyroidism, and malignancy should be considered. Specifically, Stauffer syndrome should be considered when there is a paraneoplastic rise in the alkaline phosphatase level in the setting of renal cell carcinoma without liver metastases.

AST and ALT levels may also be elevated in clinical situations and syndromes unrelated to liver disease. Rhabdomyolysis, for instance, may be associated with elevations of AST in more than 90% of cases, and ALT in more than 75%.⁷ Markers of muscle injury including serum creatine kinase should be obtained in the setting of heat stroke, muscle weakness, strenuous activity, or seizures, as related elevations in AST and ALT may not always be clinically indicative of liver injury.

Given the many conditions that may cause elevated liver enzymes, evaluation and treatment should focus on identifying and removing offending agents and targeting the underlying process with appropriate medical therapy.

FATTY LIVER

With rates of obesity and type 2 diabetes on the rise in the general population, identifying and treating nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) require increased awareness and close coordination between primary care providers and subspecialists.

According to current estimates, up to one-third of the US population (100 million people) may have NAFLD, and 1% to 3% of the population (4–6 million people) likely have NASH, defined as steatosis with inflammation. Development of NASH places patients at a significantly higher risk of fibrosis, hepatocellular injury, and cancer.⁸

NAFLD is more common in men than in women. It is present in around 80% to 90% of obese adults, two-thirds of adults with type 2 diabetes, and many people with hyperlipidemia. It is also becoming more common in children, with 40% to 70% of obese children likely having some element of NAFLD.

Diagnosis of fatty liver

Although liver enzymes are more likely to be abnormal in individuals with NAFLD, many individuals with underlying NAFLD may have normal laboratory evaluations. ALT may be elevated in only up to 20% of cases and does not likely correlate with the level of underlying liver damage, although increasing GGT may serve as a marker of fibrosis over time.^9–11 In contrast to alcohol injury, however, the AST-ALT ratio is usually less than 1.0.

Noninvasive tools for diagnosing NAFLD include the NAFLD fibrosis score, which incorporates age, hyperglycemia, body mass index, platelet count, albumin level, and AST-ALT ratio. This and related scoring algorithms may be useful in differentiating patients with minimal fibrosis from those with advanced fibrosis.^12,13

Ultrasonography is a first-line diagnostic test for steatosis, although it may demonstrate fatty infiltration only around 60% of the time. Computed tomography and magnetic resonance imaging are more sensitive, but costlier. Transient elastography (FibroScan; Echosens, Paris, France) has become more popular and has been shown to correlate with findings on liver biopsy in diagnosing or excluding advanced liver fibrosis.^14,15

The gold standard for diagnosing NAFLD and NASH is identifying fat-laden hepatocytes or portal inflammation on biopsy; however, biopsy is generally reserved for cases in which the diagnosis remains uncertain.

Behavioral treatment

The primary treatment for NAFLD consists of behavioral modification including weight loss, exercise, and adherence to a low-fat diet, in addition to tight glycemic control and treatment of any underlying lipid abnormalities. Studies have shown that a reduction of 7% to 10% of body weight is associated with a decrease in the inflammation of NAFLD, though no strict guidelines have been established.¹⁶

Given the prevalence of NAFLD and the need for longitudinal treatment, primary care physicians will play a significant role in long-term monitoring and management of patients with fatty liver disease.

Hereditary hemochromatosis

Hereditary hemochromatosis is the most common inherited liver disorder in adults of European descent,¹⁷ and can be effectively treated if discovered early. But its clinical diagnosis can be challenging, as many patients have no symptoms at presentation despite abnormal liver enzyme levels. Early symptoms may include severe fatigue, arthralgias, and, in men, impotence, before the appearance of the classic triad of “bronze diabetes” with cirrhosis, diabetes, and darkening of the skin.¹⁸

If hemochromatosis is suspected, laboratory tests should include a calculation of percent transferrin saturation, with saturation greater than 45% warranting serum ferritin measurement to evaluate for iron overload (ferritin > 200–300 ng/mL in men, > 150–200 ng/mL in women).¹⁹ If iron overload is confirmed, referral to a gastroenterologist is recommended.

Genetic evaluation is often pursued, but patients may ultimately require liver biopsy regardless of the findings, as some patients homozygous for the HFE mutation C282Y may not have clinical hemochromatosis, whereas others with hereditary hemochromatosis may not have the HFE mutation.

Therapeutic phlebotomy is the treatment of choice, and most patients tolerate it well.

Chronic hepatitis B virus and hepatitis C virus infections

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common in the United States, with HBV affecting more than 1 million people and HCV affecting an estimated 3.5 million.

Chronic HCV infection. Direct-acting antiviral drugs have revolutionized HCV treatment and have led to a sustained viral response and presumed cure at 12 weeks in more than 95% of cases across all HCV genotypes.²⁰ Given the recent development of effective and well-tolerated treatments, primary care physicians have assumed a pivotal role in screening for HCV.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America²¹ recommend screening for HCV in people who have risk factors for it, ie:

• HCV exposure
• HIV infection
• Behavioral or environmental risks for contracting the virus such as intravenous drug use or incarceration
• Birth between 1945 and 1965 (one-time testing).

If HCV antibody screening is positive, HCV RNA should be obtained to quantify the viral load and confirm active infection, and genotype testing should be performed to guide treatment. Among the 6 most common HCV genotypes, genotype 1 is the most common in North America, accounting for over 70% of cases in the United States.

Although recommendations and therapies are constantly evolving, the selection of a treatment regimen and the duration of therapy are determined by viral genotype, history of prior treatment, stage of liver fibrosis, potential drug interactions, and frequently, medication cost and insurance coverage.

HBV infection. The treatment for acute HBV infection is generally supportive, though viral suppression with tenofovir or entecavir may be required for those who develop coagulopathy, bilirubinemia, or liver failure. Treatment of chronic HBV infection may not be required and is generally considered for those with elevated ALT, high viral load, or evidence of liver fibrosis on noninvasive measurements such as transient elastography.

Autoimmune hepatitis

Autoimmune causes of liver enzyme elevations should also be considered during initial screening. Positive antinuclear antibody and positive antismooth muscle antibody tests are common in cases of autoimmune hepatitis.²² Autoimmune hepatitis affects women more often than men, with a ratio of 4:1. The peaks of incidence occur during adolescence and between ages 30 and 45.²³

Primary biliary cholangitis

Additionally, an elevated alkaline phosphatase level should raise concern for underlying primary biliary cholangitis (formerly called primary biliary cirrhosis), an autoimmune disorder that affects the small and medium intrahepatic bile ducts. Diagnosis of primary biliary cholangitis can be assisted by a positive test for antimitochondrial antibody, present in almost 90% of patients.²⁴

Primary sclerosing cholangitis

Elevated alkaline phosphatase is also the hallmark of primary sclerosing cholangitis, which is associated with inflammatory bowel disease.²⁵ Primary sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, which are visualized on MRCP and confirmed by biopsy if needed.

REFERRAL

Subspecialty referral should be considered if the cause remains ambiguous or unknown, if there is concern for a rare hepatic disorder such as an autoimmune condition, Wilson disease, or alpha-1 antitrypsin deficiency, or if there is evidence of advanced or chronic liver disease.

Primary care physicians are at the forefront of detecting and diagnosing liver disease, and close coordination with subspecialists will remain crucial in delivering patient care.

Elevated levels of circulating enzymes that are frequently of hepatic origin (aminotransferases and alkaline phosphatase) and bilirubin in the absence of symptoms are common in clinical practice. A dogmatic but true statement holds that there are no trivial elevations in these substances. All persistent elevations of liver enzymes need a methodical evaluation and an appropriate working diagnosis.¹

Here, we outline a framework for the workup and treatment of common causes of liver enzyme elevations.

PATTERN OF ELEVATION: CHOLESTATIC OR HEPATOCELLULAR

Based on the pattern of elevation, causes of elevated liver enzymes can be sorted into disorders of cholestasis and disorders of hepatocellular injury (Table 1).¹

Cholestatic disorders tend to cause elevations in alkaline phosphatase, bilirubin, and gamma-glutamyl transferase (GGT).

Hepatocellular injury raises levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

HOW SHOULD ABNORMAL RESULTS BE EVALUATED?

When approaching liver enzyme elevations, the clinician should develop a working differential diagnosis based on the medical and social history and physical examination.

Think about alcohol, drugs, and fat

The most common causes of liver enzyme elevation are alcohol toxicity, medication overdose, and fatty liver disease.

Alcohol intake should be ascertained. “Significant” consumption is defined as more than 21 drinks per week in men or more than 14 drinks per week in women, over a period of at least 2 years.²

The exact pathogenesis of alcoholic hepatitis is incompletely understood, but alcohol is primarily metabolized by the liver, and damage likely occurs during metabolism of the ingested alcohol. AST elevations tend to be higher than ALT elevations; the reason is ascribed to hepatic deficiency of pyridoxal 5´-phosphate, a cofactor of the enzymatic activity of ALT, which leads to a lesser increase in ALT than in AST.

Alcoholic liver disease can be difficult to diagnose, as many people are initially reluctant to fully disclose how much they drink, but it should be suspected when the ratio of AST to ALT is 2 or greater.

In a classic study, a ratio greater than 2 was found in 70% of patients with alcoholic hepatitis and cirrhosis, compared with 26% of patients with postnecrotic cirrhosis, 8% with chronic hepatitis, 4% with viral hepatitis, and none with obstructive jaundice.³ Importantly, the disorder is often correctable if the patient is able to remain abstinent from alcohol over time.

A detailed medication history is important and should focus especially on recently added medications, dosage changes, medication overuse, and use of nonprescription drugs and herbal supplements. Common medications that affect liver enzyme levels include statins, which cause hepatic dysfunction primarily during the first 3 months of therapy, nonsteroidal anti-inflammatory drugs, antiep­ileptic drugs, antibiotics, anabolic steroids, and acetaminophen (Table 2).¹ Use of illicit drugs and herbal remedies should be discussed, as they may cause toxin-mediated hepatitis.

Although inflammation from drug toxicity will resolve if the offending agent is discontinued, complete recovery may take weeks to months.⁴

A pertinent social history includes exposure to environmental hepatotoxins such as amatoxin (contained in some wild mushrooms) and occupational hazards (eg, vinyl chloride). Risk factors for viral hepatitis should be evaluated, including intravenous drug use, blood transfusions, unprotected sexual contact, organ transplant, perinatal transmission, and a history of work in healthcare facilities or travel to regions in which hepatitis A or E is endemic.

The medical and family history should include details of associated conditions, such as:

• Right heart failure (a cause of congestive hepatopathy)
• Metabolic syndrome (associated with fatty liver disease)
• Inflammatory bowel disease and primary sclerosing cholangitis
• Early-onset emphysema and alpha-1 antitrypsin deficiency.

The physical examination should be thorough, with emphasis on the abdomen, and search for stigmata of advanced liver disease such as hepatomegaly, splenomegaly, ascites, edema, spider angiomata, jaundice, and asterixis. Any patient with evidence of chronic liver disease should be referred to a subspecialist for further evaluation.

Abnormal liver enzyme findings or physical examination findings should direct the subsequent diagnostic workup with laboratory testing and imaging.⁵

For cholestasis. If laboratory data are consistent with cholestasis or abnormal bile flow, it should be further characterized as extrahepatic or intrahepatic. Common causes of extrahepatic cholestasis include biliary tree obstruction due to stones or malignancy, often visualized as intraductal biliary dilation on ultrasonography of the right upper quadrant. Common causes of intrahepatic cholestasis include viral and alcoholic hepatitis, nonalcoholic steatohepatitis, certain drugs and toxins such as alkylated steroids and herbal medications, infiltrative diseases such as amyloid, sarcoid, lymphoma, and tuberculosis, and primary biliary cholangitis.

Abnormal findings on ultrasonography should be further pursued with advanced imaging, ie, computed tomography or magnetic resonance cholangiopancreatography (MRCP). The confirmation of a lesion on imaging is often followed by endoscopic retrograde cholangiopancreatography (ERCP) in an attempt to obtain biopsy samples, remove obstructions, and place therapeutic stents. In instances when endoscopic attempts fail to relieve the obstruction, surgical referral may be appropriate.

For nonhepatobiliary problems. Depending on clinical presentation, it may also be important to consider nonhepatobiliary causes of elevated liver enzymes.

Alkaline phosphatase is found in many other tissue types, including bone, kidney, and the placenta, and can be elevated during pregnancy, adolescence, and even after fatty meals due to intestinal release.⁶ After screening for the aforementioned physiologic conditions, isolated elevated alkaline phosphatase should be further evaluated by obtaining GGT or 5-nucleotidase levels, which are more specifically of hepatic origin. If these levels are within normal limits, further evaluation for conditions of bone growth and cellular turnover such as Paget disease, hyperparathyroidism, and malignancy should be considered. Specifically, Stauffer syndrome should be considered when there is a paraneoplastic rise in the alkaline phosphatase level in the setting of renal cell carcinoma without liver metastases.

AST and ALT levels may also be elevated in clinical situations and syndromes unrelated to liver disease. Rhabdomyolysis, for instance, may be associated with elevations of AST in more than 90% of cases, and ALT in more than 75%.⁷ Markers of muscle injury including serum creatine kinase should be obtained in the setting of heat stroke, muscle weakness, strenuous activity, or seizures, as related elevations in AST and ALT may not always be clinically indicative of liver injury.

Given the many conditions that may cause elevated liver enzymes, evaluation and treatment should focus on identifying and removing offending agents and targeting the underlying process with appropriate medical therapy.

FATTY LIVER

With rates of obesity and type 2 diabetes on the rise in the general population, identifying and treating nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) require increased awareness and close coordination between primary care providers and subspecialists.

According to current estimates, up to one-third of the US population (100 million people) may have NAFLD, and 1% to 3% of the population (4–6 million people) likely have NASH, defined as steatosis with inflammation. Development of NASH places patients at a significantly higher risk of fibrosis, hepatocellular injury, and cancer.⁸

NAFLD is more common in men than in women. It is present in around 80% to 90% of obese adults, two-thirds of adults with type 2 diabetes, and many people with hyperlipidemia. It is also becoming more common in children, with 40% to 70% of obese children likely having some element of NAFLD.

Diagnosis of fatty liver

Although liver enzymes are more likely to be abnormal in individuals with NAFLD, many individuals with underlying NAFLD may have normal laboratory evaluations. ALT may be elevated in only up to 20% of cases and does not likely correlate with the level of underlying liver damage, although increasing GGT may serve as a marker of fibrosis over time.^9–11 In contrast to alcohol injury, however, the AST-ALT ratio is usually less than 1.0.

Noninvasive tools for diagnosing NAFLD include the NAFLD fibrosis score, which incorporates age, hyperglycemia, body mass index, platelet count, albumin level, and AST-ALT ratio. This and related scoring algorithms may be useful in differentiating patients with minimal fibrosis from those with advanced fibrosis.^12,13

Ultrasonography is a first-line diagnostic test for steatosis, although it may demonstrate fatty infiltration only around 60% of the time. Computed tomography and magnetic resonance imaging are more sensitive, but costlier. Transient elastography (FibroScan; Echosens, Paris, France) has become more popular and has been shown to correlate with findings on liver biopsy in diagnosing or excluding advanced liver fibrosis.^14,15

The gold standard for diagnosing NAFLD and NASH is identifying fat-laden hepatocytes or portal inflammation on biopsy; however, biopsy is generally reserved for cases in which the diagnosis remains uncertain.

Behavioral treatment

The primary treatment for NAFLD consists of behavioral modification including weight loss, exercise, and adherence to a low-fat diet, in addition to tight glycemic control and treatment of any underlying lipid abnormalities. Studies have shown that a reduction of 7% to 10% of body weight is associated with a decrease in the inflammation of NAFLD, though no strict guidelines have been established.¹⁶

Given the prevalence of NAFLD and the need for longitudinal treatment, primary care physicians will play a significant role in long-term monitoring and management of patients with fatty liver disease.

Hereditary hemochromatosis

Hereditary hemochromatosis is the most common inherited liver disorder in adults of European descent,¹⁷ and can be effectively treated if discovered early. But its clinical diagnosis can be challenging, as many patients have no symptoms at presentation despite abnormal liver enzyme levels. Early symptoms may include severe fatigue, arthralgias, and, in men, impotence, before the appearance of the classic triad of “bronze diabetes” with cirrhosis, diabetes, and darkening of the skin.¹⁸

If hemochromatosis is suspected, laboratory tests should include a calculation of percent transferrin saturation, with saturation greater than 45% warranting serum ferritin measurement to evaluate for iron overload (ferritin > 200–300 ng/mL in men, > 150–200 ng/mL in women).¹⁹ If iron overload is confirmed, referral to a gastroenterologist is recommended.

Genetic evaluation is often pursued, but patients may ultimately require liver biopsy regardless of the findings, as some patients homozygous for the HFE mutation C282Y may not have clinical hemochromatosis, whereas others with hereditary hemochromatosis may not have the HFE mutation.

Therapeutic phlebotomy is the treatment of choice, and most patients tolerate it well.

Chronic hepatitis B virus and hepatitis C virus infections

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are common in the United States, with HBV affecting more than 1 million people and HCV affecting an estimated 3.5 million.

Chronic HCV infection. Direct-acting antiviral drugs have revolutionized HCV treatment and have led to a sustained viral response and presumed cure at 12 weeks in more than 95% of cases across all HCV genotypes.²⁰ Given the recent development of effective and well-tolerated treatments, primary care physicians have assumed a pivotal role in screening for HCV.

The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America²¹ recommend screening for HCV in people who have risk factors for it, ie:

• HCV exposure
• HIV infection
• Behavioral or environmental risks for contracting the virus such as intravenous drug use or incarceration
• Birth between 1945 and 1965 (one-time testing).

If HCV antibody screening is positive, HCV RNA should be obtained to quantify the viral load and confirm active infection, and genotype testing should be performed to guide treatment. Among the 6 most common HCV genotypes, genotype 1 is the most common in North America, accounting for over 70% of cases in the United States.

Although recommendations and therapies are constantly evolving, the selection of a treatment regimen and the duration of therapy are determined by viral genotype, history of prior treatment, stage of liver fibrosis, potential drug interactions, and frequently, medication cost and insurance coverage.

HBV infection. The treatment for acute HBV infection is generally supportive, though viral suppression with tenofovir or entecavir may be required for those who develop coagulopathy, bilirubinemia, or liver failure. Treatment of chronic HBV infection may not be required and is generally considered for those with elevated ALT, high viral load, or evidence of liver fibrosis on noninvasive measurements such as transient elastography.

Autoimmune hepatitis

Autoimmune causes of liver enzyme elevations should also be considered during initial screening. Positive antinuclear antibody and positive antismooth muscle antibody tests are common in cases of autoimmune hepatitis.²² Autoimmune hepatitis affects women more often than men, with a ratio of 4:1. The peaks of incidence occur during adolescence and between ages 30 and 45.²³

Primary biliary cholangitis

Additionally, an elevated alkaline phosphatase level should raise concern for underlying primary biliary cholangitis (formerly called primary biliary cirrhosis), an autoimmune disorder that affects the small and medium intrahepatic bile ducts. Diagnosis of primary biliary cholangitis can be assisted by a positive test for antimitochondrial antibody, present in almost 90% of patients.²⁴

Primary sclerosing cholangitis

Elevated alkaline phosphatase is also the hallmark of primary sclerosing cholangitis, which is associated with inflammatory bowel disease.²⁵ Primary sclerosing cholangitis is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, which are visualized on MRCP and confirmed by biopsy if needed.

REFERRAL

Subspecialty referral should be considered if the cause remains ambiguous or unknown, if there is concern for a rare hepatic disorder such as an autoimmune condition, Wilson disease, or alpha-1 antitrypsin deficiency, or if there is evidence of advanced or chronic liver disease.

Primary care physicians are at the forefront of detecting and diagnosing liver disease, and close coordination with subspecialists will remain crucial in delivering patient care.

The balance between dietary intake and excretion of phosphorus can be impaired in patients with decreased renal function, leading to hyperphosphatemia. Many patients with end-stage renal disease on dialysis require phosphorus-binding drugs to control their serum phosphorus levels.

See related editorial and article

In this review, we discuss the pathophysiology of hyperphosphatemia in kidney disease, its consequences, and how to control it, focusing on the different classes of phosphorus binders.

ROLE OF THE INTERNIST

With kidney disease common and on the increase,¹ nephrologists and internists need to work together to provide optimal care.

Further, many internists in managed care plans and accountable care organizations now handle many tasks previously left to specialists—including prescribing and managing phosphorus binders in patients with kidney disease.

PATHOPHYSIOLOGY OF HYPERPHOSPHATEMIA

The pathophysiology of bone mineral disorders in kidney disease is complex. To simplify the discussion, we will address it in 3 parts:

• Phosphorus balance
• The interplay of hormones, including fibro­blast growth factor 23 (FGF23)
• The mechanism of hyperphosphatemia in kidney disease.

Phosphorus balance

Phosphorus is a macronutrient essential for a range of cellular functions that include structure, energy production, metabolism, and cell signaling. It exists primarily in the form of inorganic phosphate.

An average Western diet provides 20 mg of phosphorus per kilogram of body weight per day. Of this, 13 mg/kg is absorbed, and the rest is excreted in the feces.²

Absorption of dietary phosphorus occurs mainly in the jejunum. It is mediated by both a paracellular sodium-independent pathway (driven by high intraluminal phosphorus content) and by active sodium-dependent cotransporters. It is also influenced by diet and promoted by active vitamin D (1,25 dihydroxyvitamin D₃, also called calcitriol).³

Absorbed phosphorus enters the extracellular fluid and shifts in and out of the skeleton under the influence of parathyroid hormone.

Phosphorus excretion is handled almost entirely by the kidneys. Phosphorus is freely filtered at the glomerulus and reabsorbed mainly in the proximal tubule by sodium-phosphate cotransporters.

Normally, when phosphorus intake is adequate, most of the filtered phosphorus is reabsorbed and only 10% to 20% is excreted in the urine. However, the threshold for phosphorus reabsorption in the proximal tubule is influenced by parathyroid hormone, FGF23, and dietary phosphorus intake: low serum phosphate levels lead to an increase in the synthesis of sodium-phosphorus cotransporters, resulting in increased (nearly complete) proximal reabsorption and an increase in the serum phosphorus concentration.⁴ Conversely, both parathyroid hormone and FGF23 are phosphaturic and decrease the number of phosphorus transporters, which in turn leads to increased phosphorus excretion and a decrease in serum phosphorus concentration.⁵

Interplay of hormones

FGF23 is a phosphaturic glycoprotein secreted by osteoblasts and osteocytes. It acts by binding to fibroblastic growth receptor 1 in the presence of its coreceptor, the Klotho protein.⁶

FGF23 is regulated by serum phosphorus levels and plays a major role in the response to elevated serum phosphorus. It causes a direct increase in urinary phosphorus excretion, a decrease in intestinal phosphorus absorption (indirectly via inhibition of calcitriol), and decreased bone resorption via a decrease in parathyroid hormone production.⁷

Mechanism of hyperphosphatemia in kidney disease

In chronic kidney disease, phosphorus retention can trigger secondary hyperparathyroidism, as rising phosphorus levels stimulate FGF23. In the early stages of chronic kidney disease, this response can correct the phosphorus levels, but with several consequences:

• Decreased calcitriol due to its inhibition by FGF23⁹
• Hypocalcemia due to decreased calcitriol (leading to decreased intestinal calcium absorption) and calcium binding of retained phosphorus
• Elevated parathyroid hormone due to low calcitriol levels (lack of inhibitory feedback by calcitriol), hyperphosphatemia, and hypocalcemia (direct parathyroid hormone stimulation).

As the elevated phosphorus level is likely to be the triggering event behind secondary renal hyperparathyroidism, it needs to be controlled. This is accomplished by restricting dietary phosphorus and using phosphorus binders.

HYPERPHOSPHATEMIA MAY LEAD TO VASCULAR CALCIFICATION

Elevated serum phosphorus levels (normal range 2.48–4.65 mg/dL in adults¹¹) are associated with cardiovascular calcification and subsequent increases in mortality and morbidity rates. Elevations in serum phosphorus and calcium levels are associated with progression in vascular calcification¹² and likely account for the accelerated vascular calcification that is seen in kidney disease.¹³

Hyperphosphatemia has been identified as an independent risk factor for death in patients with end-stage renal disease,¹⁴ but that relationship is less clear in patients with chronic kidney disease. A study in patients with chronic kidney disease and not on dialysis found a lower mortality rate in those who were prescribed phosphorus binders,¹⁵ but the study was criticized for limitations in its design.

Hyperphosphatemia can also lead to adverse effects on bone health due to complications such as renal osteodystrophy.

However, in its 2017 update, the Kidney Disease: Improving Global Outcomes (KDIGO) program only “suggests” lowering elevated phosphorus levels “toward” the normal range in patients with chronic kidney disease stages G3a through G5D, ie, those with glomerular filtration rates less than 60 mL/min/1.73 m², including those on dialysis. The recommendation is graded 2C, ie, weak, based on low-quality evidence (https://kdigo.org/guidelines/ckd-mbd).

DIETARY RESTRICTION OF PHOSPHORUS

Diet is the major source of phosphorus intake. The average daily phosphorus consumption is  20 mg/kg, or 1,400 mg, and protein is the major source of dietary phosphorus.

In patients with stage 4 or 5 chronic kidney disease, the Kidney Disease Outcomes Quality Initiative recommends limiting protein intake to 0.6 mg/kg/day.¹⁶ However, in patients on hemodialysis, they recommend increasing protein intake to 1.1 mg/kg/day while limiting phosphorus intake to about 800 to 1,000 mg/day. This poses a challenge, as limiting phosphorus intake can reduce protein intake.

Sources of protein can be broadly classified as plant-based or animal-based. Animal protein contains organic phosphorus, which is easily absorbed.¹⁸ Plant protein may not be absorbed as easily.

Moe et al¹⁹ studied the importance of the protein source of phosphorus after 7 days of controlled diets. Despite equivalent protein and phosphorus concentrations in the vegetarian and meat-based diets, participants on the vegetarian diet had lower serum phosphorus levels, a trend toward lower 24-hour urinary phosphorus excretion, and significantly lower FGF23 levels than those on the meat-based diet. This suggests that a vegetarian diet may have advantages in terms of preventing hyperphosphatemia.

Another measure to reduce phosphorus absorption from meat is to boil it, which reduces the phosphorus content by 50%.²⁰

Processed foods containing additives and preservatives are very high in phosphorus²¹ and should be avoided, particularly as there is no mandate to label phosphorus content in food.

PHOSPHORUS AND DIALYSIS

Although hemodialysis removes phosphorus, it does not remove enough to keep levels within normal limits. Indeed, even when patients adhere to a daily phosphorus limit of 1,000 mg, phosphorus accumulates. If 70% of the phosphorus in the diet is absorbed, this is 4,500 to 5,000 mg in a week. A 4-hour hemodialysis session will remove only 1,000 mg of phosphorus, which equals about 3,000 mg for patients undergoing dialysis 3 times a week,²² far less than phosphorus absorption.

In patients on continuous ambulatory peritoneal dialysis, a daily regimen of 4 exchanges of 2 L per exchange removes about 200 mg of phosphorus per day. In a 2012 study, patients on nocturnal dialysis or home dialysis involving longer session length had greater lowering of phosphorus levels than patients undergoing routine hemodialysis.²³

Hence, phosphorus binders are often necessary in patients on routine hemodialysis or peritoneal dialysis.

PHOSPHORUS BINDERS

Phosphorus binders reduce serum phosphorus levels by binding with ingested phosphorus in the gastrointestinal tract and forming insoluble complexes that are not absorbed. For this reason they are much more effective when taken with meals. Phosphorus binders come in different formulations: pills, capsules, chewable tablets, liquids, and even powders that can be sprinkled on food.

The potency of each binder is quantified by its “phosphorus binder equivalent dose,” ie, its binding capacity compared with that of calcium carbonate as a reference.²⁴

Phosphorus binders are broadly divided into those that contain calcium and those that do not.

Calcium-containing binders

The 2 most commonly used preparations are calcium carbonate (eg, Tums) and calcium acetate (eg, Phoslo). While these are relatively safe, some studies suggest that their use can lead to accelerated vascular calcification.²⁵

According to KDIGO,²⁶ calcium-containing binders should be avoided in hypercalcemia and adynamic bone disease. Additionally, the daily elemental calcium intake from binders should be limited to 1,500 mg, with a total daily intake that does not exceed 2,000 mg.

The elemental calcium content of calcium carbonate is about 40% of its weight (eg, 200 mg of elemental calcium in a 500-mg tablet of Tums), while the elemental calcium content of calcium acetate is about 25%. Therefore, a patient who needs 6 g of calcium carbonate for efficacy will be ingesting 2.4 g of elemental calcium per day, and that exceeds the recommended daily maximum. The main advantage of calcium carbonate is its low cost and easy availability. Commonly reported side effects include nausea and constipation.

A less commonly used calcium-based binder is calcium citrate (eg, Calcitrate). It should, however, be avoided in chronic kidney disease because of the risk of aluminum accumulation. Calcium citrate can enhance intestinal absorption of aluminum from dietary sources, as aluminum can form complexes with citrate.²⁷

Calcium-free binders

There are several calcium-free binders. Some are based on metals such as aluminum, magnesium, iron, and lanthanum; others, such as sevelamer, are resin-based.

Aluminum- and magnesium-based binders are generally not used long-term in kidney disease because of the toxicity associated with aluminum and magnesium accumulation. However, aluminum hydroxide has an off-label use as a phosphorus binder in the acute setting, particularly when serum phosphorus levels are above 7 mg/dL.²⁸ The dose is 300 to 600 mg 3 times daily with meals for a maximum of 4 weeks.

Sevelamer. Approved by the US Food and Drug Administration (FDA) in 1998, sevelamer acts by trapping phosphorus through ion exchange and hydrogen binding. It has the advantage of being calcium-free, which makes it particularly desirable in patients with hypercalcemia.

The Renagel in New Dialysis²⁵ and Treat-To-Goal²⁹ studies were randomized controlled trials that looked at the effects of sevelamer vs calcium-based binders on the risk of vascular calcification. The primary end points were serum phosphorus and calcium levels, while the secondary end points were coronary artery calcification on computed tomography and thoracic vertebral bone density. Both studies demonstrated a higher risk of vascular calcification with the calcium-based binders.

Another possible benefit of sevelamer is an improvement in lipid profile. Sevelamer lowers total cholesterol and low-density lipoprotein cholesterol levels without affecting high-density lipoprotein cholesterol or triglyceride levels.³⁰ This is likely due to its bile acid-binding effect.³¹ Sevelamer has also been shown to lower C-reactive protein levels.³² While the cardiovascular profile appears to be improved with the treatment, there are no convincing data to confirm that those properties translate to a proven independent survival benefit.

The Calcium Acetate Renagel Evaluation³³ was a randomized controlled study comparing sevelamer and calcium acetate. The authors attempted to control for the lipid-lowering effects of sevelamer by giving atorvastatin to all patients in both groups who had a low-density lipoprotein level greater than 70 mg/dL. The study found sevelamer to be not inferior to calcium acetate in terms of mortality and coronary calcification.

Further studies such as the Brazilian Renagel and Calcium trial³⁴ and the Dialysis Clinical Outcomes Revisited trial failed to show a significant long-term benefit of sevelamer over calcium-based binders. However, a secondary statistical analysis of the latter study showed possible benefit of sevelamer over calcium acetate among those age 65 and older.³⁵

To understand how sevelamer could affect vascular calcification, Yilmaz et al³⁶ compared the effects of sevelamer vs calcium acetate on FGF23 and fetuin A levels. Fetuin A is an important inhibitor of vascular calcification and is progressively diminished in kidney disease, leading to accelerated calcification.³⁷ Patients on sevelamer had higher levels of fetuin A than their counterparts on calcium acetate.³⁷ The authors proposed increased fetuin A levels as a mechanism for decreased vascular calcification.

In summary, some studies suggest that sevelamer may offer the advantage of decreasing vascular calcification, but the data are mixed and do not provide a solid answer. The main disadvantages of sevelamer are a high pill burden and side effects of nausea and dyspepsia.

Lanthanum, a metallic element, was approved as a phosphorus binder by the FDA in 2008. It comes as a chewable tablet and offers the advantage of requiring the patient to take fewer pills than sevelamer and calcium-based binders.

Sucroferric oxyhydroxide comes as a chewable tablet. It was approved by the FDA in 2013. Although each tablet contains 500 mg of iron, it has not been shown to improve iron markers. In terms of phosphorus-lowering ability, it has been shown to be noninferior to sevelamer.³⁹ Advantages include a significantly lower pill burden. Disadvantages include gastrointestinal side effects such as diarrhea and nausea and the drug’s high cost.

Ferric citrate was approved by the FDA in 2014, and 1 g delivers 210 mg of elemental iron. The main advantage of ferric citrate is its ability to increase iron markers. The phase 3 trial that demonstrated its efficacy as a binder showed an increase in ferritin compared with the active control.⁴⁰ The study also showed a decrease in the need to use intravenous iron and erythropoesis-stimulating agents. This was thought to be due to improved iron stores, leading to decreased erythropoietin resistance.⁴¹

The mean number of ferric citrate tablets needed to achieve the desired phosphorus-lowering effect was 8 per day, containing 1,680 mg of iron. In comparison, oral ferrous sulfate typically provides 210 mg of iron per day.⁴²

Disadvantages of ferric citrate include high pill burden, high cost, and gastrointestinal side effects such as nausea and constipation.

Chitosan binds salivary phosphorus. It can potentially be used, but it is not approved, and its efficacy in lowering serum phosphorus remains unclear.⁴³

CHOOSING THE APPROPRIATE PHOSPHORUS BINDER

The choice of phosphorus binder is based on the patient’s serum calcium level and iron stores and on the drug’s side effect profile, iron pill burden, and cost. Involving patients in the choice after discussing potential side effects, pill burden, and cost is important for shared decision-making and could play a role in improving adherence.

Phosphorus binders are a major portion of the pill burden in patients with end-stage renal disease, possibly affecting patient adherence. The cost of phosphorus binders is estimated at half a billion dollars annually, underlining the significant economic impact of phosphorus control.¹¹

Calcium-based binders should be the first choice when there is secondary hyperparathyroidism without hypercalcemia. There is no clear evidence regarding the benefit of correcting hypocalcemia, but KDIGO recommends keeping the serum calcium level within the reference range. KDIGO also recommends restricting calcium-based binders in persistent hypercalcemia, arterial calcification, and adynamic bone disease. This recommendation is largely based on expert opinion.

Noncalcium-based binders, which in theory might prevent vascular calcification, should be considered for patients with at least 1 of the following⁴⁴:

• Complicated diabetes mellitus
• Vascular or valvular calcification
• Persistent inflammation.

Noncalcium-based binders are also preferred in low bone-turnover states such as adynamic bone disease, as elevated calcium can inhibit parathyroid hormone.

However, the advantage of noncalcium-based binders regarding vascular calcification is largely theoretical and has not been proven clinically. Indeed, there are data comparing long-term outcomes of the different classes of phosphorus binders, but studies were limited by short follow-up, and individual studies have lacked power to detect statistical significance between two classes of binders on long-term outcomes. Meta-analyses have provided conflicting data, with some suggesting better outcomes with sevelamer than with calcium-based binders, and with others failing to show any difference.⁴⁵

Because iron deficiency is common in kidney disease, ferric citrate, which can improve iron markers, may be a suitable option, provided its cost is covered by insurance.

SPECIAL CIRCUMSTANCES FOR THE USE OF PHOSPHORUS BINDERS

Tumor lysis syndrome

Tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.⁴⁶ Phosphorus binders in conjunction with intravenous hydration are used to treat hyperphosphatemia, but evidence about their efficacy in this setting is limited.

Hypocalcemia in tumor lysis syndrome is usually not treated unless symptomatic, as the calcium-phosphorus product can increase, leading to calcium phosphate crystallization. When the calcium-phosphorus product is greater than 60, there is a higher risk of calcium phosphate deposition in the renal tubules that can lead to acute renal failure in tumor lysis syndrome.⁴⁷ To lower the risk of calcium phosphate crystallization, calcium-based binders should be avoided in tumor lysis syndrome.

Total parenteral nutrition

Since patients on total parenteral nutrition do not eat, phosphorus binders are considered ineffective; there are no concrete data showing that phosphorus binders are effective in these patients.⁴⁸ In patients with kidney disease, the phosphorus content in the parenteral nutrition formulation must be reduced.

Pregnancy

Data on phosphorus binders in pregnancy are limited. Calcium can cross the placenta. Calcium carbonate can be used in pregnancy, and fetal harm is not expected if calcium concentrations are within normal limits.⁴⁹ Calcium acetate, sevelamer, and lanthanum are considered pregnancy category C drugs. Patients with advanced chronic kidney disease and end-stage renal disease who become pregnant must receive specialized obstetric care for high-risk pregnancy.

FUTURE DIRECTIONS

Future therapies may target FGF23 and other inflammatory markers that are up-regulated in renal hyperparathyroidism. However, trials studying these markers are needed to provide a better understanding of their role in bone mineral and cardiovascular health and in overall long-term outcomes. Additionally, randomized controlled trials are needed to study long-term nonsurrogate outcomes such as reduction in cardiovascular disease and rates of overall mortality.

The balance between dietary intake and excretion of phosphorus can be impaired in patients with decreased renal function, leading to hyperphosphatemia. Many patients with end-stage renal disease on dialysis require phosphorus-binding drugs to control their serum phosphorus levels.

See related editorial and article

In this review, we discuss the pathophysiology of hyperphosphatemia in kidney disease, its consequences, and how to control it, focusing on the different classes of phosphorus binders.

ROLE OF THE INTERNIST

With kidney disease common and on the increase,¹ nephrologists and internists need to work together to provide optimal care.

Further, many internists in managed care plans and accountable care organizations now handle many tasks previously left to specialists—including prescribing and managing phosphorus binders in patients with kidney disease.

PATHOPHYSIOLOGY OF HYPERPHOSPHATEMIA

The pathophysiology of bone mineral disorders in kidney disease is complex. To simplify the discussion, we will address it in 3 parts:

• Phosphorus balance
• The interplay of hormones, including fibro­blast growth factor 23 (FGF23)
• The mechanism of hyperphosphatemia in kidney disease.

Phosphorus balance

Phosphorus is a macronutrient essential for a range of cellular functions that include structure, energy production, metabolism, and cell signaling. It exists primarily in the form of inorganic phosphate.

An average Western diet provides 20 mg of phosphorus per kilogram of body weight per day. Of this, 13 mg/kg is absorbed, and the rest is excreted in the feces.²

Absorption of dietary phosphorus occurs mainly in the jejunum. It is mediated by both a paracellular sodium-independent pathway (driven by high intraluminal phosphorus content) and by active sodium-dependent cotransporters. It is also influenced by diet and promoted by active vitamin D (1,25 dihydroxyvitamin D₃, also called calcitriol).³

Absorbed phosphorus enters the extracellular fluid and shifts in and out of the skeleton under the influence of parathyroid hormone.

Phosphorus excretion is handled almost entirely by the kidneys. Phosphorus is freely filtered at the glomerulus and reabsorbed mainly in the proximal tubule by sodium-phosphate cotransporters.

Normally, when phosphorus intake is adequate, most of the filtered phosphorus is reabsorbed and only 10% to 20% is excreted in the urine. However, the threshold for phosphorus reabsorption in the proximal tubule is influenced by parathyroid hormone, FGF23, and dietary phosphorus intake: low serum phosphate levels lead to an increase in the synthesis of sodium-phosphorus cotransporters, resulting in increased (nearly complete) proximal reabsorption and an increase in the serum phosphorus concentration.⁴ Conversely, both parathyroid hormone and FGF23 are phosphaturic and decrease the number of phosphorus transporters, which in turn leads to increased phosphorus excretion and a decrease in serum phosphorus concentration.⁵

Interplay of hormones

FGF23 is a phosphaturic glycoprotein secreted by osteoblasts and osteocytes. It acts by binding to fibroblastic growth receptor 1 in the presence of its coreceptor, the Klotho protein.⁶

FGF23 is regulated by serum phosphorus levels and plays a major role in the response to elevated serum phosphorus. It causes a direct increase in urinary phosphorus excretion, a decrease in intestinal phosphorus absorption (indirectly via inhibition of calcitriol), and decreased bone resorption via a decrease in parathyroid hormone production.⁷

Mechanism of hyperphosphatemia in kidney disease

In chronic kidney disease, phosphorus retention can trigger secondary hyperparathyroidism, as rising phosphorus levels stimulate FGF23. In the early stages of chronic kidney disease, this response can correct the phosphorus levels, but with several consequences:

• Decreased calcitriol due to its inhibition by FGF23⁹
• Hypocalcemia due to decreased calcitriol (leading to decreased intestinal calcium absorption) and calcium binding of retained phosphorus
• Elevated parathyroid hormone due to low calcitriol levels (lack of inhibitory feedback by calcitriol), hyperphosphatemia, and hypocalcemia (direct parathyroid hormone stimulation).

As the elevated phosphorus level is likely to be the triggering event behind secondary renal hyperparathyroidism, it needs to be controlled. This is accomplished by restricting dietary phosphorus and using phosphorus binders.

HYPERPHOSPHATEMIA MAY LEAD TO VASCULAR CALCIFICATION

Elevated serum phosphorus levels (normal range 2.48–4.65 mg/dL in adults¹¹) are associated with cardiovascular calcification and subsequent increases in mortality and morbidity rates. Elevations in serum phosphorus and calcium levels are associated with progression in vascular calcification¹² and likely account for the accelerated vascular calcification that is seen in kidney disease.¹³

Hyperphosphatemia has been identified as an independent risk factor for death in patients with end-stage renal disease,¹⁴ but that relationship is less clear in patients with chronic kidney disease. A study in patients with chronic kidney disease and not on dialysis found a lower mortality rate in those who were prescribed phosphorus binders,¹⁵ but the study was criticized for limitations in its design.

Hyperphosphatemia can also lead to adverse effects on bone health due to complications such as renal osteodystrophy.

However, in its 2017 update, the Kidney Disease: Improving Global Outcomes (KDIGO) program only “suggests” lowering elevated phosphorus levels “toward” the normal range in patients with chronic kidney disease stages G3a through G5D, ie, those with glomerular filtration rates less than 60 mL/min/1.73 m², including those on dialysis. The recommendation is graded 2C, ie, weak, based on low-quality evidence (https://kdigo.org/guidelines/ckd-mbd).

DIETARY RESTRICTION OF PHOSPHORUS

Diet is the major source of phosphorus intake. The average daily phosphorus consumption is  20 mg/kg, or 1,400 mg, and protein is the major source of dietary phosphorus.

In patients with stage 4 or 5 chronic kidney disease, the Kidney Disease Outcomes Quality Initiative recommends limiting protein intake to 0.6 mg/kg/day.¹⁶ However, in patients on hemodialysis, they recommend increasing protein intake to 1.1 mg/kg/day while limiting phosphorus intake to about 800 to 1,000 mg/day. This poses a challenge, as limiting phosphorus intake can reduce protein intake.

Sources of protein can be broadly classified as plant-based or animal-based. Animal protein contains organic phosphorus, which is easily absorbed.¹⁸ Plant protein may not be absorbed as easily.

Moe et al¹⁹ studied the importance of the protein source of phosphorus after 7 days of controlled diets. Despite equivalent protein and phosphorus concentrations in the vegetarian and meat-based diets, participants on the vegetarian diet had lower serum phosphorus levels, a trend toward lower 24-hour urinary phosphorus excretion, and significantly lower FGF23 levels than those on the meat-based diet. This suggests that a vegetarian diet may have advantages in terms of preventing hyperphosphatemia.

Another measure to reduce phosphorus absorption from meat is to boil it, which reduces the phosphorus content by 50%.²⁰

Processed foods containing additives and preservatives are very high in phosphorus²¹ and should be avoided, particularly as there is no mandate to label phosphorus content in food.

PHOSPHORUS AND DIALYSIS

Although hemodialysis removes phosphorus, it does not remove enough to keep levels within normal limits. Indeed, even when patients adhere to a daily phosphorus limit of 1,000 mg, phosphorus accumulates. If 70% of the phosphorus in the diet is absorbed, this is 4,500 to 5,000 mg in a week. A 4-hour hemodialysis session will remove only 1,000 mg of phosphorus, which equals about 3,000 mg for patients undergoing dialysis 3 times a week,²² far less than phosphorus absorption.

In patients on continuous ambulatory peritoneal dialysis, a daily regimen of 4 exchanges of 2 L per exchange removes about 200 mg of phosphorus per day. In a 2012 study, patients on nocturnal dialysis or home dialysis involving longer session length had greater lowering of phosphorus levels than patients undergoing routine hemodialysis.²³

Hence, phosphorus binders are often necessary in patients on routine hemodialysis or peritoneal dialysis.

PHOSPHORUS BINDERS

Phosphorus binders reduce serum phosphorus levels by binding with ingested phosphorus in the gastrointestinal tract and forming insoluble complexes that are not absorbed. For this reason they are much more effective when taken with meals. Phosphorus binders come in different formulations: pills, capsules, chewable tablets, liquids, and even powders that can be sprinkled on food.

The potency of each binder is quantified by its “phosphorus binder equivalent dose,” ie, its binding capacity compared with that of calcium carbonate as a reference.²⁴

Phosphorus binders are broadly divided into those that contain calcium and those that do not.

Calcium-containing binders

The 2 most commonly used preparations are calcium carbonate (eg, Tums) and calcium acetate (eg, Phoslo). While these are relatively safe, some studies suggest that their use can lead to accelerated vascular calcification.²⁵

According to KDIGO,²⁶ calcium-containing binders should be avoided in hypercalcemia and adynamic bone disease. Additionally, the daily elemental calcium intake from binders should be limited to 1,500 mg, with a total daily intake that does not exceed 2,000 mg.

The elemental calcium content of calcium carbonate is about 40% of its weight (eg, 200 mg of elemental calcium in a 500-mg tablet of Tums), while the elemental calcium content of calcium acetate is about 25%. Therefore, a patient who needs 6 g of calcium carbonate for efficacy will be ingesting 2.4 g of elemental calcium per day, and that exceeds the recommended daily maximum. The main advantage of calcium carbonate is its low cost and easy availability. Commonly reported side effects include nausea and constipation.

A less commonly used calcium-based binder is calcium citrate (eg, Calcitrate). It should, however, be avoided in chronic kidney disease because of the risk of aluminum accumulation. Calcium citrate can enhance intestinal absorption of aluminum from dietary sources, as aluminum can form complexes with citrate.²⁷

Calcium-free binders

There are several calcium-free binders. Some are based on metals such as aluminum, magnesium, iron, and lanthanum; others, such as sevelamer, are resin-based.

Aluminum- and magnesium-based binders are generally not used long-term in kidney disease because of the toxicity associated with aluminum and magnesium accumulation. However, aluminum hydroxide has an off-label use as a phosphorus binder in the acute setting, particularly when serum phosphorus levels are above 7 mg/dL.²⁸ The dose is 300 to 600 mg 3 times daily with meals for a maximum of 4 weeks.

Sevelamer. Approved by the US Food and Drug Administration (FDA) in 1998, sevelamer acts by trapping phosphorus through ion exchange and hydrogen binding. It has the advantage of being calcium-free, which makes it particularly desirable in patients with hypercalcemia.

The Renagel in New Dialysis²⁵ and Treat-To-Goal²⁹ studies were randomized controlled trials that looked at the effects of sevelamer vs calcium-based binders on the risk of vascular calcification. The primary end points were serum phosphorus and calcium levels, while the secondary end points were coronary artery calcification on computed tomography and thoracic vertebral bone density. Both studies demonstrated a higher risk of vascular calcification with the calcium-based binders.

Another possible benefit of sevelamer is an improvement in lipid profile. Sevelamer lowers total cholesterol and low-density lipoprotein cholesterol levels without affecting high-density lipoprotein cholesterol or triglyceride levels.³⁰ This is likely due to its bile acid-binding effect.³¹ Sevelamer has also been shown to lower C-reactive protein levels.³² While the cardiovascular profile appears to be improved with the treatment, there are no convincing data to confirm that those properties translate to a proven independent survival benefit.

The Calcium Acetate Renagel Evaluation³³ was a randomized controlled study comparing sevelamer and calcium acetate. The authors attempted to control for the lipid-lowering effects of sevelamer by giving atorvastatin to all patients in both groups who had a low-density lipoprotein level greater than 70 mg/dL. The study found sevelamer to be not inferior to calcium acetate in terms of mortality and coronary calcification.

Further studies such as the Brazilian Renagel and Calcium trial³⁴ and the Dialysis Clinical Outcomes Revisited trial failed to show a significant long-term benefit of sevelamer over calcium-based binders. However, a secondary statistical analysis of the latter study showed possible benefit of sevelamer over calcium acetate among those age 65 and older.³⁵

To understand how sevelamer could affect vascular calcification, Yilmaz et al³⁶ compared the effects of sevelamer vs calcium acetate on FGF23 and fetuin A levels. Fetuin A is an important inhibitor of vascular calcification and is progressively diminished in kidney disease, leading to accelerated calcification.³⁷ Patients on sevelamer had higher levels of fetuin A than their counterparts on calcium acetate.³⁷ The authors proposed increased fetuin A levels as a mechanism for decreased vascular calcification.

In summary, some studies suggest that sevelamer may offer the advantage of decreasing vascular calcification, but the data are mixed and do not provide a solid answer. The main disadvantages of sevelamer are a high pill burden and side effects of nausea and dyspepsia.

Lanthanum, a metallic element, was approved as a phosphorus binder by the FDA in 2008. It comes as a chewable tablet and offers the advantage of requiring the patient to take fewer pills than sevelamer and calcium-based binders.

Sucroferric oxyhydroxide comes as a chewable tablet. It was approved by the FDA in 2013. Although each tablet contains 500 mg of iron, it has not been shown to improve iron markers. In terms of phosphorus-lowering ability, it has been shown to be noninferior to sevelamer.³⁹ Advantages include a significantly lower pill burden. Disadvantages include gastrointestinal side effects such as diarrhea and nausea and the drug’s high cost.

Ferric citrate was approved by the FDA in 2014, and 1 g delivers 210 mg of elemental iron. The main advantage of ferric citrate is its ability to increase iron markers. The phase 3 trial that demonstrated its efficacy as a binder showed an increase in ferritin compared with the active control.⁴⁰ The study also showed a decrease in the need to use intravenous iron and erythropoesis-stimulating agents. This was thought to be due to improved iron stores, leading to decreased erythropoietin resistance.⁴¹

The mean number of ferric citrate tablets needed to achieve the desired phosphorus-lowering effect was 8 per day, containing 1,680 mg of iron. In comparison, oral ferrous sulfate typically provides 210 mg of iron per day.⁴²

Disadvantages of ferric citrate include high pill burden, high cost, and gastrointestinal side effects such as nausea and constipation.

Chitosan binds salivary phosphorus. It can potentially be used, but it is not approved, and its efficacy in lowering serum phosphorus remains unclear.⁴³

CHOOSING THE APPROPRIATE PHOSPHORUS BINDER

The choice of phosphorus binder is based on the patient’s serum calcium level and iron stores and on the drug’s side effect profile, iron pill burden, and cost. Involving patients in the choice after discussing potential side effects, pill burden, and cost is important for shared decision-making and could play a role in improving adherence.

Phosphorus binders are a major portion of the pill burden in patients with end-stage renal disease, possibly affecting patient adherence. The cost of phosphorus binders is estimated at half a billion dollars annually, underlining the significant economic impact of phosphorus control.¹¹

Calcium-based binders should be the first choice when there is secondary hyperparathyroidism without hypercalcemia. There is no clear evidence regarding the benefit of correcting hypocalcemia, but KDIGO recommends keeping the serum calcium level within the reference range. KDIGO also recommends restricting calcium-based binders in persistent hypercalcemia, arterial calcification, and adynamic bone disease. This recommendation is largely based on expert opinion.

Noncalcium-based binders, which in theory might prevent vascular calcification, should be considered for patients with at least 1 of the following⁴⁴:

• Complicated diabetes mellitus
• Vascular or valvular calcification
• Persistent inflammation.

Noncalcium-based binders are also preferred in low bone-turnover states such as adynamic bone disease, as elevated calcium can inhibit parathyroid hormone.

However, the advantage of noncalcium-based binders regarding vascular calcification is largely theoretical and has not been proven clinically. Indeed, there are data comparing long-term outcomes of the different classes of phosphorus binders, but studies were limited by short follow-up, and individual studies have lacked power to detect statistical significance between two classes of binders on long-term outcomes. Meta-analyses have provided conflicting data, with some suggesting better outcomes with sevelamer than with calcium-based binders, and with others failing to show any difference.⁴⁵

Because iron deficiency is common in kidney disease, ferric citrate, which can improve iron markers, may be a suitable option, provided its cost is covered by insurance.

SPECIAL CIRCUMSTANCES FOR THE USE OF PHOSPHORUS BINDERS

Tumor lysis syndrome

Tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.⁴⁶ Phosphorus binders in conjunction with intravenous hydration are used to treat hyperphosphatemia, but evidence about their efficacy in this setting is limited.

Hypocalcemia in tumor lysis syndrome is usually not treated unless symptomatic, as the calcium-phosphorus product can increase, leading to calcium phosphate crystallization. When the calcium-phosphorus product is greater than 60, there is a higher risk of calcium phosphate deposition in the renal tubules that can lead to acute renal failure in tumor lysis syndrome.⁴⁷ To lower the risk of calcium phosphate crystallization, calcium-based binders should be avoided in tumor lysis syndrome.

Total parenteral nutrition

Since patients on total parenteral nutrition do not eat, phosphorus binders are considered ineffective; there are no concrete data showing that phosphorus binders are effective in these patients.⁴⁸ In patients with kidney disease, the phosphorus content in the parenteral nutrition formulation must be reduced.

Pregnancy

Data on phosphorus binders in pregnancy are limited. Calcium can cross the placenta. Calcium carbonate can be used in pregnancy, and fetal harm is not expected if calcium concentrations are within normal limits.⁴⁹ Calcium acetate, sevelamer, and lanthanum are considered pregnancy category C drugs. Patients with advanced chronic kidney disease and end-stage renal disease who become pregnant must receive specialized obstetric care for high-risk pregnancy.

FUTURE DIRECTIONS

Future therapies may target FGF23 and other inflammatory markers that are up-regulated in renal hyperparathyroidism. However, trials studying these markers are needed to provide a better understanding of their role in bone mineral and cardiovascular health and in overall long-term outcomes. Additionally, randomized controlled trials are needed to study long-term nonsurrogate outcomes such as reduction in cardiovascular disease and rates of overall mortality.

The balance between dietary intake and excretion of phosphorus can be impaired in patients with decreased renal function, leading to hyperphosphatemia. Many patients with end-stage renal disease on dialysis require phosphorus-binding drugs to control their serum phosphorus levels.

See related editorial and article

In this review, we discuss the pathophysiology of hyperphosphatemia in kidney disease, its consequences, and how to control it, focusing on the different classes of phosphorus binders.

ROLE OF THE INTERNIST

With kidney disease common and on the increase,¹ nephrologists and internists need to work together to provide optimal care.

Further, many internists in managed care plans and accountable care organizations now handle many tasks previously left to specialists—including prescribing and managing phosphorus binders in patients with kidney disease.

PATHOPHYSIOLOGY OF HYPERPHOSPHATEMIA

The pathophysiology of bone mineral disorders in kidney disease is complex. To simplify the discussion, we will address it in 3 parts:

• Phosphorus balance
• The interplay of hormones, including fibro­blast growth factor 23 (FGF23)
• The mechanism of hyperphosphatemia in kidney disease.

Phosphorus balance

Phosphorus is a macronutrient essential for a range of cellular functions that include structure, energy production, metabolism, and cell signaling. It exists primarily in the form of inorganic phosphate.

An average Western diet provides 20 mg of phosphorus per kilogram of body weight per day. Of this, 13 mg/kg is absorbed, and the rest is excreted in the feces.²

Absorption of dietary phosphorus occurs mainly in the jejunum. It is mediated by both a paracellular sodium-independent pathway (driven by high intraluminal phosphorus content) and by active sodium-dependent cotransporters. It is also influenced by diet and promoted by active vitamin D (1,25 dihydroxyvitamin D₃, also called calcitriol).³

Absorbed phosphorus enters the extracellular fluid and shifts in and out of the skeleton under the influence of parathyroid hormone.

Phosphorus excretion is handled almost entirely by the kidneys. Phosphorus is freely filtered at the glomerulus and reabsorbed mainly in the proximal tubule by sodium-phosphate cotransporters.

Normally, when phosphorus intake is adequate, most of the filtered phosphorus is reabsorbed and only 10% to 20% is excreted in the urine. However, the threshold for phosphorus reabsorption in the proximal tubule is influenced by parathyroid hormone, FGF23, and dietary phosphorus intake: low serum phosphate levels lead to an increase in the synthesis of sodium-phosphorus cotransporters, resulting in increased (nearly complete) proximal reabsorption and an increase in the serum phosphorus concentration.⁴ Conversely, both parathyroid hormone and FGF23 are phosphaturic and decrease the number of phosphorus transporters, which in turn leads to increased phosphorus excretion and a decrease in serum phosphorus concentration.⁵

Interplay of hormones

FGF23 is a phosphaturic glycoprotein secreted by osteoblasts and osteocytes. It acts by binding to fibroblastic growth receptor 1 in the presence of its coreceptor, the Klotho protein.⁶

FGF23 is regulated by serum phosphorus levels and plays a major role in the response to elevated serum phosphorus. It causes a direct increase in urinary phosphorus excretion, a decrease in intestinal phosphorus absorption (indirectly via inhibition of calcitriol), and decreased bone resorption via a decrease in parathyroid hormone production.⁷

Mechanism of hyperphosphatemia in kidney disease

In chronic kidney disease, phosphorus retention can trigger secondary hyperparathyroidism, as rising phosphorus levels stimulate FGF23. In the early stages of chronic kidney disease, this response can correct the phosphorus levels, but with several consequences:

• Decreased calcitriol due to its inhibition by FGF23⁹
• Hypocalcemia due to decreased calcitriol (leading to decreased intestinal calcium absorption) and calcium binding of retained phosphorus
• Elevated parathyroid hormone due to low calcitriol levels (lack of inhibitory feedback by calcitriol), hyperphosphatemia, and hypocalcemia (direct parathyroid hormone stimulation).

As the elevated phosphorus level is likely to be the triggering event behind secondary renal hyperparathyroidism, it needs to be controlled. This is accomplished by restricting dietary phosphorus and using phosphorus binders.

HYPERPHOSPHATEMIA MAY LEAD TO VASCULAR CALCIFICATION

Elevated serum phosphorus levels (normal range 2.48–4.65 mg/dL in adults¹¹) are associated with cardiovascular calcification and subsequent increases in mortality and morbidity rates. Elevations in serum phosphorus and calcium levels are associated with progression in vascular calcification¹² and likely account for the accelerated vascular calcification that is seen in kidney disease.¹³

Hyperphosphatemia has been identified as an independent risk factor for death in patients with end-stage renal disease,¹⁴ but that relationship is less clear in patients with chronic kidney disease. A study in patients with chronic kidney disease and not on dialysis found a lower mortality rate in those who were prescribed phosphorus binders,¹⁵ but the study was criticized for limitations in its design.

Hyperphosphatemia can also lead to adverse effects on bone health due to complications such as renal osteodystrophy.

However, in its 2017 update, the Kidney Disease: Improving Global Outcomes (KDIGO) program only “suggests” lowering elevated phosphorus levels “toward” the normal range in patients with chronic kidney disease stages G3a through G5D, ie, those with glomerular filtration rates less than 60 mL/min/1.73 m², including those on dialysis. The recommendation is graded 2C, ie, weak, based on low-quality evidence (https://kdigo.org/guidelines/ckd-mbd).

DIETARY RESTRICTION OF PHOSPHORUS

Diet is the major source of phosphorus intake. The average daily phosphorus consumption is  20 mg/kg, or 1,400 mg, and protein is the major source of dietary phosphorus.

In patients with stage 4 or 5 chronic kidney disease, the Kidney Disease Outcomes Quality Initiative recommends limiting protein intake to 0.6 mg/kg/day.¹⁶ However, in patients on hemodialysis, they recommend increasing protein intake to 1.1 mg/kg/day while limiting phosphorus intake to about 800 to 1,000 mg/day. This poses a challenge, as limiting phosphorus intake can reduce protein intake.

Sources of protein can be broadly classified as plant-based or animal-based. Animal protein contains organic phosphorus, which is easily absorbed.¹⁸ Plant protein may not be absorbed as easily.

Moe et al¹⁹ studied the importance of the protein source of phosphorus after 7 days of controlled diets. Despite equivalent protein and phosphorus concentrations in the vegetarian and meat-based diets, participants on the vegetarian diet had lower serum phosphorus levels, a trend toward lower 24-hour urinary phosphorus excretion, and significantly lower FGF23 levels than those on the meat-based diet. This suggests that a vegetarian diet may have advantages in terms of preventing hyperphosphatemia.

Another measure to reduce phosphorus absorption from meat is to boil it, which reduces the phosphorus content by 50%.²⁰

Processed foods containing additives and preservatives are very high in phosphorus²¹ and should be avoided, particularly as there is no mandate to label phosphorus content in food.

PHOSPHORUS AND DIALYSIS

Although hemodialysis removes phosphorus, it does not remove enough to keep levels within normal limits. Indeed, even when patients adhere to a daily phosphorus limit of 1,000 mg, phosphorus accumulates. If 70% of the phosphorus in the diet is absorbed, this is 4,500 to 5,000 mg in a week. A 4-hour hemodialysis session will remove only 1,000 mg of phosphorus, which equals about 3,000 mg for patients undergoing dialysis 3 times a week,²² far less than phosphorus absorption.

In patients on continuous ambulatory peritoneal dialysis, a daily regimen of 4 exchanges of 2 L per exchange removes about 200 mg of phosphorus per day. In a 2012 study, patients on nocturnal dialysis or home dialysis involving longer session length had greater lowering of phosphorus levels than patients undergoing routine hemodialysis.²³

Hence, phosphorus binders are often necessary in patients on routine hemodialysis or peritoneal dialysis.

PHOSPHORUS BINDERS

Phosphorus binders reduce serum phosphorus levels by binding with ingested phosphorus in the gastrointestinal tract and forming insoluble complexes that are not absorbed. For this reason they are much more effective when taken with meals. Phosphorus binders come in different formulations: pills, capsules, chewable tablets, liquids, and even powders that can be sprinkled on food.

The potency of each binder is quantified by its “phosphorus binder equivalent dose,” ie, its binding capacity compared with that of calcium carbonate as a reference.²⁴

Phosphorus binders are broadly divided into those that contain calcium and those that do not.

Calcium-containing binders

The 2 most commonly used preparations are calcium carbonate (eg, Tums) and calcium acetate (eg, Phoslo). While these are relatively safe, some studies suggest that their use can lead to accelerated vascular calcification.²⁵

According to KDIGO,²⁶ calcium-containing binders should be avoided in hypercalcemia and adynamic bone disease. Additionally, the daily elemental calcium intake from binders should be limited to 1,500 mg, with a total daily intake that does not exceed 2,000 mg.

The elemental calcium content of calcium carbonate is about 40% of its weight (eg, 200 mg of elemental calcium in a 500-mg tablet of Tums), while the elemental calcium content of calcium acetate is about 25%. Therefore, a patient who needs 6 g of calcium carbonate for efficacy will be ingesting 2.4 g of elemental calcium per day, and that exceeds the recommended daily maximum. The main advantage of calcium carbonate is its low cost and easy availability. Commonly reported side effects include nausea and constipation.

A less commonly used calcium-based binder is calcium citrate (eg, Calcitrate). It should, however, be avoided in chronic kidney disease because of the risk of aluminum accumulation. Calcium citrate can enhance intestinal absorption of aluminum from dietary sources, as aluminum can form complexes with citrate.²⁷

Calcium-free binders

There are several calcium-free binders. Some are based on metals such as aluminum, magnesium, iron, and lanthanum; others, such as sevelamer, are resin-based.

Aluminum- and magnesium-based binders are generally not used long-term in kidney disease because of the toxicity associated with aluminum and magnesium accumulation. However, aluminum hydroxide has an off-label use as a phosphorus binder in the acute setting, particularly when serum phosphorus levels are above 7 mg/dL.²⁸ The dose is 300 to 600 mg 3 times daily with meals for a maximum of 4 weeks.

Sevelamer. Approved by the US Food and Drug Administration (FDA) in 1998, sevelamer acts by trapping phosphorus through ion exchange and hydrogen binding. It has the advantage of being calcium-free, which makes it particularly desirable in patients with hypercalcemia.

The Renagel in New Dialysis²⁵ and Treat-To-Goal²⁹ studies were randomized controlled trials that looked at the effects of sevelamer vs calcium-based binders on the risk of vascular calcification. The primary end points were serum phosphorus and calcium levels, while the secondary end points were coronary artery calcification on computed tomography and thoracic vertebral bone density. Both studies demonstrated a higher risk of vascular calcification with the calcium-based binders.

Another possible benefit of sevelamer is an improvement in lipid profile. Sevelamer lowers total cholesterol and low-density lipoprotein cholesterol levels without affecting high-density lipoprotein cholesterol or triglyceride levels.³⁰ This is likely due to its bile acid-binding effect.³¹ Sevelamer has also been shown to lower C-reactive protein levels.³² While the cardiovascular profile appears to be improved with the treatment, there are no convincing data to confirm that those properties translate to a proven independent survival benefit.

The Calcium Acetate Renagel Evaluation³³ was a randomized controlled study comparing sevelamer and calcium acetate. The authors attempted to control for the lipid-lowering effects of sevelamer by giving atorvastatin to all patients in both groups who had a low-density lipoprotein level greater than 70 mg/dL. The study found sevelamer to be not inferior to calcium acetate in terms of mortality and coronary calcification.

Further studies such as the Brazilian Renagel and Calcium trial³⁴ and the Dialysis Clinical Outcomes Revisited trial failed to show a significant long-term benefit of sevelamer over calcium-based binders. However, a secondary statistical analysis of the latter study showed possible benefit of sevelamer over calcium acetate among those age 65 and older.³⁵

To understand how sevelamer could affect vascular calcification, Yilmaz et al³⁶ compared the effects of sevelamer vs calcium acetate on FGF23 and fetuin A levels. Fetuin A is an important inhibitor of vascular calcification and is progressively diminished in kidney disease, leading to accelerated calcification.³⁷ Patients on sevelamer had higher levels of fetuin A than their counterparts on calcium acetate.³⁷ The authors proposed increased fetuin A levels as a mechanism for decreased vascular calcification.

In summary, some studies suggest that sevelamer may offer the advantage of decreasing vascular calcification, but the data are mixed and do not provide a solid answer. The main disadvantages of sevelamer are a high pill burden and side effects of nausea and dyspepsia.

Lanthanum, a metallic element, was approved as a phosphorus binder by the FDA in 2008. It comes as a chewable tablet and offers the advantage of requiring the patient to take fewer pills than sevelamer and calcium-based binders.

Sucroferric oxyhydroxide comes as a chewable tablet. It was approved by the FDA in 2013. Although each tablet contains 500 mg of iron, it has not been shown to improve iron markers. In terms of phosphorus-lowering ability, it has been shown to be noninferior to sevelamer.³⁹ Advantages include a significantly lower pill burden. Disadvantages include gastrointestinal side effects such as diarrhea and nausea and the drug’s high cost.

Ferric citrate was approved by the FDA in 2014, and 1 g delivers 210 mg of elemental iron. The main advantage of ferric citrate is its ability to increase iron markers. The phase 3 trial that demonstrated its efficacy as a binder showed an increase in ferritin compared with the active control.⁴⁰ The study also showed a decrease in the need to use intravenous iron and erythropoesis-stimulating agents. This was thought to be due to improved iron stores, leading to decreased erythropoietin resistance.⁴¹

The mean number of ferric citrate tablets needed to achieve the desired phosphorus-lowering effect was 8 per day, containing 1,680 mg of iron. In comparison, oral ferrous sulfate typically provides 210 mg of iron per day.⁴²

Disadvantages of ferric citrate include high pill burden, high cost, and gastrointestinal side effects such as nausea and constipation.

Chitosan binds salivary phosphorus. It can potentially be used, but it is not approved, and its efficacy in lowering serum phosphorus remains unclear.⁴³

CHOOSING THE APPROPRIATE PHOSPHORUS BINDER

The choice of phosphorus binder is based on the patient’s serum calcium level and iron stores and on the drug’s side effect profile, iron pill burden, and cost. Involving patients in the choice after discussing potential side effects, pill burden, and cost is important for shared decision-making and could play a role in improving adherence.

Phosphorus binders are a major portion of the pill burden in patients with end-stage renal disease, possibly affecting patient adherence. The cost of phosphorus binders is estimated at half a billion dollars annually, underlining the significant economic impact of phosphorus control.¹¹

Calcium-based binders should be the first choice when there is secondary hyperparathyroidism without hypercalcemia. There is no clear evidence regarding the benefit of correcting hypocalcemia, but KDIGO recommends keeping the serum calcium level within the reference range. KDIGO also recommends restricting calcium-based binders in persistent hypercalcemia, arterial calcification, and adynamic bone disease. This recommendation is largely based on expert opinion.

Noncalcium-based binders, which in theory might prevent vascular calcification, should be considered for patients with at least 1 of the following⁴⁴:

• Complicated diabetes mellitus
• Vascular or valvular calcification
• Persistent inflammation.

Noncalcium-based binders are also preferred in low bone-turnover states such as adynamic bone disease, as elevated calcium can inhibit parathyroid hormone.

However, the advantage of noncalcium-based binders regarding vascular calcification is largely theoretical and has not been proven clinically. Indeed, there are data comparing long-term outcomes of the different classes of phosphorus binders, but studies were limited by short follow-up, and individual studies have lacked power to detect statistical significance between two classes of binders on long-term outcomes. Meta-analyses have provided conflicting data, with some suggesting better outcomes with sevelamer than with calcium-based binders, and with others failing to show any difference.⁴⁵

Because iron deficiency is common in kidney disease, ferric citrate, which can improve iron markers, may be a suitable option, provided its cost is covered by insurance.

SPECIAL CIRCUMSTANCES FOR THE USE OF PHOSPHORUS BINDERS

Tumor lysis syndrome

Tumor lysis syndrome occurs when tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy, leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.⁴⁶ Phosphorus binders in conjunction with intravenous hydration are used to treat hyperphosphatemia, but evidence about their efficacy in this setting is limited.

Hypocalcemia in tumor lysis syndrome is usually not treated unless symptomatic, as the calcium-phosphorus product can increase, leading to calcium phosphate crystallization. When the calcium-phosphorus product is greater than 60, there is a higher risk of calcium phosphate deposition in the renal tubules that can lead to acute renal failure in tumor lysis syndrome.⁴⁷ To lower the risk of calcium phosphate crystallization, calcium-based binders should be avoided in tumor lysis syndrome.

Total parenteral nutrition

Since patients on total parenteral nutrition do not eat, phosphorus binders are considered ineffective; there are no concrete data showing that phosphorus binders are effective in these patients.⁴⁸ In patients with kidney disease, the phosphorus content in the parenteral nutrition formulation must be reduced.

Pregnancy

Data on phosphorus binders in pregnancy are limited. Calcium can cross the placenta. Calcium carbonate can be used in pregnancy, and fetal harm is not expected if calcium concentrations are within normal limits.⁴⁹ Calcium acetate, sevelamer, and lanthanum are considered pregnancy category C drugs. Patients with advanced chronic kidney disease and end-stage renal disease who become pregnant must receive specialized obstetric care for high-risk pregnancy.

FUTURE DIRECTIONS

Future therapies may target FGF23 and other inflammatory markers that are up-regulated in renal hyperparathyroidism. However, trials studying these markers are needed to provide a better understanding of their role in bone mineral and cardiovascular health and in overall long-term outcomes. Additionally, randomized controlled trials are needed to study long-term nonsurrogate outcomes such as reduction in cardiovascular disease and rates of overall mortality.

A 29-year-old nulliparous woman presents for a routine checkup. She has hypertension and type 2 diabetes mellitus. Her current medications are chlorpropamide 500 mg daily, metformin 500 mg twice a day, lisinopril 40 mg daily, simvastatin 40 mg daily, and aspirin 81 mg daily. Her body mass index is 37 kg/m² and her blood pressure is 130/80 mm Hg. Her hemoglobin A_1c level is 7.8% and her low-density lipoprotein cholesterol 90 mg/dL.

She is considering pregnancy. How would you counsel her?

DEFINING DIABETES IN PREGNANCY

Diabetes in pregnant women, both gestational and pregestational, is the most common medical complication associated with pregnancy.¹

• Gestational diabetes is defined as diabetes that is diagnosed during the second or third trimester of pregnancy and that is not clearly pregestational.²
• Pregestational diabetes exists before pregnancy and can be either type 1 or type 2.

Most cases of diabetes diagnosed during the first trimester reflect pregestational diabetes, as gestational diabetes occurs when insulin resistance increases in the later trimesters.

Type 1 diabetes involves autoimmune destruction of pancreatic islet cells, leading to insulin deficiency and the need for insulin therapy. Type 2 diabetes is characterized by insulin resistance rather than overall insulin deficiency. Type 2 diabetes tends to be associated with comorbidities such as obesity and hypertension, which are independent risk factors for adverse perinatal outcomes.^3,4

Gestational diabetes accounts for most cases of diabetes during pregnancy. Although both pregestational and gestational diabetes increase the risk of maternal and fetal complications, pregestational diabetes is associated with significantly greater risks.¹

IMPACT OF DIABETES ON THE MOTHER

Pregnancy increases the risk of maternal hypoglycemia, especially during the first trimester in patients with type 1 diabetes, as insulin sensitivity increases in early pregnancy.¹ Pregnant women with diabetes may also have an altered counterregulatory response and less hypoglycemic awareness.¹ Insulin resistance rises during the second and early third trimesters, increasing the risk of hyperglycemia in women with diabetes.¹

Glycemic control during pregnancy is usually easier to achieve in patients with type 2 diabetes than with type 1, but it may require much higher insulin doses.

Because pregnancy is inherently a ketogenic state, women with type 1 diabetes are at higher risk of diabetic ketoacidosis, particularly during the second and third trimesters.¹ There are reports of euglycemic diabetic ketoacidosis in pregnant women with either gestational or pregestational diabetes.⁵

Diabetes is associated with a risk of preeclampsia 4 times higher than in nondiabetic women.⁶ Other potential pregnancy-related complications include infections, polyhydram­nios, spontaneous abortion, and cesarean delivery.^1,7 The risk of pregnancy loss is similar in women with either type 1 or type 2 diabetes (2.6% and 3.7%, respectively), but the causes are different.⁸ Although preexisting diabetic complications such as retinopathy, nephropathy, and gastroparesis can be exacerbated during pregnancy,¹ only severe gastroparesis and advanced renal disease are considered relative contraindications to pregnancy.

IMPACT OF DIABETES ON THE FETUS

Fetal complications of maternal diabetes include embryopathy (fetal malformations) and fetopathy (overgrowth, ie, fetus large for gestational age, and increased risk of fetal death or distress). Maternal hyperglycemia is associated with diabetic embryopathy, resulting in major birth defects in 5% to 25% of pregnancies and spontaneous abortions in 15% to 20%.^9,10 There is a 2- to 6-fold increase in risk of congenital malformations.6

The most common diabetes-associated congenital malformations affect the cardiovascular system. Congenital heart disease includes tetralogy of Fallot, transposition of the great vessels, septal defects, and anomalous pulmonary venous return. Other relatively common defects involve the fetal central nervous system, spine, orofacial system, kidneys, urogenital system, gastrointestinal tract, and skeleton.¹¹

The risk of fetopathy is proportional to the degree of maternal hyperglycemia. Excess maternal glucose and fatty acid levels can lead to fetal hyperglycemia and overgrowth, which increases fetal oxygen requirements. Erythro­poietin levels rise, causing an increase in red cell mass, with subsequent hyperviscosity within the placenta and higher risk of fetal death.

Other complications include intrauterine growth restriction, prematurity, and preterm delivery. Fetal macrosomia (birth weight > 90th percentile or 4 kg, approximately 8 lb, 13 oz) occurs in 27% to 62% of children born to mothers with diabetes, a rate 10 times higher than in patients without diabetes. It contributes to shoulder dystocia (risk 2 to 4 times higher in diabetic pregnancies) and cesarean delivery.⁶ Infants born to mothers with diabetes also have higher risks of neonatal hypoglycemia, erythrocytosis, hyperbilirubinemia, hypocalcemia, respiratory distress, cardiomyopathy, and death, as well as for developing diabetes, obesity, and other adverse cardiometabolic outcomes later in life.¹¹

Nearly half of pregnancies in the general population are unplanned,¹⁵ so preconception diabetes assessment needs to be part of routine medical care for all reproductive-age women. Because most organogenesis occurs during the first 5 to 8 weeks after fertilization—potentially before a woman realizes she is pregnant—achieving optimal glycemic control before conception is necessary to improve pregnancy outcomes.¹

EVERY VISIT IS AN OPPORTUNITY

Every medical visit with a reproductive-age woman with diabetes is an opportunity for counseling about pregnancy. Topics that need to be discussed include the risks of unplanned pregnancy and of poor metabolic control, and the benefits of improved maternal and fetal outcomes with appropriate pregnancy planning and diabetes management.

Referral to a registered dietitian for individualized counseling about proper nutrition, particularly during pregnancy, has been associated with positive outcomes.¹⁶ Patients with diabetes and at high risk of pregnancy complications should be referred to a clinic that specializes in high-risk pregnancies.

Practitioners also should emphasize the importance of regular exercise and encourage patients to maintain or achieve a medically optimal weight before conception. Ideally, this would be a normal body mass index; however, this is not always possible.

In women who are planning pregnancy or are not on effective contraception, medications should be reviewed for potential teratogenicity. If needed, discuss alternative medications or switch to safer ones. However, these changes should not interrupt diabetes treatment.

In addition, ensure that the patient is up to date on age- and disease-appropriate preventive care (eg, immunizations, screening for sexually transmitted disease and malignancy). Counseling and intervention for use of tobacco, alcohol, and recreational drugs are also important. As with any preconception counseling, the patient (and her partner, if possible) should be advised to avoid travel to areas where Zika virus is endemic, and informed about the availability of expanded carrier genetic screening through her obstetric provider.

Finally, pregnant women with diabetes benefit from screening for diabetic complications including hypertension, retinopathy, cardiovascular disease, neuropathy, and nephropathy.

ASSESSING RISKS

Blood pressure

Chronic (preexisting) hypertension is defined as a systolic pressure 140 mm Hg or higher or a diastolic pressure 90 mm Hg or higher, or both, that antedates pregnancy or is present before the 20th week of pregnancy.³ Chronic hypertension has been reported in up to 5% of pregnant women and is associated with increased risk of preterm delivery, superimposed preeclampsia, low birth weight, and perinatal death.³

Reproductive-age women with diabetes and high blood pressure benefit from lifestyle and behavioral modifications.¹⁷ If drug therapy is needed, antihypertensive drugs that are safe for the fetus should be used. Treatment of mild or moderate hypertension during pregnancy reduces the risk of progression to severe hypertension but may not improve obstetric outcomes.

Diabetic retinopathy

Diabetic retinopathy can significantly worsen during pregnancy: the risk of progression is double that in the nonpregnant state.¹⁸ Women with diabetes who are contemplating pregnancy should have a comprehensive eye examination before conception, and any active proliferative retinopathy needs to be treated. These patients may require ophthalmologic monitoring and treatment during pregnancy. (Note: laser photocoagulation is not contraindicated during pregnancy.)

Cardiovascular disease

Cardiovascular physiology changes dramatically during pregnancy. Cardiovascular disease, especially when superimposed on diabetes, can increase the risk of maternal death. Thus, evaluation for cardiovascular risk factors as well as cardiovascular system integrity before conception is important. Listen for arterial bruits and murmurs, and assess peripheral pulses. Consideration should be given to obtaining a preconception resting electrocardiogram in women with diabetes who are over age 35 or who are suspected of having cardiovascular disease.¹⁶

Neurologic disorders

Peripheral neuropathy, the most common neurologic complication of diabetes, is associated with injury and infection.¹⁹

Autonomic neuropathy is associated with decreased cardiac responsiveness and orthostatic hypotension.¹⁹ Diabetic gastroparesis alone can precipitate serious complications during pregnancy, including extreme hypoglycemia and hyperglycemia, increased risk of diabetic ketoacidosis, weight loss, malnutrition, frequent hospitalizations, and increased requirement for parenteral nutrition.²⁰

Although diabetic neuropathy does not significantly worsen during pregnancy, women with preexisting gastroparesis should be counseled on the substantial risks associated with pregnancy. Screening for neuropathy should be part of all diabetic preconception examinations.

Renal complications

Pregnancy in women with diabetes and preexisting renal dysfunction increases their risk of accelerated progression of diabetic kidney disease.²¹ Preexisting renal dysfunction also increases the risk of pregnancy-related complications, such as stillbirth, intrauterine growth restriction, gestational hypertension, preeclampsia, and preterm delivery.^19,21,22 Further, the risk of pregnancy complications correlates directly with the severity of renal dysfunction.²²

Psychiatric disorders

Emotional wellness is essential for optimal diabetes management. It is important to recognize the emotional impact of diabetes in pregnant women and to conduct routine screening for depression, anxiety, stress, and eating disorders.¹⁶

Hemoglobin A_1c. The general consensus is to achieve the lowest hemoglobin A_1c level possible that does not increase the risk of hypoglycemia. The American Diabetes Association (ADA) recommends that, before attempting to conceive, women should lower their hemoglobin A_1c to below 6.5%.¹

Thyroid measures. Autoimmune thyroid disease is the most common autoimmune disorder associated with diabetes and has been reported in 35% to 40% of women with type 1 diabetes.²³ Recommendations are to check thyroid-stimulating hormone and thyroid peroxidase antibody levels before conception or early in pregnancy in all women with diabetes.^1,24 Overt hypothyroidism should be treated before conception, given that early fetal brain development depends on maternal thyroxine.

Renal function testing. Preconception assessment of renal function is important for counseling and risk stratification. This assessment should include serum creatinine level, estimated glomerular filtration rate, and urinary albumin excretion.²¹

Celiac screening. Because women with type 1 diabetes are more susceptible to autoimmune diseases, they should be screened for celiac disease before conception, with testing for  immunoglobulin A (IgA) and tissue transglutaminase antibodies, with or without IgA endomysial antibodies.^16,25,26 An estimated 6% of patients with type 1 diabetes have celiac disease vs 1% of the general population.²⁵ Celiac disease is 2 to 3 times more common in women, and asymptomatic people with type 1 diabetes are considered at increased risk for celiac disease.²⁶

The association between type 1 diabetes and celiac disease most likely relates to the overlap in human leukocyte antigens of the diseases. There is no established link between type 2 diabetes and celiac disease.²⁵

Undiagnosed celiac disease increases a woman’s risk of obstetric complications such as preterm birth, low birth weight, and stillbirth.²⁶ The most likely explanation for these adverse effects is nutrient malabsorption, which is characteristic of celiac disease. Adherence to a gluten-free diet before and during gestation may reduce the risk of preterm delivery by as much as 20%.²⁶

Vitamin B₁₂ level. Celiac disease interferes with the absorption of vitamin B₁₂-instrinsic factor in the ileum, which can lead to vitamin B₁₂ deficiency. Therefore, baseline vitamin B₁₂ levels should be checked before conception in women with celiac disease. Levels should also be checked in women taking metformin, which also decreases vitamin B₁₂ absorption. Of note, increased folate levels due to taking supplements can potentially mask vitamin B₁₂ deficiency.

MEDICATIONS TO REVIEW FOR PREGNANCY INTERACTIONS

Diabetic medications

Insulin is the first-line pharmacotherapy for pregnant patients with type 1, type 2, or gestational diabetes. Insulin does not cross the placenta to a measurable extent, and most insulin preparations have been classified as category B,¹ meaning no risks to the fetus have been found in humans.

Insulin dosing during pregnancy is not static. Beginning around mid-gestation, insulin requirements increase,^28,29 but after 32 weeks the need may decrease. These changes require practitioners to closely monitor blood glucose throughout pregnancy.

Both basal-bolus injections and continuous subcutaneous infusion are reasonable options during pregnancy.³⁰ However, the need for multiple and potentially painful insulin injections daily can lead to poor compliance. This inconvenience has led to studies using oral hypoglycemic medications instead of insulin for patients with gestational and type 2 diabetes.

Metformin is an oral biguanide that decreases hepatic gluconeogenesis and intestinal glucose absorption while peripherally increasing glucose utilization and uptake. Metformin does not pose a risk of hypoglycemia because its mechanism of action does not involve increased insulin production.⁷

Metformin does cross the placenta, resulting in umbilical cord blood levels higher than maternal levels. Nevertheless, studies support the efficacy and short-term safety of metformin use during a pregnancy complicated by gestational or type 2 diabetes.^7,31 Moreover, metformin has been associated with a lower risk of neonatal hypoglycemia and maternal weight gain than insulin.³² However, this agent should be used with caution, as long-term data are not yet available, and it may slightly increase the risk of premature delivery.

Glyburide is another oral hypoglycemic medication that has been used during pregnancy. This second-generation sulfonylurea enhances the release of insulin from the pancreas by binding beta islet cell ATP-calcium channel receptors. Compared with other sulfonylureas, glyburide has the lowest rate of maternal-to-fetal transfer, with umbilical cord plasma concentrations 70% of maternal levels.³³ Although some trials support the efficacy and short-term safety of glyburide treatment for gestational diabetes,³⁴ recent studies have associated glyburide use during pregnancy with a higher rate of neonatal hypoglycemia, neonatal respiratory distress, macrosomia, and neonatal intensive care unit admissions than insulin and metformin.^1,35

Patients treated with oral agents should be informed that these drugs cross the placenta, and that although no adverse effects on the fetus have been demonstrated, long-term safety data are lacking. In addition, oral agents are ineffective in type 1 diabetes and may be insufficient to overcome the insulin resistance in type 2 diabetes.

Antihypertensive drugs

All antihypertensive drugs cross the placenta, but several have an acceptable safety profile in pregnancy, including methyldopa, labeta­lol, clonidine, prazosin, and nifedipine. Hydralazine and labetalol are short-acting, come in intravenous formulations, and can be used for urgent blood pressure control during pregnancy. Diltiazem may be used for heart rate control during pregnancy, and it has been shown to lower blood pressure and proteinuria in pregnant patients with underlying renal disease.^36,37 The ADA recommends against chronic use of diuretics during pregnancy because of potential reductions in maternal plasma volume and uteroplacental perfusion.¹

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors are contraindicated during pregnancy because of the risk of fetal defects, particularly in the renal system.^21,38 Although there is evidence to question the association between first semester exposure and fetotoxicity,³⁹ we avoid these drugs during pregnancy and switch to a different agent in women planning pregnancy.

Other drugs

Statins are contraindicated in pregnancy because they interfere with the development of the fetal nervous system.²¹ Although preliminary data from a small study did not identify safety risks associated with pravastatin use after 12 weeks of gestation,⁴⁰ we recommend discontinuing statins in women attempting pregnancy.

Aspirin. The US Preventive Services Task Force41 recommends low-dose aspirin (81 mg/day) after 12 weeks of gestation for women with type 1 or type 2 diabetes, as well as those with renal disease or chronic hypertension, to prevent preeclampsia. Of note, higher doses need to be used with caution during pregnancy because fetal abnormalities have been reported, such as disruption of fetal vasculature (mesenteric vessels), gastroschisis, and small intestinal atresia.¹⁶

Folate supplementation (0.6–4 mg/day) is recommended in women with celiac disease to prevent neural tube defects in the offspring, and the US Preventive Services Task Force recommends 0.4 mg daily of folic acid supplementation for all women planning or capable of pregnancy.^42–44 Higher doses, ranging from 0.6 to 5 mg/day, have been proposed for patients with diabetes,¹³ and we recommend at least 1 mg for this group, based on data suggesting that higher doses further reduce the risk of neural tube defects.⁴³

Maternal diabetes, insulin therapy, and oral hypoglycemic agents are not contraindications to breastfeeding. The US Preventive Services Task Force recommends interventions by primary care physicians to promote and support breastfeeding.⁴⁵ Breastfeeding is encouraged based on various short- and long-term health benefits for both breastfed infants and breastfeeding mothers. Breastfeeding decreases a woman’s insulin requirements and increases the risk for hypoglycemia, especially in patients with insulin-dependent type 1 diabetes.¹

Additionally, insulin sensitivity increases immediately following delivery of the placenta.¹ Therefore, it is prudent to adjust insulin doses postpartum, especially while a patient is breastfeeding, or to suggest high-carbohydrate snacks before feeds.^9,29

Antihypertensive drugs considered safe to use during lactation include captopril, enalapril, quinapril, labetalol, propranolol, nifedipine, and hydralazine.^21,46 Methyldopa is not contraindicated, but it causes fatigue and worsened postpartum depression and should not be used as first-line therapy. Diuretics and ARBs are not recommended during lactation.²¹ Both metformin and glyburide enter breast milk in small enough amounts that they are not contraindicated during breastfeeding.¹⁶ The Lactmed database (www.toxnet.nlm.nih.gov) provides information about drugs and breastfeeding.

WHAT ABOUT CONTRACEPTIVES?

The ADA recommends contraception for women with diabetes because, just as in women without diabetes, the risks of unplanned pregnancy outweigh those of contraceptives.¹

We recommend low-dose combination estrogen-progestin oral contraceptives to normotensive women under age 35 with diabetes but without underlying microvascular disease. For women over age 35 or for those with microvascular disease, additional options include intrauterine devices or progestin implants. We prefer not to use injectable depot medroxyprogesterone acetate because of its side effects of insulin resistance and weight gain.⁴⁷

CASE DISCUSSION: NEXT STEPS

Our patient’s interest in family planning presents an opportunity for preconception counseling. We recommend a prenatal folic acid supplement, diet and regular exercise for weight loss, and screening tests including a comprehensive metabolic panel, hemoglobin A_1c, thyroid-stimulating hormone, and dilated eye examination. We make sure she is up to date on her indicated health maintenance (eg, immunizations, disease screening), and we review her medications for potential teratogens. She denies any recreational drug use. Also, she has no plans for long-distance travel.

Our counseling includes discussions of pregnancy risks associated with pregestational diabetes and suboptimal glycemic control. We encourage her to use effective contraception until she is “medically optimized” for pregnancy—ie, until her hemoglobin A_1c is lower than 6.5% and she has achieved a medically optimal weight. If feasible, a reduction of weight (7% or so) through lifestyle modification should be attempted, and if her hemoglobin A_1c remains elevated, adding insulin would be recommended.

Pregnant patients or patients contemplating pregnancy are usually motivated to modify their behavior, making this a good time to reinforce lifestyle modifications. Many patients benefit from individualized counseling by a registered dietitian to help achieve the recommended weight and glycemic control.

Our physical examination in this patient includes screening for micro- and macrovascular complications of diabetes, and the test results are negative. Patients with active proliferative retinopathy should be referred to an ophthalmologist for assessment and treatment.

We review her medications for potential teratogenic effects and stop her ACE inhibitor (lisinopril) and statin (simvastatin). We switch her from a first-generation sulfonylurea (chlorpropamide) to glyburide, a second-generation sulfonylurea. Second-generation sulfonylureas are considered more “fetus-friendly” because first-generation sulfonylureas cross the placenta more easily and can cause fetal hyperinsulinemia, leading to macrosomia and neonatal hypoglycemia.⁷

The management of diabetes during pregnancy leans toward insulin use, given the lack of information regarding long-term outcomes with oral agents. If insulin is needed, it is best to initiate it before the patient conceives, and then to stop other diabetes medications. We would not make any changes to her aspirin or metformin use.

Educating the patient and her family about prevention, recognition, and treatment of hypoglycemia is important to prevent and manage the increased risk of hypoglycemia with insulin therapy and in early pregnancy.¹ Consideration should be given to providing ketone strips as well as education on diabetic ketoacidosis prevention and detection.¹ If the patient conceives, begin prenatal care early to allow adequate planning for care of her disease and evaluation of the fetus. Because of the complexity of insulin management in pregnancy, the ADA recommends referral, if possible, to a center offering team-based care, including an obstetrician specialized in high-risk pregnancies, an endocrinologist, and a dietitian.¹

A 29-year-old nulliparous woman presents for a routine checkup. She has hypertension and type 2 diabetes mellitus. Her current medications are chlorpropamide 500 mg daily, metformin 500 mg twice a day, lisinopril 40 mg daily, simvastatin 40 mg daily, and aspirin 81 mg daily. Her body mass index is 37 kg/m² and her blood pressure is 130/80 mm Hg. Her hemoglobin A_1c level is 7.8% and her low-density lipoprotein cholesterol 90 mg/dL.

She is considering pregnancy. How would you counsel her?

DEFINING DIABETES IN PREGNANCY

Diabetes in pregnant women, both gestational and pregestational, is the most common medical complication associated with pregnancy.¹

• Gestational diabetes is defined as diabetes that is diagnosed during the second or third trimester of pregnancy and that is not clearly pregestational.²
• Pregestational diabetes exists before pregnancy and can be either type 1 or type 2.

Most cases of diabetes diagnosed during the first trimester reflect pregestational diabetes, as gestational diabetes occurs when insulin resistance increases in the later trimesters.

Type 1 diabetes involves autoimmune destruction of pancreatic islet cells, leading to insulin deficiency and the need for insulin therapy. Type 2 diabetes is characterized by insulin resistance rather than overall insulin deficiency. Type 2 diabetes tends to be associated with comorbidities such as obesity and hypertension, which are independent risk factors for adverse perinatal outcomes.^3,4

Gestational diabetes accounts for most cases of diabetes during pregnancy. Although both pregestational and gestational diabetes increase the risk of maternal and fetal complications, pregestational diabetes is associated with significantly greater risks.¹

IMPACT OF DIABETES ON THE MOTHER

Pregnancy increases the risk of maternal hypoglycemia, especially during the first trimester in patients with type 1 diabetes, as insulin sensitivity increases in early pregnancy.¹ Pregnant women with diabetes may also have an altered counterregulatory response and less hypoglycemic awareness.¹ Insulin resistance rises during the second and early third trimesters, increasing the risk of hyperglycemia in women with diabetes.¹

Glycemic control during pregnancy is usually easier to achieve in patients with type 2 diabetes than with type 1, but it may require much higher insulin doses.

Because pregnancy is inherently a ketogenic state, women with type 1 diabetes are at higher risk of diabetic ketoacidosis, particularly during the second and third trimesters.¹ There are reports of euglycemic diabetic ketoacidosis in pregnant women with either gestational or pregestational diabetes.⁵

Diabetes is associated with a risk of preeclampsia 4 times higher than in nondiabetic women.⁶ Other potential pregnancy-related complications include infections, polyhydram­nios, spontaneous abortion, and cesarean delivery.^1,7 The risk of pregnancy loss is similar in women with either type 1 or type 2 diabetes (2.6% and 3.7%, respectively), but the causes are different.⁸ Although preexisting diabetic complications such as retinopathy, nephropathy, and gastroparesis can be exacerbated during pregnancy,¹ only severe gastroparesis and advanced renal disease are considered relative contraindications to pregnancy.

IMPACT OF DIABETES ON THE FETUS

Fetal complications of maternal diabetes include embryopathy (fetal malformations) and fetopathy (overgrowth, ie, fetus large for gestational age, and increased risk of fetal death or distress). Maternal hyperglycemia is associated with diabetic embryopathy, resulting in major birth defects in 5% to 25% of pregnancies and spontaneous abortions in 15% to 20%.^9,10 There is a 2- to 6-fold increase in risk of congenital malformations.6

The most common diabetes-associated congenital malformations affect the cardiovascular system. Congenital heart disease includes tetralogy of Fallot, transposition of the great vessels, septal defects, and anomalous pulmonary venous return. Other relatively common defects involve the fetal central nervous system, spine, orofacial system, kidneys, urogenital system, gastrointestinal tract, and skeleton.¹¹

The risk of fetopathy is proportional to the degree of maternal hyperglycemia. Excess maternal glucose and fatty acid levels can lead to fetal hyperglycemia and overgrowth, which increases fetal oxygen requirements. Erythro­poietin levels rise, causing an increase in red cell mass, with subsequent hyperviscosity within the placenta and higher risk of fetal death.

Other complications include intrauterine growth restriction, prematurity, and preterm delivery. Fetal macrosomia (birth weight > 90th percentile or 4 kg, approximately 8 lb, 13 oz) occurs in 27% to 62% of children born to mothers with diabetes, a rate 10 times higher than in patients without diabetes. It contributes to shoulder dystocia (risk 2 to 4 times higher in diabetic pregnancies) and cesarean delivery.⁶ Infants born to mothers with diabetes also have higher risks of neonatal hypoglycemia, erythrocytosis, hyperbilirubinemia, hypocalcemia, respiratory distress, cardiomyopathy, and death, as well as for developing diabetes, obesity, and other adverse cardiometabolic outcomes later in life.¹¹

Nearly half of pregnancies in the general population are unplanned,¹⁵ so preconception diabetes assessment needs to be part of routine medical care for all reproductive-age women. Because most organogenesis occurs during the first 5 to 8 weeks after fertilization—potentially before a woman realizes she is pregnant—achieving optimal glycemic control before conception is necessary to improve pregnancy outcomes.¹

EVERY VISIT IS AN OPPORTUNITY

Every medical visit with a reproductive-age woman with diabetes is an opportunity for counseling about pregnancy. Topics that need to be discussed include the risks of unplanned pregnancy and of poor metabolic control, and the benefits of improved maternal and fetal outcomes with appropriate pregnancy planning and diabetes management.

Referral to a registered dietitian for individualized counseling about proper nutrition, particularly during pregnancy, has been associated with positive outcomes.¹⁶ Patients with diabetes and at high risk of pregnancy complications should be referred to a clinic that specializes in high-risk pregnancies.

Practitioners also should emphasize the importance of regular exercise and encourage patients to maintain or achieve a medically optimal weight before conception. Ideally, this would be a normal body mass index; however, this is not always possible.

In women who are planning pregnancy or are not on effective contraception, medications should be reviewed for potential teratogenicity. If needed, discuss alternative medications or switch to safer ones. However, these changes should not interrupt diabetes treatment.

In addition, ensure that the patient is up to date on age- and disease-appropriate preventive care (eg, immunizations, screening for sexually transmitted disease and malignancy). Counseling and intervention for use of tobacco, alcohol, and recreational drugs are also important. As with any preconception counseling, the patient (and her partner, if possible) should be advised to avoid travel to areas where Zika virus is endemic, and informed about the availability of expanded carrier genetic screening through her obstetric provider.

Finally, pregnant women with diabetes benefit from screening for diabetic complications including hypertension, retinopathy, cardiovascular disease, neuropathy, and nephropathy.

ASSESSING RISKS

Blood pressure

Chronic (preexisting) hypertension is defined as a systolic pressure 140 mm Hg or higher or a diastolic pressure 90 mm Hg or higher, or both, that antedates pregnancy or is present before the 20th week of pregnancy.³ Chronic hypertension has been reported in up to 5% of pregnant women and is associated with increased risk of preterm delivery, superimposed preeclampsia, low birth weight, and perinatal death.³

Reproductive-age women with diabetes and high blood pressure benefit from lifestyle and behavioral modifications.¹⁷ If drug therapy is needed, antihypertensive drugs that are safe for the fetus should be used. Treatment of mild or moderate hypertension during pregnancy reduces the risk of progression to severe hypertension but may not improve obstetric outcomes.

Diabetic retinopathy

Diabetic retinopathy can significantly worsen during pregnancy: the risk of progression is double that in the nonpregnant state.¹⁸ Women with diabetes who are contemplating pregnancy should have a comprehensive eye examination before conception, and any active proliferative retinopathy needs to be treated. These patients may require ophthalmologic monitoring and treatment during pregnancy. (Note: laser photocoagulation is not contraindicated during pregnancy.)

Cardiovascular disease

Cardiovascular physiology changes dramatically during pregnancy. Cardiovascular disease, especially when superimposed on diabetes, can increase the risk of maternal death. Thus, evaluation for cardiovascular risk factors as well as cardiovascular system integrity before conception is important. Listen for arterial bruits and murmurs, and assess peripheral pulses. Consideration should be given to obtaining a preconception resting electrocardiogram in women with diabetes who are over age 35 or who are suspected of having cardiovascular disease.¹⁶

Neurologic disorders

Peripheral neuropathy, the most common neurologic complication of diabetes, is associated with injury and infection.¹⁹

Autonomic neuropathy is associated with decreased cardiac responsiveness and orthostatic hypotension.¹⁹ Diabetic gastroparesis alone can precipitate serious complications during pregnancy, including extreme hypoglycemia and hyperglycemia, increased risk of diabetic ketoacidosis, weight loss, malnutrition, frequent hospitalizations, and increased requirement for parenteral nutrition.²⁰

Although diabetic neuropathy does not significantly worsen during pregnancy, women with preexisting gastroparesis should be counseled on the substantial risks associated with pregnancy. Screening for neuropathy should be part of all diabetic preconception examinations.

Renal complications

Pregnancy in women with diabetes and preexisting renal dysfunction increases their risk of accelerated progression of diabetic kidney disease.²¹ Preexisting renal dysfunction also increases the risk of pregnancy-related complications, such as stillbirth, intrauterine growth restriction, gestational hypertension, preeclampsia, and preterm delivery.^19,21,22 Further, the risk of pregnancy complications correlates directly with the severity of renal dysfunction.²²

Psychiatric disorders

Emotional wellness is essential for optimal diabetes management. It is important to recognize the emotional impact of diabetes in pregnant women and to conduct routine screening for depression, anxiety, stress, and eating disorders.¹⁶

Hemoglobin A_1c. The general consensus is to achieve the lowest hemoglobin A_1c level possible that does not increase the risk of hypoglycemia. The American Diabetes Association (ADA) recommends that, before attempting to conceive, women should lower their hemoglobin A_1c to below 6.5%.¹

Thyroid measures. Autoimmune thyroid disease is the most common autoimmune disorder associated with diabetes and has been reported in 35% to 40% of women with type 1 diabetes.²³ Recommendations are to check thyroid-stimulating hormone and thyroid peroxidase antibody levels before conception or early in pregnancy in all women with diabetes.^1,24 Overt hypothyroidism should be treated before conception, given that early fetal brain development depends on maternal thyroxine.

Renal function testing. Preconception assessment of renal function is important for counseling and risk stratification. This assessment should include serum creatinine level, estimated glomerular filtration rate, and urinary albumin excretion.²¹

Celiac screening. Because women with type 1 diabetes are more susceptible to autoimmune diseases, they should be screened for celiac disease before conception, with testing for  immunoglobulin A (IgA) and tissue transglutaminase antibodies, with or without IgA endomysial antibodies.^16,25,26 An estimated 6% of patients with type 1 diabetes have celiac disease vs 1% of the general population.²⁵ Celiac disease is 2 to 3 times more common in women, and asymptomatic people with type 1 diabetes are considered at increased risk for celiac disease.²⁶

The association between type 1 diabetes and celiac disease most likely relates to the overlap in human leukocyte antigens of the diseases. There is no established link between type 2 diabetes and celiac disease.²⁵

Undiagnosed celiac disease increases a woman’s risk of obstetric complications such as preterm birth, low birth weight, and stillbirth.²⁶ The most likely explanation for these adverse effects is nutrient malabsorption, which is characteristic of celiac disease. Adherence to a gluten-free diet before and during gestation may reduce the risk of preterm delivery by as much as 20%.²⁶

Vitamin B₁₂ level. Celiac disease interferes with the absorption of vitamin B₁₂-instrinsic factor in the ileum, which can lead to vitamin B₁₂ deficiency. Therefore, baseline vitamin B₁₂ levels should be checked before conception in women with celiac disease. Levels should also be checked in women taking metformin, which also decreases vitamin B₁₂ absorption. Of note, increased folate levels due to taking supplements can potentially mask vitamin B₁₂ deficiency.

MEDICATIONS TO REVIEW FOR PREGNANCY INTERACTIONS

Diabetic medications

Insulin is the first-line pharmacotherapy for pregnant patients with type 1, type 2, or gestational diabetes. Insulin does not cross the placenta to a measurable extent, and most insulin preparations have been classified as category B,¹ meaning no risks to the fetus have been found in humans.

Insulin dosing during pregnancy is not static. Beginning around mid-gestation, insulin requirements increase,^28,29 but after 32 weeks the need may decrease. These changes require practitioners to closely monitor blood glucose throughout pregnancy.

Both basal-bolus injections and continuous subcutaneous infusion are reasonable options during pregnancy.³⁰ However, the need for multiple and potentially painful insulin injections daily can lead to poor compliance. This inconvenience has led to studies using oral hypoglycemic medications instead of insulin for patients with gestational and type 2 diabetes.

Metformin is an oral biguanide that decreases hepatic gluconeogenesis and intestinal glucose absorption while peripherally increasing glucose utilization and uptake. Metformin does not pose a risk of hypoglycemia because its mechanism of action does not involve increased insulin production.⁷

Metformin does cross the placenta, resulting in umbilical cord blood levels higher than maternal levels. Nevertheless, studies support the efficacy and short-term safety of metformin use during a pregnancy complicated by gestational or type 2 diabetes.^7,31 Moreover, metformin has been associated with a lower risk of neonatal hypoglycemia and maternal weight gain than insulin.³² However, this agent should be used with caution, as long-term data are not yet available, and it may slightly increase the risk of premature delivery.

Glyburide is another oral hypoglycemic medication that has been used during pregnancy. This second-generation sulfonylurea enhances the release of insulin from the pancreas by binding beta islet cell ATP-calcium channel receptors. Compared with other sulfonylureas, glyburide has the lowest rate of maternal-to-fetal transfer, with umbilical cord plasma concentrations 70% of maternal levels.³³ Although some trials support the efficacy and short-term safety of glyburide treatment for gestational diabetes,³⁴ recent studies have associated glyburide use during pregnancy with a higher rate of neonatal hypoglycemia, neonatal respiratory distress, macrosomia, and neonatal intensive care unit admissions than insulin and metformin.^1,35

Patients treated with oral agents should be informed that these drugs cross the placenta, and that although no adverse effects on the fetus have been demonstrated, long-term safety data are lacking. In addition, oral agents are ineffective in type 1 diabetes and may be insufficient to overcome the insulin resistance in type 2 diabetes.

Antihypertensive drugs

All antihypertensive drugs cross the placenta, but several have an acceptable safety profile in pregnancy, including methyldopa, labeta­lol, clonidine, prazosin, and nifedipine. Hydralazine and labetalol are short-acting, come in intravenous formulations, and can be used for urgent blood pressure control during pregnancy. Diltiazem may be used for heart rate control during pregnancy, and it has been shown to lower blood pressure and proteinuria in pregnant patients with underlying renal disease.^36,37 The ADA recommends against chronic use of diuretics during pregnancy because of potential reductions in maternal plasma volume and uteroplacental perfusion.¹

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors are contraindicated during pregnancy because of the risk of fetal defects, particularly in the renal system.^21,38 Although there is evidence to question the association between first semester exposure and fetotoxicity,³⁹ we avoid these drugs during pregnancy and switch to a different agent in women planning pregnancy.

Other drugs

Statins are contraindicated in pregnancy because they interfere with the development of the fetal nervous system.²¹ Although preliminary data from a small study did not identify safety risks associated with pravastatin use after 12 weeks of gestation,⁴⁰ we recommend discontinuing statins in women attempting pregnancy.

Aspirin. The US Preventive Services Task Force41 recommends low-dose aspirin (81 mg/day) after 12 weeks of gestation for women with type 1 or type 2 diabetes, as well as those with renal disease or chronic hypertension, to prevent preeclampsia. Of note, higher doses need to be used with caution during pregnancy because fetal abnormalities have been reported, such as disruption of fetal vasculature (mesenteric vessels), gastroschisis, and small intestinal atresia.¹⁶

Folate supplementation (0.6–4 mg/day) is recommended in women with celiac disease to prevent neural tube defects in the offspring, and the US Preventive Services Task Force recommends 0.4 mg daily of folic acid supplementation for all women planning or capable of pregnancy.^42–44 Higher doses, ranging from 0.6 to 5 mg/day, have been proposed for patients with diabetes,¹³ and we recommend at least 1 mg for this group, based on data suggesting that higher doses further reduce the risk of neural tube defects.⁴³

Maternal diabetes, insulin therapy, and oral hypoglycemic agents are not contraindications to breastfeeding. The US Preventive Services Task Force recommends interventions by primary care physicians to promote and support breastfeeding.⁴⁵ Breastfeeding is encouraged based on various short- and long-term health benefits for both breastfed infants and breastfeeding mothers. Breastfeeding decreases a woman’s insulin requirements and increases the risk for hypoglycemia, especially in patients with insulin-dependent type 1 diabetes.¹

Additionally, insulin sensitivity increases immediately following delivery of the placenta.¹ Therefore, it is prudent to adjust insulin doses postpartum, especially while a patient is breastfeeding, or to suggest high-carbohydrate snacks before feeds.^9,29

Antihypertensive drugs considered safe to use during lactation include captopril, enalapril, quinapril, labetalol, propranolol, nifedipine, and hydralazine.^21,46 Methyldopa is not contraindicated, but it causes fatigue and worsened postpartum depression and should not be used as first-line therapy. Diuretics and ARBs are not recommended during lactation.²¹ Both metformin and glyburide enter breast milk in small enough amounts that they are not contraindicated during breastfeeding.¹⁶ The Lactmed database (www.toxnet.nlm.nih.gov) provides information about drugs and breastfeeding.

WHAT ABOUT CONTRACEPTIVES?

The ADA recommends contraception for women with diabetes because, just as in women without diabetes, the risks of unplanned pregnancy outweigh those of contraceptives.¹

We recommend low-dose combination estrogen-progestin oral contraceptives to normotensive women under age 35 with diabetes but without underlying microvascular disease. For women over age 35 or for those with microvascular disease, additional options include intrauterine devices or progestin implants. We prefer not to use injectable depot medroxyprogesterone acetate because of its side effects of insulin resistance and weight gain.⁴⁷

CASE DISCUSSION: NEXT STEPS

Our patient’s interest in family planning presents an opportunity for preconception counseling. We recommend a prenatal folic acid supplement, diet and regular exercise for weight loss, and screening tests including a comprehensive metabolic panel, hemoglobin A_1c, thyroid-stimulating hormone, and dilated eye examination. We make sure she is up to date on her indicated health maintenance (eg, immunizations, disease screening), and we review her medications for potential teratogens. She denies any recreational drug use. Also, she has no plans for long-distance travel.

Our counseling includes discussions of pregnancy risks associated with pregestational diabetes and suboptimal glycemic control. We encourage her to use effective contraception until she is “medically optimized” for pregnancy—ie, until her hemoglobin A_1c is lower than 6.5% and she has achieved a medically optimal weight. If feasible, a reduction of weight (7% or so) through lifestyle modification should be attempted, and if her hemoglobin A_1c remains elevated, adding insulin would be recommended.

Pregnant patients or patients contemplating pregnancy are usually motivated to modify their behavior, making this a good time to reinforce lifestyle modifications. Many patients benefit from individualized counseling by a registered dietitian to help achieve the recommended weight and glycemic control.

Our physical examination in this patient includes screening for micro- and macrovascular complications of diabetes, and the test results are negative. Patients with active proliferative retinopathy should be referred to an ophthalmologist for assessment and treatment.

We review her medications for potential teratogenic effects and stop her ACE inhibitor (lisinopril) and statin (simvastatin). We switch her from a first-generation sulfonylurea (chlorpropamide) to glyburide, a second-generation sulfonylurea. Second-generation sulfonylureas are considered more “fetus-friendly” because first-generation sulfonylureas cross the placenta more easily and can cause fetal hyperinsulinemia, leading to macrosomia and neonatal hypoglycemia.⁷

The management of diabetes during pregnancy leans toward insulin use, given the lack of information regarding long-term outcomes with oral agents. If insulin is needed, it is best to initiate it before the patient conceives, and then to stop other diabetes medications. We would not make any changes to her aspirin or metformin use.

Educating the patient and her family about prevention, recognition, and treatment of hypoglycemia is important to prevent and manage the increased risk of hypoglycemia with insulin therapy and in early pregnancy.¹ Consideration should be given to providing ketone strips as well as education on diabetic ketoacidosis prevention and detection.¹ If the patient conceives, begin prenatal care early to allow adequate planning for care of her disease and evaluation of the fetus. Because of the complexity of insulin management in pregnancy, the ADA recommends referral, if possible, to a center offering team-based care, including an obstetrician specialized in high-risk pregnancies, an endocrinologist, and a dietitian.¹

A 29-year-old nulliparous woman presents for a routine checkup. She has hypertension and type 2 diabetes mellitus. Her current medications are chlorpropamide 500 mg daily, metformin 500 mg twice a day, lisinopril 40 mg daily, simvastatin 40 mg daily, and aspirin 81 mg daily. Her body mass index is 37 kg/m² and her blood pressure is 130/80 mm Hg. Her hemoglobin A_1c level is 7.8% and her low-density lipoprotein cholesterol 90 mg/dL.

She is considering pregnancy. How would you counsel her?

DEFINING DIABETES IN PREGNANCY

Diabetes in pregnant women, both gestational and pregestational, is the most common medical complication associated with pregnancy.¹

• Gestational diabetes is defined as diabetes that is diagnosed during the second or third trimester of pregnancy and that is not clearly pregestational.²
• Pregestational diabetes exists before pregnancy and can be either type 1 or type 2.

Most cases of diabetes diagnosed during the first trimester reflect pregestational diabetes, as gestational diabetes occurs when insulin resistance increases in the later trimesters.

Type 1 diabetes involves autoimmune destruction of pancreatic islet cells, leading to insulin deficiency and the need for insulin therapy. Type 2 diabetes is characterized by insulin resistance rather than overall insulin deficiency. Type 2 diabetes tends to be associated with comorbidities such as obesity and hypertension, which are independent risk factors for adverse perinatal outcomes.^3,4

Gestational diabetes accounts for most cases of diabetes during pregnancy. Although both pregestational and gestational diabetes increase the risk of maternal and fetal complications, pregestational diabetes is associated with significantly greater risks.¹

IMPACT OF DIABETES ON THE MOTHER

Pregnancy increases the risk of maternal hypoglycemia, especially during the first trimester in patients with type 1 diabetes, as insulin sensitivity increases in early pregnancy.¹ Pregnant women with diabetes may also have an altered counterregulatory response and less hypoglycemic awareness.¹ Insulin resistance rises during the second and early third trimesters, increasing the risk of hyperglycemia in women with diabetes.¹

Glycemic control during pregnancy is usually easier to achieve in patients with type 2 diabetes than with type 1, but it may require much higher insulin doses.

Because pregnancy is inherently a ketogenic state, women with type 1 diabetes are at higher risk of diabetic ketoacidosis, particularly during the second and third trimesters.¹ There are reports of euglycemic diabetic ketoacidosis in pregnant women with either gestational or pregestational diabetes.⁵

Diabetes is associated with a risk of preeclampsia 4 times higher than in nondiabetic women.⁶ Other potential pregnancy-related complications include infections, polyhydram­nios, spontaneous abortion, and cesarean delivery.^1,7 The risk of pregnancy loss is similar in women with either type 1 or type 2 diabetes (2.6% and 3.7%, respectively), but the causes are different.⁸ Although preexisting diabetic complications such as retinopathy, nephropathy, and gastroparesis can be exacerbated during pregnancy,¹ only severe gastroparesis and advanced renal disease are considered relative contraindications to pregnancy.

IMPACT OF DIABETES ON THE FETUS

Fetal complications of maternal diabetes include embryopathy (fetal malformations) and fetopathy (overgrowth, ie, fetus large for gestational age, and increased risk of fetal death or distress). Maternal hyperglycemia is associated with diabetic embryopathy, resulting in major birth defects in 5% to 25% of pregnancies and spontaneous abortions in 15% to 20%.^9,10 There is a 2- to 6-fold increase in risk of congenital malformations.6

The most common diabetes-associated congenital malformations affect the cardiovascular system. Congenital heart disease includes tetralogy of Fallot, transposition of the great vessels, septal defects, and anomalous pulmonary venous return. Other relatively common defects involve the fetal central nervous system, spine, orofacial system, kidneys, urogenital system, gastrointestinal tract, and skeleton.¹¹

The risk of fetopathy is proportional to the degree of maternal hyperglycemia. Excess maternal glucose and fatty acid levels can lead to fetal hyperglycemia and overgrowth, which increases fetal oxygen requirements. Erythro­poietin levels rise, causing an increase in red cell mass, with subsequent hyperviscosity within the placenta and higher risk of fetal death.

Other complications include intrauterine growth restriction, prematurity, and preterm delivery. Fetal macrosomia (birth weight > 90th percentile or 4 kg, approximately 8 lb, 13 oz) occurs in 27% to 62% of children born to mothers with diabetes, a rate 10 times higher than in patients without diabetes. It contributes to shoulder dystocia (risk 2 to 4 times higher in diabetic pregnancies) and cesarean delivery.⁶ Infants born to mothers with diabetes also have higher risks of neonatal hypoglycemia, erythrocytosis, hyperbilirubinemia, hypocalcemia, respiratory distress, cardiomyopathy, and death, as well as for developing diabetes, obesity, and other adverse cardiometabolic outcomes later in life.¹¹

Nearly half of pregnancies in the general population are unplanned,¹⁵ so preconception diabetes assessment needs to be part of routine medical care for all reproductive-age women. Because most organogenesis occurs during the first 5 to 8 weeks after fertilization—potentially before a woman realizes she is pregnant—achieving optimal glycemic control before conception is necessary to improve pregnancy outcomes.¹

EVERY VISIT IS AN OPPORTUNITY

Every medical visit with a reproductive-age woman with diabetes is an opportunity for counseling about pregnancy. Topics that need to be discussed include the risks of unplanned pregnancy and of poor metabolic control, and the benefits of improved maternal and fetal outcomes with appropriate pregnancy planning and diabetes management.

Referral to a registered dietitian for individualized counseling about proper nutrition, particularly during pregnancy, has been associated with positive outcomes.¹⁶ Patients with diabetes and at high risk of pregnancy complications should be referred to a clinic that specializes in high-risk pregnancies.

Practitioners also should emphasize the importance of regular exercise and encourage patients to maintain or achieve a medically optimal weight before conception. Ideally, this would be a normal body mass index; however, this is not always possible.

In women who are planning pregnancy or are not on effective contraception, medications should be reviewed for potential teratogenicity. If needed, discuss alternative medications or switch to safer ones. However, these changes should not interrupt diabetes treatment.

In addition, ensure that the patient is up to date on age- and disease-appropriate preventive care (eg, immunizations, screening for sexually transmitted disease and malignancy). Counseling and intervention for use of tobacco, alcohol, and recreational drugs are also important. As with any preconception counseling, the patient (and her partner, if possible) should be advised to avoid travel to areas where Zika virus is endemic, and informed about the availability of expanded carrier genetic screening through her obstetric provider.

Finally, pregnant women with diabetes benefit from screening for diabetic complications including hypertension, retinopathy, cardiovascular disease, neuropathy, and nephropathy.

ASSESSING RISKS

Blood pressure

Chronic (preexisting) hypertension is defined as a systolic pressure 140 mm Hg or higher or a diastolic pressure 90 mm Hg or higher, or both, that antedates pregnancy or is present before the 20th week of pregnancy.³ Chronic hypertension has been reported in up to 5% of pregnant women and is associated with increased risk of preterm delivery, superimposed preeclampsia, low birth weight, and perinatal death.³

Reproductive-age women with diabetes and high blood pressure benefit from lifestyle and behavioral modifications.¹⁷ If drug therapy is needed, antihypertensive drugs that are safe for the fetus should be used. Treatment of mild or moderate hypertension during pregnancy reduces the risk of progression to severe hypertension but may not improve obstetric outcomes.

Diabetic retinopathy

Diabetic retinopathy can significantly worsen during pregnancy: the risk of progression is double that in the nonpregnant state.¹⁸ Women with diabetes who are contemplating pregnancy should have a comprehensive eye examination before conception, and any active proliferative retinopathy needs to be treated. These patients may require ophthalmologic monitoring and treatment during pregnancy. (Note: laser photocoagulation is not contraindicated during pregnancy.)

Cardiovascular disease

Cardiovascular physiology changes dramatically during pregnancy. Cardiovascular disease, especially when superimposed on diabetes, can increase the risk of maternal death. Thus, evaluation for cardiovascular risk factors as well as cardiovascular system integrity before conception is important. Listen for arterial bruits and murmurs, and assess peripheral pulses. Consideration should be given to obtaining a preconception resting electrocardiogram in women with diabetes who are over age 35 or who are suspected of having cardiovascular disease.¹⁶

Neurologic disorders

Peripheral neuropathy, the most common neurologic complication of diabetes, is associated with injury and infection.¹⁹

Autonomic neuropathy is associated with decreased cardiac responsiveness and orthostatic hypotension.¹⁹ Diabetic gastroparesis alone can precipitate serious complications during pregnancy, including extreme hypoglycemia and hyperglycemia, increased risk of diabetic ketoacidosis, weight loss, malnutrition, frequent hospitalizations, and increased requirement for parenteral nutrition.²⁰

Although diabetic neuropathy does not significantly worsen during pregnancy, women with preexisting gastroparesis should be counseled on the substantial risks associated with pregnancy. Screening for neuropathy should be part of all diabetic preconception examinations.

Renal complications

Pregnancy in women with diabetes and preexisting renal dysfunction increases their risk of accelerated progression of diabetic kidney disease.²¹ Preexisting renal dysfunction also increases the risk of pregnancy-related complications, such as stillbirth, intrauterine growth restriction, gestational hypertension, preeclampsia, and preterm delivery.^19,21,22 Further, the risk of pregnancy complications correlates directly with the severity of renal dysfunction.²²

Psychiatric disorders

Emotional wellness is essential for optimal diabetes management. It is important to recognize the emotional impact of diabetes in pregnant women and to conduct routine screening for depression, anxiety, stress, and eating disorders.¹⁶

Hemoglobin A_1c. The general consensus is to achieve the lowest hemoglobin A_1c level possible that does not increase the risk of hypoglycemia. The American Diabetes Association (ADA) recommends that, before attempting to conceive, women should lower their hemoglobin A_1c to below 6.5%.¹

Thyroid measures. Autoimmune thyroid disease is the most common autoimmune disorder associated with diabetes and has been reported in 35% to 40% of women with type 1 diabetes.²³ Recommendations are to check thyroid-stimulating hormone and thyroid peroxidase antibody levels before conception or early in pregnancy in all women with diabetes.^1,24 Overt hypothyroidism should be treated before conception, given that early fetal brain development depends on maternal thyroxine.

Renal function testing. Preconception assessment of renal function is important for counseling and risk stratification. This assessment should include serum creatinine level, estimated glomerular filtration rate, and urinary albumin excretion.²¹

Celiac screening. Because women with type 1 diabetes are more susceptible to autoimmune diseases, they should be screened for celiac disease before conception, with testing for  immunoglobulin A (IgA) and tissue transglutaminase antibodies, with or without IgA endomysial antibodies.^16,25,26 An estimated 6% of patients with type 1 diabetes have celiac disease vs 1% of the general population.²⁵ Celiac disease is 2 to 3 times more common in women, and asymptomatic people with type 1 diabetes are considered at increased risk for celiac disease.²⁶

The association between type 1 diabetes and celiac disease most likely relates to the overlap in human leukocyte antigens of the diseases. There is no established link between type 2 diabetes and celiac disease.²⁵

Undiagnosed celiac disease increases a woman’s risk of obstetric complications such as preterm birth, low birth weight, and stillbirth.²⁶ The most likely explanation for these adverse effects is nutrient malabsorption, which is characteristic of celiac disease. Adherence to a gluten-free diet before and during gestation may reduce the risk of preterm delivery by as much as 20%.²⁶

Vitamin B₁₂ level. Celiac disease interferes with the absorption of vitamin B₁₂-instrinsic factor in the ileum, which can lead to vitamin B₁₂ deficiency. Therefore, baseline vitamin B₁₂ levels should be checked before conception in women with celiac disease. Levels should also be checked in women taking metformin, which also decreases vitamin B₁₂ absorption. Of note, increased folate levels due to taking supplements can potentially mask vitamin B₁₂ deficiency.

MEDICATIONS TO REVIEW FOR PREGNANCY INTERACTIONS

Diabetic medications

Insulin is the first-line pharmacotherapy for pregnant patients with type 1, type 2, or gestational diabetes. Insulin does not cross the placenta to a measurable extent, and most insulin preparations have been classified as category B,¹ meaning no risks to the fetus have been found in humans.

Insulin dosing during pregnancy is not static. Beginning around mid-gestation, insulin requirements increase,^28,29 but after 32 weeks the need may decrease. These changes require practitioners to closely monitor blood glucose throughout pregnancy.

Both basal-bolus injections and continuous subcutaneous infusion are reasonable options during pregnancy.³⁰ However, the need for multiple and potentially painful insulin injections daily can lead to poor compliance. This inconvenience has led to studies using oral hypoglycemic medications instead of insulin for patients with gestational and type 2 diabetes.

Metformin is an oral biguanide that decreases hepatic gluconeogenesis and intestinal glucose absorption while peripherally increasing glucose utilization and uptake. Metformin does not pose a risk of hypoglycemia because its mechanism of action does not involve increased insulin production.⁷

Metformin does cross the placenta, resulting in umbilical cord blood levels higher than maternal levels. Nevertheless, studies support the efficacy and short-term safety of metformin use during a pregnancy complicated by gestational or type 2 diabetes.^7,31 Moreover, metformin has been associated with a lower risk of neonatal hypoglycemia and maternal weight gain than insulin.³² However, this agent should be used with caution, as long-term data are not yet available, and it may slightly increase the risk of premature delivery.

Glyburide is another oral hypoglycemic medication that has been used during pregnancy. This second-generation sulfonylurea enhances the release of insulin from the pancreas by binding beta islet cell ATP-calcium channel receptors. Compared with other sulfonylureas, glyburide has the lowest rate of maternal-to-fetal transfer, with umbilical cord plasma concentrations 70% of maternal levels.³³ Although some trials support the efficacy and short-term safety of glyburide treatment for gestational diabetes,³⁴ recent studies have associated glyburide use during pregnancy with a higher rate of neonatal hypoglycemia, neonatal respiratory distress, macrosomia, and neonatal intensive care unit admissions than insulin and metformin.^1,35

Patients treated with oral agents should be informed that these drugs cross the placenta, and that although no adverse effects on the fetus have been demonstrated, long-term safety data are lacking. In addition, oral agents are ineffective in type 1 diabetes and may be insufficient to overcome the insulin resistance in type 2 diabetes.

Antihypertensive drugs

All antihypertensive drugs cross the placenta, but several have an acceptable safety profile in pregnancy, including methyldopa, labeta­lol, clonidine, prazosin, and nifedipine. Hydralazine and labetalol are short-acting, come in intravenous formulations, and can be used for urgent blood pressure control during pregnancy. Diltiazem may be used for heart rate control during pregnancy, and it has been shown to lower blood pressure and proteinuria in pregnant patients with underlying renal disease.^36,37 The ADA recommends against chronic use of diuretics during pregnancy because of potential reductions in maternal plasma volume and uteroplacental perfusion.¹

Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and direct renin inhibitors are contraindicated during pregnancy because of the risk of fetal defects, particularly in the renal system.^21,38 Although there is evidence to question the association between first semester exposure and fetotoxicity,³⁹ we avoid these drugs during pregnancy and switch to a different agent in women planning pregnancy.

Other drugs

Statins are contraindicated in pregnancy because they interfere with the development of the fetal nervous system.²¹ Although preliminary data from a small study did not identify safety risks associated with pravastatin use after 12 weeks of gestation,⁴⁰ we recommend discontinuing statins in women attempting pregnancy.

Aspirin. The US Preventive Services Task Force41 recommends low-dose aspirin (81 mg/day) after 12 weeks of gestation for women with type 1 or type 2 diabetes, as well as those with renal disease or chronic hypertension, to prevent preeclampsia. Of note, higher doses need to be used with caution during pregnancy because fetal abnormalities have been reported, such as disruption of fetal vasculature (mesenteric vessels), gastroschisis, and small intestinal atresia.¹⁶

Folate supplementation (0.6–4 mg/day) is recommended in women with celiac disease to prevent neural tube defects in the offspring, and the US Preventive Services Task Force recommends 0.4 mg daily of folic acid supplementation for all women planning or capable of pregnancy.^42–44 Higher doses, ranging from 0.6 to 5 mg/day, have been proposed for patients with diabetes,¹³ and we recommend at least 1 mg for this group, based on data suggesting that higher doses further reduce the risk of neural tube defects.⁴³

Maternal diabetes, insulin therapy, and oral hypoglycemic agents are not contraindications to breastfeeding. The US Preventive Services Task Force recommends interventions by primary care physicians to promote and support breastfeeding.⁴⁵ Breastfeeding is encouraged based on various short- and long-term health benefits for both breastfed infants and breastfeeding mothers. Breastfeeding decreases a woman’s insulin requirements and increases the risk for hypoglycemia, especially in patients with insulin-dependent type 1 diabetes.¹

Additionally, insulin sensitivity increases immediately following delivery of the placenta.¹ Therefore, it is prudent to adjust insulin doses postpartum, especially while a patient is breastfeeding, or to suggest high-carbohydrate snacks before feeds.^9,29

Antihypertensive drugs considered safe to use during lactation include captopril, enalapril, quinapril, labetalol, propranolol, nifedipine, and hydralazine.^21,46 Methyldopa is not contraindicated, but it causes fatigue and worsened postpartum depression and should not be used as first-line therapy. Diuretics and ARBs are not recommended during lactation.²¹ Both metformin and glyburide enter breast milk in small enough amounts that they are not contraindicated during breastfeeding.¹⁶ The Lactmed database (www.toxnet.nlm.nih.gov) provides information about drugs and breastfeeding.

WHAT ABOUT CONTRACEPTIVES?

The ADA recommends contraception for women with diabetes because, just as in women without diabetes, the risks of unplanned pregnancy outweigh those of contraceptives.¹

We recommend low-dose combination estrogen-progestin oral contraceptives to normotensive women under age 35 with diabetes but without underlying microvascular disease. For women over age 35 or for those with microvascular disease, additional options include intrauterine devices or progestin implants. We prefer not to use injectable depot medroxyprogesterone acetate because of its side effects of insulin resistance and weight gain.⁴⁷

CASE DISCUSSION: NEXT STEPS

Our patient’s interest in family planning presents an opportunity for preconception counseling. We recommend a prenatal folic acid supplement, diet and regular exercise for weight loss, and screening tests including a comprehensive metabolic panel, hemoglobin A_1c, thyroid-stimulating hormone, and dilated eye examination. We make sure she is up to date on her indicated health maintenance (eg, immunizations, disease screening), and we review her medications for potential teratogens. She denies any recreational drug use. Also, she has no plans for long-distance travel.

Our counseling includes discussions of pregnancy risks associated with pregestational diabetes and suboptimal glycemic control. We encourage her to use effective contraception until she is “medically optimized” for pregnancy—ie, until her hemoglobin A_1c is lower than 6.5% and she has achieved a medically optimal weight. If feasible, a reduction of weight (7% or so) through lifestyle modification should be attempted, and if her hemoglobin A_1c remains elevated, adding insulin would be recommended.

Pregnant patients or patients contemplating pregnancy are usually motivated to modify their behavior, making this a good time to reinforce lifestyle modifications. Many patients benefit from individualized counseling by a registered dietitian to help achieve the recommended weight and glycemic control.

Our physical examination in this patient includes screening for micro- and macrovascular complications of diabetes, and the test results are negative. Patients with active proliferative retinopathy should be referred to an ophthalmologist for assessment and treatment.

We review her medications for potential teratogenic effects and stop her ACE inhibitor (lisinopril) and statin (simvastatin). We switch her from a first-generation sulfonylurea (chlorpropamide) to glyburide, a second-generation sulfonylurea. Second-generation sulfonylureas are considered more “fetus-friendly” because first-generation sulfonylureas cross the placenta more easily and can cause fetal hyperinsulinemia, leading to macrosomia and neonatal hypoglycemia.⁷

The management of diabetes during pregnancy leans toward insulin use, given the lack of information regarding long-term outcomes with oral agents. If insulin is needed, it is best to initiate it before the patient conceives, and then to stop other diabetes medications. We would not make any changes to her aspirin or metformin use.

Educating the patient and her family about prevention, recognition, and treatment of hypoglycemia is important to prevent and manage the increased risk of hypoglycemia with insulin therapy and in early pregnancy.¹ Consideration should be given to providing ketone strips as well as education on diabetic ketoacidosis prevention and detection.¹ If the patient conceives, begin prenatal care early to allow adequate planning for care of her disease and evaluation of the fetus. Because of the complexity of insulin management in pregnancy, the ADA recommends referral, if possible, to a center offering team-based care, including an obstetrician specialized in high-risk pregnancies, an endocrinologist, and a dietitian.¹

Is catatonia a rare condition that belongs in the history books, or is it more prevalent than we think? If we think we don’t see it often, how will we recognize it? And how do we treat it? This article reviews the evolution of our understanding of the phenomenology and therapy of this interesting and complex condition.

History of the concept

In 1874, Kahlbaum^1,2 was the first to propose a syndrome of motor dysfunction characterized by mutism, immobility, staring gaze, negativism, stereotyped behavior, waxy flexibility, and verbal stereotypies that he called catatonia. Kahlbaum conceptualized catatonia as a distinct disorder,³ but Kraepelin reformulated it as a feature of dementia praecox.⁴ Although Bleuler felt that catatonia could occur in other psychiatric disorders and in normal people,⁴ he also included catatonia as a marker of schizophrenia, where it remained from DSM-I through DSM-IV.³ As was believed to be true of schizophrenia, Kraepelin considered catatonia to be characterized by poor prognosis, whereas Bleuler eliminated poor prognosis as a criterion for catatonia.³

In DSM-IV, catatonia was still a subtype of schizophrenia, but for the first time it was expanded diagnostically to become both a specifier in mood disorders, and a syndrome resulting from a general medical condition.^5,6 In DSM-5, catatonic schizophrenia was deleted, and catatonia became a specifier for 10 disorders, including schizophrenia, mood disorders, and general medical conditions.^3,5-9 In ICD-10, however, catatonia is still associated primarily with schizophrenia.¹⁰

A wide range of presentations

Catatonia is a cyclical syndrome characterized by alterations in motor, behavioral, and vocal signs occurring in the context of medical, neurologic, and psychiatric disorders.⁸ The most common features are immobility, waxy flexibility, stupor, mutism, negativism, echolalia, echopraxia, peculiarities of voluntary movement, and rigidity.^7,11 Features of catatonia that have been repeatedly described through the years are summarized in Table 1.^8,12,13 In general, presentations of catatonia are not specific to any psychiatric or medical etiology.^13,14

Catatonia often is described along a continuum from retarded/stuporous to excited,^14,15 and from benign to malignant.¹³ Examples of these ranges of presentation include^{5,12,13,15-19}:

Stuporous/retarded catatonia (Kahlbaum syndrome) is a primarily negative syndrome in which stupor, mutism, negativism, obsessional slowness, and posturing predominate. Akinetic mutism and coma vigil are sometimes considered to be types of stuporous catatonia, as occasionally are locked-in syndrome and abulia caused by anterior cingulate lesions.

Excited catatonia (hyperkinetic variant, Bell’s mania, oneirophrenia, oneroid state/syndrome, catatonia raptus) is characterized by agitation, combativeness, verbigeration, stereotypies, grimacing, and echo phenomena (echopraxia and echolalia).

Continue to: Malignant (lethal) catatonia

Several specific subtypes of catatonia that may exist anywhere along dimensions of activity and severity also have been described:

Periodic catatonia. In 1908, Kraepelin described a form of periodic catatonia, with rapid shifts from excitement to stupor.⁴ Later, Gjessing described periodic catatonia in schizophrenia and reported success treating it with high doses of thyroid hormone.⁴ Today, periodic catatonia refers to the rapid onset of recurrent, brief hypokinetic or hyperkinetic episodes lasting 4 to 10 days and recurring during the course of weeks to years. Patients often are asymptomatic between episodes except for grimacing, stereotypies, and negativism later in the course.^13,15 At least some forms of periodic catatonia are familial,⁴ with autosomal dominant transmission possibly linked to chromosome 15q15.¹³

A familial form of catatonia has been described that has a poor response to standard therapies (benzodiazepines and electroconvulsive therapy [ECT]), but in view of the high comorbidity of catatonia and bipolar disorder, it is difficult to determine whether this is a separate condition, or a group of patients with bipolar disorder.⁵

Late (ie, late-onset) catatonia is well described in the Japanese literature.¹⁰ Reported primarily in women without a known medical illness or brain disorder, late catatonia begins with prodromal hypochondriacal or depressive symptoms during a stressful situation, followed by unprovoked anxiety and agitation. Some patients develop hallucinations, delusions, and recurrent excitement, along with anxiety and agitation. The next stage involves typical catatonic features (mainly excitement, retardation, negativism, and autonomic disturbance), progressing to stupor, mutism, verbal stereotypies, and negativism, including refusal of food. Most patients have residual symptoms following improvement. A few cases have been noted to remit with ECT, with relapse when treatment was discontinued. Late catatonia has been thought to be associated with late-onset schizophrenia or bipolar disorder, or to be an independent entity.

Continue to: Untreated catatonia can have...

Not as rare as you might think

With the shift from inpatient to outpatient care driven by deinstitutionalization, longitudinal close observation became less common, and clinicians got the impression that the dramatic catatonia that was common in the hospital had become rare.³ The impression that catatonia was unimportant was strengthened by expanding industry promotion of antipsychotic medications while ignoring catatonia, for which the industry had no specific treatment.³ With recent research, however, catatonia has been reported in 7% to 38% of adult psychiatric patients, including 9% to 25% of inpatients, 20% to 25% of patients with mania,^3,5 and 20% of patients with major depressive episodes.⁷ Catatonia has been noted in .6% to 18% of adolescent psychiatric inpatients (especially in communication and social disorders programs),^5,8,22 some children,⁵ and 6% to 18% of adult and juvenile patients with autism spectrum disorder (ASD).²³ In the medical setting, catatonia occurs in 12% to 37% of patients with delirium,^{8,14,17,18,20,24} 7% to 45% of medically ill patients, including those with no psychiatric history,^12,13 and 4% of ICU patients.¹² Several substances have been linked to catatonia; these are discussed later.¹¹ Contrary to earlier impressions, catatonia is more common in mood disorders, particularly mixed bipolar disorder, especially mania,⁵ than in schizophrenia.^7,8,17,25

Pathophysiology/etiology

Conditions associated with catatonia have different features that act through a final common pathway,⁷ possibly related to the neurobiology of an extreme fear response called tonic immobility that has been conserved through evolution.⁸ This mechanism may be mediated by decreased dopamine signaling in basal ganglia, orbitofrontal, and limbic systems, including the hypothalamus and basal forebrain.^3,17,20 Subcortical reduction of dopaminergic neurotransmission appears to be related to reduced GABA_A receptor signaling and dysfunction of N-methyl-d-aspartate (NMDA) receptors with glutaminergic excess in striato-cortical or frontal cortico-cortical systems.^13,20,26,27

Up to one-quarter of cases of catatonia are secondary to medical (mostly neurologic) factors or substances.¹⁵Table 2^5,13,15 lists common medical and neurological causes. Medications and substances known to cause catatonia are noted in Table 3.^5,8,13,16,26

Catatonia can be a specifier, or a separate condition

DSM-5 criteria for catatonia are summarized in Table 4.²⁸ With these features, catatonia can be a specifier for depressive, bipolar, or psychotic disorders; a complication of a medical disorder; or another separate diagnosis.⁸ The diagnosis of catatonia in DSM-5 is made when the clinical picture is dominated by ≥3 of the following core features^8,15:

• motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor
• excessive purposeless motor activity that is not influenced by external stimuli
• extreme negativism or mutism
• peculiarities of voluntary movement such as posturing, stereotyped movements, prominent mannerisms, or prominent grimacing
• echolalia or echopraxia.

Continue to: DSM-5 criteria for the diagnosis of catatonia are more...

DSM-5 criteria for the diagnosis of catatonia are more restrictive than DSM-IV criteria. As a result, they exclude a significant number of patients who would be considered catatonic in other systems.²⁹ For example, DSM-5 criteria do not include common features noted in Table 1,^8,12,13 such as rigidity and staring.^14,29 If the diagnosis is not obvious, it might be suspected in the presence of >1 of posturing, automatic obedience, or waxy flexibility, or >2 of echopraxia/echolalia, gegenhalten, negativism, mitgehen, or stereotypy/vergiberation.¹² Clues to catatonia that are not included in formal diagnostic systems and are easily confused with features of psychosis include whispered or robotic speech, uncharacteristic foreign accent, tiptoe walking, hopping, rituals, and odd mannerisms.⁵

There are several catatonia rating scales containing between 14 and 40 items that are useful in diagnosing and following treatment response in catatonia (Table 5^8,13,15,29). Of these, the Kanner Scale is primarily applied in neuropsychiatric settings, while the Bush-Francis Catatonia Rating Scale (BFCRS) has had the most widespread use. The BFCRS consists of 23 items, the first 14 of which are used as a screening instrument. It requires 2 of its first 14 items to diagnose catatonia, while DSM-5 requires 3 of 12 signs.²⁹ If the diagnosis remains in doubt, a benzodiazepine agonist test can be instructive.^9,12 The presence of catatonia is suggested by significant improvement, ideally assessed prospectively by improvement of BFCRS scores, shortly after administration of a single dose of 1 to 2 mg lorazepam or 5 mg diazepam IV, or 10 mg zolpidem orally. Further evaluation generally consists of a careful medical and psychiatric histories of patient and family, review of all medications, history of substance use with toxicology as indicated, physical examination focusing on autonomic dysregulation, examination for delirium, and laboratory tests as suggested by the history and examination that may include complete blood count, creatine kinase, serum iron, blood urea nitrogen, electrolytes, creatinine, prolactin, anti-NMDA antibodies, thyroid function tests, serology, metabolic panel, human immunodeficiency virus testing, EEG, and neuroimaging.^8,15,16

A complex differential diagnosis

Manifestations of numerous psychiatric and neurologic disorders can mimic or be identical to those of catatonia. The differential diagnosis is complicated by the fact that some of these disorders can cause catatonia, which is then masked by the primary disorder; some disorders (eg, NMS) are forms of catatonia. Table 6^{5,8,12,19,26,30} lists conditions to consider.

Some of these conditions warrant discussion. ASD may have catatonia-like features such as echolalia, echopraxia, excitement, combativeness, grimacing, mutism, logorrhea, verbigeration, catalepsy, mannerisms, rigidity, staring and withdrawal.⁸ Catatonia may also be a stage of deterioration of autism, in which case it is characterized by increases in slowness of movement and speech, reliance on physical or verbal prompting from others, passivity, and lack of motivation.²³ At the same time, catatonic features such as mutism, stereotypic speech, repetitive behavior, echolalia, posturing, mannerisms, purposeless agitation, and rigidity in catatonia can be misinterpreted as signs of ASD.⁸ Catatonia should be suspected as a complication of longstanding ASD in the presence of a consistent, marked change in motor behavior, such as immobility, decreased speech, stupor, excitement, or mixtures or alternations of stupor and excitement.⁸ Freezing while doing something, difficulty crossing lines, or uncharacteristic persistence of a particular behavior may also herald the presence of catatonia with ASD.⁸

Catatonia caused by a neurologic or metabolic factor or a substance can be difficult to distinguish from delirium complicated by catatonia. Delirium may be identified in patients with catatonia by the presence of a waxing and waning level of consciousness (vs fluctuating behavior in catatonia) and slowing of the EEG.^12,15 Antipsychotic medications can improve delirium but worsen catatonia, while benzodiazepines can improve catatonia but worsen delirium.

Continue to: Among other neurologic syndromes...

Benzodiazepines, ECT are the usual treatments

Experience dictates that the general principles of treatment noted in Table 7^12,15,23,31 apply to all patients with catatonia. Since the first reported improvement of catatonia with amobarbital in 1930,⁶ there have been no controlled studies of specific treatments of catatonia.¹³ Meaningful treatment trials are either naturalistic, or have been performed only for NMS and malignant catatonia.⁵ However, multiple case reports and case series suggest that treatments with agents that have anticonvulsant properties (benzodiazepines, barbiturates) and ECT are effective.⁵

Benzodiazepines and related compounds. Case series have suggested a 60% to 80% remission rate of catatonia with benzodiazepines, the most commonly utilized of which has been lorazepam.^7,13,32 Treatment begins with a lorazepam challenge test of 1 to 2 mg in adults and 0.5 to 1 mg in children and geriatric patients,^9,15 administered orally (including via nasogastric tube), IM, or IV. Following a response (≥50% improvement), the dose is increased to 2 mg 3 times per day. The dose is further increased to 6 to 16 mg/d, and sometimes up to 30 mg/d.^9,11 Oral is less effective than sublingual or IM administration.¹¹ Diazepam can be helpful at doses 5 times the lorazepam dose.^9,17 A zolpidem challenge test of 10 mg orally or via nasogastric tube has also been utilized.¹⁵ Response is brief and is usually followed by lorazepam, although zolpidem up to 40 mg/d has been used for ongoing treatment.⁹

One alternative benzodiazepine protocol utilizes an initial IV dose of 2 mg lorazepam, repeated 3 to 5 times per day; the dose is increased to 10 to 12 mg/d if the first doses are partially effective.¹⁶ A lorazepam/diazepam approach involves a combination of IM lorazepam and IV diazepam.¹¹ The protocol begins with 2 mg of IM lorazepam. If there is no effect within 2 hours, a second 2 mg dose is administered, followed by an IV infusion of 10 mg diazepam in 500 ml of normal saline at 1.25 mg/hour until catatonia remits.

An Indian study of 107 patients (mean age 26) receiving relatively low doses of lorazepam (3 to 6 mg/d for at least 3 days) found that factors suggesting a robust response include a shorter duration of catatonia and waxy flexibility, while passivity, mutism, and auditory hallucinations describing the patient in the third person were associated with a poorer acute response.³¹ Catatonia with marked retardation and mutism complicating schizophrenia, especially with chronic negative symptoms, may be associated with a lower response rate to benzodiazepines.^20,33 Maintenance lorazepam has been effective in reducing relapse and recurrence.¹¹ There are no controlled studies of maintenance treatment with benzodiazepines, but clinical reports suggest that doses in the range of 4 to 10 mg/d are effective.³²

Continue to: ECT was used for catatonia in 1934...

ECT was first used for catatonia in 1934, when Laszlo Meduna used chemically induced seizures in catatonic patients who had been on tube feeding for months and no longer needed it after treatment.^6,7 As was true for other disorders, this approach was replaced by ECT.⁷ In various case series, the effectiveness of ECT in catatonia has been 53% to 100%.^7,13,15 Right unilateral ECT has been reported to be effective with 1 treatment.²¹ However, the best-established approach is with bitemporal ECT with a suprathreshold stimulus,⁹ usually with an acute course of 6 to 20 treatments.²⁰ ECT has been reported to be equally safe and effective in adolescents and adults.³⁴ Continued ECT is usually necessary until the patient has returned to baseline.⁹

ECT usually is recommended within 24 hours for treatment-resistant malignant catatonia or refusal to eat or drink, and within 2 to 3 days if medications are not sufficiently effective in other forms of catatonia.^12,15,20 If ECT is initiated after a benzodiazepine trial, the benzodiazepine antagonist flumazenil is administered first to reverse the anticonvulsant effect.⁹ Some experts recommend using a muscle relaxant other than succinylcholine in the presence of evidence of muscle damage.⁷

Alternatives to benzodiazepines and ECT. Based on case reports, the treatments described in Table 8^{13,15,17,20,25} have been used for patients with catatonia who do not tolerate or respond to standard treatments. The largest number of case reports have been with NMDA antagonists, while the presumed involvement of reduced dopamine signaling suggests that dopaminergic medications should be helpful. Dantrolene, which blocks release of calcium from intracellular stores and has been used to treat malignant hyperthermia, is sometimes used for NMS, often with disappointing results.

Whereas first-generation antipsychotics definitely increase the risk of catatonia and second-generation antipsychotics (SGAs) probably do so, SGAs are sometimes necessary to treat persistent psychosis in patients with schizophrenia who develop catatonia. Of these medications, clozapine may be most desirable because of low potency for dopamine receptor blockade and modulation of glutamatergic signaling. Partial dopamine agonism by aripiprazole, and the potential for increased subcortical prefrontal dopamine release resulting from serotonin 5HT2A antagonism and 5HT1A agonism by other SGAs, could also be helpful or at least not harmful in catatonia. Lorazepam is usually administered along with these medications to ameliorate treatment-emergent exacerbation of catatonia.

There are no controlled studies of any of these treatments. Based on case reports, most experts would recommend initiating treatment of catatonia with lorazepam, followed by ECT if necessary or in the presence of life-threatening catatonia. If ECT is not available, ineffective, or not tolerated, the first alternatives to be considered would be an NMDA antagonist or an anticonvulsant.²⁰

Continue to: Course varies by patient, underlying cause

Course varies by patient, underlying cause

The response to benzodiazepines or ECT can vary from episode to episode¹¹ and is similar in adults and younger patients.²² Many patients recover completely after a single episode, while relapse after remission occurs repeatedly in periodic catatonia, which involves chronic alternating stupor and excitement waxing and waning over years.¹¹ Relapses may occur frequently, or every few years.¹¹ Some cases of catatonia initially have an episodic course and become chronic and deteriorating, possibly paralleling the original descriptions of the natural history of untreated catatonia, while malignant catatonia can be complicated by medical morbidity or death.⁴ The long-term prognosis generally depends on the underlying cause of catatonia.⁵

Bottom Line

Much more common than many clinicians realize, catatonia can be overlooked because symptoms can mimic or overlap with features of an underlying medical or neurologic disorder. Suspect catatonia when one of these illnesses has an unexpected course or an inadequate treatment response. Be alert to characteristic changes in behavior and speech. A benzodiazepine challenge can be used to diagnose and begin treatment of catatonia. Consider electroconvulsive therapy sooner rather than later, especially for severely ill patients.

Related Resources

• Gibson RC, Walcott G. Benzodiazepines for catatonia in people with schizophrenia and other serious mental illnesses. Cochrane Database Syst Rev. 2008;(4):CD006570. 
• Newcastle University. Catatonia. https://youtu.be/_s1lzxHRO4U.

Drug Brand Names

Amantadine • Symmetrel
Amobarbital • Amytal
Aripiprazole • Abilify
Azithromycin • Zithromax
Baclofen • Lioresal
Benztropine • Cogentin
Carbamazepine • Carbatrol, Tegretol
Carbidopa/levodopa • Sinemet
Ciprofloxacin • Cipro
Clozapine • Clozaril
Dantrolene • Dantrium
Dexamethasone • Decadron
Dextromethorphan/quinidine • Neudexta
Diazepam • Valium
Disulfiram • Antabuse
Flumazenil • Romazicon
Fluoxetine • Prozac
Fluvoxamine • Luvox
Levetiracetam • Keppra
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Memantine • Namenda
Methylphenidate • Ritalin
Minocycline • Minocin
Olanzapine • Zyprexa
Risperidone • Risperdal
Succinylcholine • Anectine
Topiramate • Topamax
Trihexyphenidyl • Artane
Valproate • Depakote
Ziprasidone • Geodon
Zolpidem • Ambien

Is catatonia a rare condition that belongs in the history books, or is it more prevalent than we think? If we think we don’t see it often, how will we recognize it? And how do we treat it? This article reviews the evolution of our understanding of the phenomenology and therapy of this interesting and complex condition.

History of the concept

In 1874, Kahlbaum^1,2 was the first to propose a syndrome of motor dysfunction characterized by mutism, immobility, staring gaze, negativism, stereotyped behavior, waxy flexibility, and verbal stereotypies that he called catatonia. Kahlbaum conceptualized catatonia as a distinct disorder,³ but Kraepelin reformulated it as a feature of dementia praecox.⁴ Although Bleuler felt that catatonia could occur in other psychiatric disorders and in normal people,⁴ he also included catatonia as a marker of schizophrenia, where it remained from DSM-I through DSM-IV.³ As was believed to be true of schizophrenia, Kraepelin considered catatonia to be characterized by poor prognosis, whereas Bleuler eliminated poor prognosis as a criterion for catatonia.³

In DSM-IV, catatonia was still a subtype of schizophrenia, but for the first time it was expanded diagnostically to become both a specifier in mood disorders, and a syndrome resulting from a general medical condition.^5,6 In DSM-5, catatonic schizophrenia was deleted, and catatonia became a specifier for 10 disorders, including schizophrenia, mood disorders, and general medical conditions.^3,5-9 In ICD-10, however, catatonia is still associated primarily with schizophrenia.¹⁰

A wide range of presentations

Catatonia is a cyclical syndrome characterized by alterations in motor, behavioral, and vocal signs occurring in the context of medical, neurologic, and psychiatric disorders.⁸ The most common features are immobility, waxy flexibility, stupor, mutism, negativism, echolalia, echopraxia, peculiarities of voluntary movement, and rigidity.^7,11 Features of catatonia that have been repeatedly described through the years are summarized in Table 1.^8,12,13 In general, presentations of catatonia are not specific to any psychiatric or medical etiology.^13,14

Catatonia often is described along a continuum from retarded/stuporous to excited,^14,15 and from benign to malignant.¹³ Examples of these ranges of presentation include^{5,12,13,15-19}:

Stuporous/retarded catatonia (Kahlbaum syndrome) is a primarily negative syndrome in which stupor, mutism, negativism, obsessional slowness, and posturing predominate. Akinetic mutism and coma vigil are sometimes considered to be types of stuporous catatonia, as occasionally are locked-in syndrome and abulia caused by anterior cingulate lesions.

Excited catatonia (hyperkinetic variant, Bell’s mania, oneirophrenia, oneroid state/syndrome, catatonia raptus) is characterized by agitation, combativeness, verbigeration, stereotypies, grimacing, and echo phenomena (echopraxia and echolalia).

Continue to: Malignant (lethal) catatonia

Several specific subtypes of catatonia that may exist anywhere along dimensions of activity and severity also have been described:

Periodic catatonia. In 1908, Kraepelin described a form of periodic catatonia, with rapid shifts from excitement to stupor.⁴ Later, Gjessing described periodic catatonia in schizophrenia and reported success treating it with high doses of thyroid hormone.⁴ Today, periodic catatonia refers to the rapid onset of recurrent, brief hypokinetic or hyperkinetic episodes lasting 4 to 10 days and recurring during the course of weeks to years. Patients often are asymptomatic between episodes except for grimacing, stereotypies, and negativism later in the course.^13,15 At least some forms of periodic catatonia are familial,⁴ with autosomal dominant transmission possibly linked to chromosome 15q15.¹³

A familial form of catatonia has been described that has a poor response to standard therapies (benzodiazepines and electroconvulsive therapy [ECT]), but in view of the high comorbidity of catatonia and bipolar disorder, it is difficult to determine whether this is a separate condition, or a group of patients with bipolar disorder.⁵

Late (ie, late-onset) catatonia is well described in the Japanese literature.¹⁰ Reported primarily in women without a known medical illness or brain disorder, late catatonia begins with prodromal hypochondriacal or depressive symptoms during a stressful situation, followed by unprovoked anxiety and agitation. Some patients develop hallucinations, delusions, and recurrent excitement, along with anxiety and agitation. The next stage involves typical catatonic features (mainly excitement, retardation, negativism, and autonomic disturbance), progressing to stupor, mutism, verbal stereotypies, and negativism, including refusal of food. Most patients have residual symptoms following improvement. A few cases have been noted to remit with ECT, with relapse when treatment was discontinued. Late catatonia has been thought to be associated with late-onset schizophrenia or bipolar disorder, or to be an independent entity.

Continue to: Untreated catatonia can have...

Not as rare as you might think

With the shift from inpatient to outpatient care driven by deinstitutionalization, longitudinal close observation became less common, and clinicians got the impression that the dramatic catatonia that was common in the hospital had become rare.³ The impression that catatonia was unimportant was strengthened by expanding industry promotion of antipsychotic medications while ignoring catatonia, for which the industry had no specific treatment.³ With recent research, however, catatonia has been reported in 7% to 38% of adult psychiatric patients, including 9% to 25% of inpatients, 20% to 25% of patients with mania,^3,5 and 20% of patients with major depressive episodes.⁷ Catatonia has been noted in .6% to 18% of adolescent psychiatric inpatients (especially in communication and social disorders programs),^5,8,22 some children,⁵ and 6% to 18% of adult and juvenile patients with autism spectrum disorder (ASD).²³ In the medical setting, catatonia occurs in 12% to 37% of patients with delirium,^{8,14,17,18,20,24} 7% to 45% of medically ill patients, including those with no psychiatric history,^12,13 and 4% of ICU patients.¹² Several substances have been linked to catatonia; these are discussed later.¹¹ Contrary to earlier impressions, catatonia is more common in mood disorders, particularly mixed bipolar disorder, especially mania,⁵ than in schizophrenia.^7,8,17,25

Pathophysiology/etiology

Conditions associated with catatonia have different features that act through a final common pathway,⁷ possibly related to the neurobiology of an extreme fear response called tonic immobility that has been conserved through evolution.⁸ This mechanism may be mediated by decreased dopamine signaling in basal ganglia, orbitofrontal, and limbic systems, including the hypothalamus and basal forebrain.^3,17,20 Subcortical reduction of dopaminergic neurotransmission appears to be related to reduced GABA_A receptor signaling and dysfunction of N-methyl-d-aspartate (NMDA) receptors with glutaminergic excess in striato-cortical or frontal cortico-cortical systems.^13,20,26,27

Up to one-quarter of cases of catatonia are secondary to medical (mostly neurologic) factors or substances.¹⁵Table 2^5,13,15 lists common medical and neurological causes. Medications and substances known to cause catatonia are noted in Table 3.^5,8,13,16,26

Catatonia can be a specifier, or a separate condition

DSM-5 criteria for catatonia are summarized in Table 4.²⁸ With these features, catatonia can be a specifier for depressive, bipolar, or psychotic disorders; a complication of a medical disorder; or another separate diagnosis.⁸ The diagnosis of catatonia in DSM-5 is made when the clinical picture is dominated by ≥3 of the following core features^8,15:

• motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor
• excessive purposeless motor activity that is not influenced by external stimuli
• extreme negativism or mutism
• peculiarities of voluntary movement such as posturing, stereotyped movements, prominent mannerisms, or prominent grimacing
• echolalia or echopraxia.

Continue to: DSM-5 criteria for the diagnosis of catatonia are more...

DSM-5 criteria for the diagnosis of catatonia are more restrictive than DSM-IV criteria. As a result, they exclude a significant number of patients who would be considered catatonic in other systems.²⁹ For example, DSM-5 criteria do not include common features noted in Table 1,^8,12,13 such as rigidity and staring.^14,29 If the diagnosis is not obvious, it might be suspected in the presence of >1 of posturing, automatic obedience, or waxy flexibility, or >2 of echopraxia/echolalia, gegenhalten, negativism, mitgehen, or stereotypy/vergiberation.¹² Clues to catatonia that are not included in formal diagnostic systems and are easily confused with features of psychosis include whispered or robotic speech, uncharacteristic foreign accent, tiptoe walking, hopping, rituals, and odd mannerisms.⁵

There are several catatonia rating scales containing between 14 and 40 items that are useful in diagnosing and following treatment response in catatonia (Table 5^8,13,15,29). Of these, the Kanner Scale is primarily applied in neuropsychiatric settings, while the Bush-Francis Catatonia Rating Scale (BFCRS) has had the most widespread use. The BFCRS consists of 23 items, the first 14 of which are used as a screening instrument. It requires 2 of its first 14 items to diagnose catatonia, while DSM-5 requires 3 of 12 signs.²⁹ If the diagnosis remains in doubt, a benzodiazepine agonist test can be instructive.^9,12 The presence of catatonia is suggested by significant improvement, ideally assessed prospectively by improvement of BFCRS scores, shortly after administration of a single dose of 1 to 2 mg lorazepam or 5 mg diazepam IV, or 10 mg zolpidem orally. Further evaluation generally consists of a careful medical and psychiatric histories of patient and family, review of all medications, history of substance use with toxicology as indicated, physical examination focusing on autonomic dysregulation, examination for delirium, and laboratory tests as suggested by the history and examination that may include complete blood count, creatine kinase, serum iron, blood urea nitrogen, electrolytes, creatinine, prolactin, anti-NMDA antibodies, thyroid function tests, serology, metabolic panel, human immunodeficiency virus testing, EEG, and neuroimaging.^8,15,16

A complex differential diagnosis

Manifestations of numerous psychiatric and neurologic disorders can mimic or be identical to those of catatonia. The differential diagnosis is complicated by the fact that some of these disorders can cause catatonia, which is then masked by the primary disorder; some disorders (eg, NMS) are forms of catatonia. Table 6^{5,8,12,19,26,30} lists conditions to consider.

Some of these conditions warrant discussion. ASD may have catatonia-like features such as echolalia, echopraxia, excitement, combativeness, grimacing, mutism, logorrhea, verbigeration, catalepsy, mannerisms, rigidity, staring and withdrawal.⁸ Catatonia may also be a stage of deterioration of autism, in which case it is characterized by increases in slowness of movement and speech, reliance on physical or verbal prompting from others, passivity, and lack of motivation.²³ At the same time, catatonic features such as mutism, stereotypic speech, repetitive behavior, echolalia, posturing, mannerisms, purposeless agitation, and rigidity in catatonia can be misinterpreted as signs of ASD.⁸ Catatonia should be suspected as a complication of longstanding ASD in the presence of a consistent, marked change in motor behavior, such as immobility, decreased speech, stupor, excitement, or mixtures or alternations of stupor and excitement.⁸ Freezing while doing something, difficulty crossing lines, or uncharacteristic persistence of a particular behavior may also herald the presence of catatonia with ASD.⁸

Catatonia caused by a neurologic or metabolic factor or a substance can be difficult to distinguish from delirium complicated by catatonia. Delirium may be identified in patients with catatonia by the presence of a waxing and waning level of consciousness (vs fluctuating behavior in catatonia) and slowing of the EEG.^12,15 Antipsychotic medications can improve delirium but worsen catatonia, while benzodiazepines can improve catatonia but worsen delirium.

Continue to: Among other neurologic syndromes...

Benzodiazepines, ECT are the usual treatments

Experience dictates that the general principles of treatment noted in Table 7^12,15,23,31 apply to all patients with catatonia. Since the first reported improvement of catatonia with amobarbital in 1930,⁶ there have been no controlled studies of specific treatments of catatonia.¹³ Meaningful treatment trials are either naturalistic, or have been performed only for NMS and malignant catatonia.⁵ However, multiple case reports and case series suggest that treatments with agents that have anticonvulsant properties (benzodiazepines, barbiturates) and ECT are effective.⁵

Benzodiazepines and related compounds. Case series have suggested a 60% to 80% remission rate of catatonia with benzodiazepines, the most commonly utilized of which has been lorazepam.^7,13,32 Treatment begins with a lorazepam challenge test of 1 to 2 mg in adults and 0.5 to 1 mg in children and geriatric patients,^9,15 administered orally (including via nasogastric tube), IM, or IV. Following a response (≥50% improvement), the dose is increased to 2 mg 3 times per day. The dose is further increased to 6 to 16 mg/d, and sometimes up to 30 mg/d.^9,11 Oral is less effective than sublingual or IM administration.¹¹ Diazepam can be helpful at doses 5 times the lorazepam dose.^9,17 A zolpidem challenge test of 10 mg orally or via nasogastric tube has also been utilized.¹⁵ Response is brief and is usually followed by lorazepam, although zolpidem up to 40 mg/d has been used for ongoing treatment.⁹

One alternative benzodiazepine protocol utilizes an initial IV dose of 2 mg lorazepam, repeated 3 to 5 times per day; the dose is increased to 10 to 12 mg/d if the first doses are partially effective.¹⁶ A lorazepam/diazepam approach involves a combination of IM lorazepam and IV diazepam.¹¹ The protocol begins with 2 mg of IM lorazepam. If there is no effect within 2 hours, a second 2 mg dose is administered, followed by an IV infusion of 10 mg diazepam in 500 ml of normal saline at 1.25 mg/hour until catatonia remits.

An Indian study of 107 patients (mean age 26) receiving relatively low doses of lorazepam (3 to 6 mg/d for at least 3 days) found that factors suggesting a robust response include a shorter duration of catatonia and waxy flexibility, while passivity, mutism, and auditory hallucinations describing the patient in the third person were associated with a poorer acute response.³¹ Catatonia with marked retardation and mutism complicating schizophrenia, especially with chronic negative symptoms, may be associated with a lower response rate to benzodiazepines.^20,33 Maintenance lorazepam has been effective in reducing relapse and recurrence.¹¹ There are no controlled studies of maintenance treatment with benzodiazepines, but clinical reports suggest that doses in the range of 4 to 10 mg/d are effective.³²

Continue to: ECT was used for catatonia in 1934...

ECT was first used for catatonia in 1934, when Laszlo Meduna used chemically induced seizures in catatonic patients who had been on tube feeding for months and no longer needed it after treatment.^6,7 As was true for other disorders, this approach was replaced by ECT.⁷ In various case series, the effectiveness of ECT in catatonia has been 53% to 100%.^7,13,15 Right unilateral ECT has been reported to be effective with 1 treatment.²¹ However, the best-established approach is with bitemporal ECT with a suprathreshold stimulus,⁹ usually with an acute course of 6 to 20 treatments.²⁰ ECT has been reported to be equally safe and effective in adolescents and adults.³⁴ Continued ECT is usually necessary until the patient has returned to baseline.⁹

ECT usually is recommended within 24 hours for treatment-resistant malignant catatonia or refusal to eat or drink, and within 2 to 3 days if medications are not sufficiently effective in other forms of catatonia.^12,15,20 If ECT is initiated after a benzodiazepine trial, the benzodiazepine antagonist flumazenil is administered first to reverse the anticonvulsant effect.⁹ Some experts recommend using a muscle relaxant other than succinylcholine in the presence of evidence of muscle damage.⁷

Alternatives to benzodiazepines and ECT. Based on case reports, the treatments described in Table 8^{13,15,17,20,25} have been used for patients with catatonia who do not tolerate or respond to standard treatments. The largest number of case reports have been with NMDA antagonists, while the presumed involvement of reduced dopamine signaling suggests that dopaminergic medications should be helpful. Dantrolene, which blocks release of calcium from intracellular stores and has been used to treat malignant hyperthermia, is sometimes used for NMS, often with disappointing results.

Whereas first-generation antipsychotics definitely increase the risk of catatonia and second-generation antipsychotics (SGAs) probably do so, SGAs are sometimes necessary to treat persistent psychosis in patients with schizophrenia who develop catatonia. Of these medications, clozapine may be most desirable because of low potency for dopamine receptor blockade and modulation of glutamatergic signaling. Partial dopamine agonism by aripiprazole, and the potential for increased subcortical prefrontal dopamine release resulting from serotonin 5HT2A antagonism and 5HT1A agonism by other SGAs, could also be helpful or at least not harmful in catatonia. Lorazepam is usually administered along with these medications to ameliorate treatment-emergent exacerbation of catatonia.

There are no controlled studies of any of these treatments. Based on case reports, most experts would recommend initiating treatment of catatonia with lorazepam, followed by ECT if necessary or in the presence of life-threatening catatonia. If ECT is not available, ineffective, or not tolerated, the first alternatives to be considered would be an NMDA antagonist or an anticonvulsant.²⁰

Continue to: Course varies by patient, underlying cause

Course varies by patient, underlying cause

The response to benzodiazepines or ECT can vary from episode to episode¹¹ and is similar in adults and younger patients.²² Many patients recover completely after a single episode, while relapse after remission occurs repeatedly in periodic catatonia, which involves chronic alternating stupor and excitement waxing and waning over years.¹¹ Relapses may occur frequently, or every few years.¹¹ Some cases of catatonia initially have an episodic course and become chronic and deteriorating, possibly paralleling the original descriptions of the natural history of untreated catatonia, while malignant catatonia can be complicated by medical morbidity or death.⁴ The long-term prognosis generally depends on the underlying cause of catatonia.⁵

Bottom Line

Much more common than many clinicians realize, catatonia can be overlooked because symptoms can mimic or overlap with features of an underlying medical or neurologic disorder. Suspect catatonia when one of these illnesses has an unexpected course or an inadequate treatment response. Be alert to characteristic changes in behavior and speech. A benzodiazepine challenge can be used to diagnose and begin treatment of catatonia. Consider electroconvulsive therapy sooner rather than later, especially for severely ill patients.

Related Resources

• Gibson RC, Walcott G. Benzodiazepines for catatonia in people with schizophrenia and other serious mental illnesses. Cochrane Database Syst Rev. 2008;(4):CD006570. 
• Newcastle University. Catatonia. https://youtu.be/_s1lzxHRO4U.

Drug Brand Names

Amantadine • Symmetrel
Amobarbital • Amytal
Aripiprazole • Abilify
Azithromycin • Zithromax
Baclofen • Lioresal
Benztropine • Cogentin
Carbamazepine • Carbatrol, Tegretol
Carbidopa/levodopa • Sinemet
Ciprofloxacin • Cipro
Clozapine • Clozaril
Dantrolene • Dantrium
Dexamethasone • Decadron
Dextromethorphan/quinidine • Neudexta
Diazepam • Valium
Disulfiram • Antabuse
Flumazenil • Romazicon
Fluoxetine • Prozac
Fluvoxamine • Luvox
Levetiracetam • Keppra
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Memantine • Namenda
Methylphenidate • Ritalin
Minocycline • Minocin
Olanzapine • Zyprexa
Risperidone • Risperdal
Succinylcholine • Anectine
Topiramate • Topamax
Trihexyphenidyl • Artane
Valproate • Depakote
Ziprasidone • Geodon
Zolpidem • Ambien

Is catatonia a rare condition that belongs in the history books, or is it more prevalent than we think? If we think we don’t see it often, how will we recognize it? And how do we treat it? This article reviews the evolution of our understanding of the phenomenology and therapy of this interesting and complex condition.

History of the concept

In 1874, Kahlbaum^1,2 was the first to propose a syndrome of motor dysfunction characterized by mutism, immobility, staring gaze, negativism, stereotyped behavior, waxy flexibility, and verbal stereotypies that he called catatonia. Kahlbaum conceptualized catatonia as a distinct disorder,³ but Kraepelin reformulated it as a feature of dementia praecox.⁴ Although Bleuler felt that catatonia could occur in other psychiatric disorders and in normal people,⁴ he also included catatonia as a marker of schizophrenia, where it remained from DSM-I through DSM-IV.³ As was believed to be true of schizophrenia, Kraepelin considered catatonia to be characterized by poor prognosis, whereas Bleuler eliminated poor prognosis as a criterion for catatonia.³

In DSM-IV, catatonia was still a subtype of schizophrenia, but for the first time it was expanded diagnostically to become both a specifier in mood disorders, and a syndrome resulting from a general medical condition.^5,6 In DSM-5, catatonic schizophrenia was deleted, and catatonia became a specifier for 10 disorders, including schizophrenia, mood disorders, and general medical conditions.^3,5-9 In ICD-10, however, catatonia is still associated primarily with schizophrenia.¹⁰

A wide range of presentations

Catatonia is a cyclical syndrome characterized by alterations in motor, behavioral, and vocal signs occurring in the context of medical, neurologic, and psychiatric disorders.⁸ The most common features are immobility, waxy flexibility, stupor, mutism, negativism, echolalia, echopraxia, peculiarities of voluntary movement, and rigidity.^7,11 Features of catatonia that have been repeatedly described through the years are summarized in Table 1.^8,12,13 In general, presentations of catatonia are not specific to any psychiatric or medical etiology.^13,14

Catatonia often is described along a continuum from retarded/stuporous to excited,^14,15 and from benign to malignant.¹³ Examples of these ranges of presentation include^{5,12,13,15-19}:

Stuporous/retarded catatonia (Kahlbaum syndrome) is a primarily negative syndrome in which stupor, mutism, negativism, obsessional slowness, and posturing predominate. Akinetic mutism and coma vigil are sometimes considered to be types of stuporous catatonia, as occasionally are locked-in syndrome and abulia caused by anterior cingulate lesions.

Excited catatonia (hyperkinetic variant, Bell’s mania, oneirophrenia, oneroid state/syndrome, catatonia raptus) is characterized by agitation, combativeness, verbigeration, stereotypies, grimacing, and echo phenomena (echopraxia and echolalia).

Continue to: Malignant (lethal) catatonia

Several specific subtypes of catatonia that may exist anywhere along dimensions of activity and severity also have been described:

Periodic catatonia. In 1908, Kraepelin described a form of periodic catatonia, with rapid shifts from excitement to stupor.⁴ Later, Gjessing described periodic catatonia in schizophrenia and reported success treating it with high doses of thyroid hormone.⁴ Today, periodic catatonia refers to the rapid onset of recurrent, brief hypokinetic or hyperkinetic episodes lasting 4 to 10 days and recurring during the course of weeks to years. Patients often are asymptomatic between episodes except for grimacing, stereotypies, and negativism later in the course.^13,15 At least some forms of periodic catatonia are familial,⁴ with autosomal dominant transmission possibly linked to chromosome 15q15.¹³

A familial form of catatonia has been described that has a poor response to standard therapies (benzodiazepines and electroconvulsive therapy [ECT]), but in view of the high comorbidity of catatonia and bipolar disorder, it is difficult to determine whether this is a separate condition, or a group of patients with bipolar disorder.⁵

Late (ie, late-onset) catatonia is well described in the Japanese literature.¹⁰ Reported primarily in women without a known medical illness or brain disorder, late catatonia begins with prodromal hypochondriacal or depressive symptoms during a stressful situation, followed by unprovoked anxiety and agitation. Some patients develop hallucinations, delusions, and recurrent excitement, along with anxiety and agitation. The next stage involves typical catatonic features (mainly excitement, retardation, negativism, and autonomic disturbance), progressing to stupor, mutism, verbal stereotypies, and negativism, including refusal of food. Most patients have residual symptoms following improvement. A few cases have been noted to remit with ECT, with relapse when treatment was discontinued. Late catatonia has been thought to be associated with late-onset schizophrenia or bipolar disorder, or to be an independent entity.

Continue to: Untreated catatonia can have...

Not as rare as you might think

With the shift from inpatient to outpatient care driven by deinstitutionalization, longitudinal close observation became less common, and clinicians got the impression that the dramatic catatonia that was common in the hospital had become rare.³ The impression that catatonia was unimportant was strengthened by expanding industry promotion of antipsychotic medications while ignoring catatonia, for which the industry had no specific treatment.³ With recent research, however, catatonia has been reported in 7% to 38% of adult psychiatric patients, including 9% to 25% of inpatients, 20% to 25% of patients with mania,^3,5 and 20% of patients with major depressive episodes.⁷ Catatonia has been noted in .6% to 18% of adolescent psychiatric inpatients (especially in communication and social disorders programs),^5,8,22 some children,⁵ and 6% to 18% of adult and juvenile patients with autism spectrum disorder (ASD).²³ In the medical setting, catatonia occurs in 12% to 37% of patients with delirium,^{8,14,17,18,20,24} 7% to 45% of medically ill patients, including those with no psychiatric history,^12,13 and 4% of ICU patients.¹² Several substances have been linked to catatonia; these are discussed later.¹¹ Contrary to earlier impressions, catatonia is more common in mood disorders, particularly mixed bipolar disorder, especially mania,⁵ than in schizophrenia.^7,8,17,25

Pathophysiology/etiology

Conditions associated with catatonia have different features that act through a final common pathway,⁷ possibly related to the neurobiology of an extreme fear response called tonic immobility that has been conserved through evolution.⁸ This mechanism may be mediated by decreased dopamine signaling in basal ganglia, orbitofrontal, and limbic systems, including the hypothalamus and basal forebrain.^3,17,20 Subcortical reduction of dopaminergic neurotransmission appears to be related to reduced GABA_A receptor signaling and dysfunction of N-methyl-d-aspartate (NMDA) receptors with glutaminergic excess in striato-cortical or frontal cortico-cortical systems.^13,20,26,27

Up to one-quarter of cases of catatonia are secondary to medical (mostly neurologic) factors or substances.¹⁵Table 2^5,13,15 lists common medical and neurological causes. Medications and substances known to cause catatonia are noted in Table 3.^5,8,13,16,26

Catatonia can be a specifier, or a separate condition

DSM-5 criteria for catatonia are summarized in Table 4.²⁸ With these features, catatonia can be a specifier for depressive, bipolar, or psychotic disorders; a complication of a medical disorder; or another separate diagnosis.⁸ The diagnosis of catatonia in DSM-5 is made when the clinical picture is dominated by ≥3 of the following core features^8,15:

• motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor
• excessive purposeless motor activity that is not influenced by external stimuli
• extreme negativism or mutism
• peculiarities of voluntary movement such as posturing, stereotyped movements, prominent mannerisms, or prominent grimacing
• echolalia or echopraxia.

Continue to: DSM-5 criteria for the diagnosis of catatonia are more...

DSM-5 criteria for the diagnosis of catatonia are more restrictive than DSM-IV criteria. As a result, they exclude a significant number of patients who would be considered catatonic in other systems.²⁹ For example, DSM-5 criteria do not include common features noted in Table 1,^8,12,13 such as rigidity and staring.^14,29 If the diagnosis is not obvious, it might be suspected in the presence of >1 of posturing, automatic obedience, or waxy flexibility, or >2 of echopraxia/echolalia, gegenhalten, negativism, mitgehen, or stereotypy/vergiberation.¹² Clues to catatonia that are not included in formal diagnostic systems and are easily confused with features of psychosis include whispered or robotic speech, uncharacteristic foreign accent, tiptoe walking, hopping, rituals, and odd mannerisms.⁵

There are several catatonia rating scales containing between 14 and 40 items that are useful in diagnosing and following treatment response in catatonia (Table 5^8,13,15,29). Of these, the Kanner Scale is primarily applied in neuropsychiatric settings, while the Bush-Francis Catatonia Rating Scale (BFCRS) has had the most widespread use. The BFCRS consists of 23 items, the first 14 of which are used as a screening instrument. It requires 2 of its first 14 items to diagnose catatonia, while DSM-5 requires 3 of 12 signs.²⁹ If the diagnosis remains in doubt, a benzodiazepine agonist test can be instructive.^9,12 The presence of catatonia is suggested by significant improvement, ideally assessed prospectively by improvement of BFCRS scores, shortly after administration of a single dose of 1 to 2 mg lorazepam or 5 mg diazepam IV, or 10 mg zolpidem orally. Further evaluation generally consists of a careful medical and psychiatric histories of patient and family, review of all medications, history of substance use with toxicology as indicated, physical examination focusing on autonomic dysregulation, examination for delirium, and laboratory tests as suggested by the history and examination that may include complete blood count, creatine kinase, serum iron, blood urea nitrogen, electrolytes, creatinine, prolactin, anti-NMDA antibodies, thyroid function tests, serology, metabolic panel, human immunodeficiency virus testing, EEG, and neuroimaging.^8,15,16

A complex differential diagnosis

Manifestations of numerous psychiatric and neurologic disorders can mimic or be identical to those of catatonia. The differential diagnosis is complicated by the fact that some of these disorders can cause catatonia, which is then masked by the primary disorder; some disorders (eg, NMS) are forms of catatonia. Table 6^{5,8,12,19,26,30} lists conditions to consider.

Some of these conditions warrant discussion. ASD may have catatonia-like features such as echolalia, echopraxia, excitement, combativeness, grimacing, mutism, logorrhea, verbigeration, catalepsy, mannerisms, rigidity, staring and withdrawal.⁸ Catatonia may also be a stage of deterioration of autism, in which case it is characterized by increases in slowness of movement and speech, reliance on physical or verbal prompting from others, passivity, and lack of motivation.²³ At the same time, catatonic features such as mutism, stereotypic speech, repetitive behavior, echolalia, posturing, mannerisms, purposeless agitation, and rigidity in catatonia can be misinterpreted as signs of ASD.⁸ Catatonia should be suspected as a complication of longstanding ASD in the presence of a consistent, marked change in motor behavior, such as immobility, decreased speech, stupor, excitement, or mixtures or alternations of stupor and excitement.⁸ Freezing while doing something, difficulty crossing lines, or uncharacteristic persistence of a particular behavior may also herald the presence of catatonia with ASD.⁸

Catatonia caused by a neurologic or metabolic factor or a substance can be difficult to distinguish from delirium complicated by catatonia. Delirium may be identified in patients with catatonia by the presence of a waxing and waning level of consciousness (vs fluctuating behavior in catatonia) and slowing of the EEG.^12,15 Antipsychotic medications can improve delirium but worsen catatonia, while benzodiazepines can improve catatonia but worsen delirium.

Continue to: Among other neurologic syndromes...

Benzodiazepines, ECT are the usual treatments

Experience dictates that the general principles of treatment noted in Table 7^12,15,23,31 apply to all patients with catatonia. Since the first reported improvement of catatonia with amobarbital in 1930,⁶ there have been no controlled studies of specific treatments of catatonia.¹³ Meaningful treatment trials are either naturalistic, or have been performed only for NMS and malignant catatonia.⁵ However, multiple case reports and case series suggest that treatments with agents that have anticonvulsant properties (benzodiazepines, barbiturates) and ECT are effective.⁵

Benzodiazepines and related compounds. Case series have suggested a 60% to 80% remission rate of catatonia with benzodiazepines, the most commonly utilized of which has been lorazepam.^7,13,32 Treatment begins with a lorazepam challenge test of 1 to 2 mg in adults and 0.5 to 1 mg in children and geriatric patients,^9,15 administered orally (including via nasogastric tube), IM, or IV. Following a response (≥50% improvement), the dose is increased to 2 mg 3 times per day. The dose is further increased to 6 to 16 mg/d, and sometimes up to 30 mg/d.^9,11 Oral is less effective than sublingual or IM administration.¹¹ Diazepam can be helpful at doses 5 times the lorazepam dose.^9,17 A zolpidem challenge test of 10 mg orally or via nasogastric tube has also been utilized.¹⁵ Response is brief and is usually followed by lorazepam, although zolpidem up to 40 mg/d has been used for ongoing treatment.⁹

One alternative benzodiazepine protocol utilizes an initial IV dose of 2 mg lorazepam, repeated 3 to 5 times per day; the dose is increased to 10 to 12 mg/d if the first doses are partially effective.¹⁶ A lorazepam/diazepam approach involves a combination of IM lorazepam and IV diazepam.¹¹ The protocol begins with 2 mg of IM lorazepam. If there is no effect within 2 hours, a second 2 mg dose is administered, followed by an IV infusion of 10 mg diazepam in 500 ml of normal saline at 1.25 mg/hour until catatonia remits.

An Indian study of 107 patients (mean age 26) receiving relatively low doses of lorazepam (3 to 6 mg/d for at least 3 days) found that factors suggesting a robust response include a shorter duration of catatonia and waxy flexibility, while passivity, mutism, and auditory hallucinations describing the patient in the third person were associated with a poorer acute response.³¹ Catatonia with marked retardation and mutism complicating schizophrenia, especially with chronic negative symptoms, may be associated with a lower response rate to benzodiazepines.^20,33 Maintenance lorazepam has been effective in reducing relapse and recurrence.¹¹ There are no controlled studies of maintenance treatment with benzodiazepines, but clinical reports suggest that doses in the range of 4 to 10 mg/d are effective.³²

Continue to: ECT was used for catatonia in 1934...

ECT was first used for catatonia in 1934, when Laszlo Meduna used chemically induced seizures in catatonic patients who had been on tube feeding for months and no longer needed it after treatment.^6,7 As was true for other disorders, this approach was replaced by ECT.⁷ In various case series, the effectiveness of ECT in catatonia has been 53% to 100%.^7,13,15 Right unilateral ECT has been reported to be effective with 1 treatment.²¹ However, the best-established approach is with bitemporal ECT with a suprathreshold stimulus,⁹ usually with an acute course of 6 to 20 treatments.²⁰ ECT has been reported to be equally safe and effective in adolescents and adults.³⁴ Continued ECT is usually necessary until the patient has returned to baseline.⁹

ECT usually is recommended within 24 hours for treatment-resistant malignant catatonia or refusal to eat or drink, and within 2 to 3 days if medications are not sufficiently effective in other forms of catatonia.^12,15,20 If ECT is initiated after a benzodiazepine trial, the benzodiazepine antagonist flumazenil is administered first to reverse the anticonvulsant effect.⁹ Some experts recommend using a muscle relaxant other than succinylcholine in the presence of evidence of muscle damage.⁷

Alternatives to benzodiazepines and ECT. Based on case reports, the treatments described in Table 8^{13,15,17,20,25} have been used for patients with catatonia who do not tolerate or respond to standard treatments. The largest number of case reports have been with NMDA antagonists, while the presumed involvement of reduced dopamine signaling suggests that dopaminergic medications should be helpful. Dantrolene, which blocks release of calcium from intracellular stores and has been used to treat malignant hyperthermia, is sometimes used for NMS, often with disappointing results.

Whereas first-generation antipsychotics definitely increase the risk of catatonia and second-generation antipsychotics (SGAs) probably do so, SGAs are sometimes necessary to treat persistent psychosis in patients with schizophrenia who develop catatonia. Of these medications, clozapine may be most desirable because of low potency for dopamine receptor blockade and modulation of glutamatergic signaling. Partial dopamine agonism by aripiprazole, and the potential for increased subcortical prefrontal dopamine release resulting from serotonin 5HT2A antagonism and 5HT1A agonism by other SGAs, could also be helpful or at least not harmful in catatonia. Lorazepam is usually administered along with these medications to ameliorate treatment-emergent exacerbation of catatonia.

There are no controlled studies of any of these treatments. Based on case reports, most experts would recommend initiating treatment of catatonia with lorazepam, followed by ECT if necessary or in the presence of life-threatening catatonia. If ECT is not available, ineffective, or not tolerated, the first alternatives to be considered would be an NMDA antagonist or an anticonvulsant.²⁰

Continue to: Course varies by patient, underlying cause

Course varies by patient, underlying cause

The response to benzodiazepines or ECT can vary from episode to episode¹¹ and is similar in adults and younger patients.²² Many patients recover completely after a single episode, while relapse after remission occurs repeatedly in periodic catatonia, which involves chronic alternating stupor and excitement waxing and waning over years.¹¹ Relapses may occur frequently, or every few years.¹¹ Some cases of catatonia initially have an episodic course and become chronic and deteriorating, possibly paralleling the original descriptions of the natural history of untreated catatonia, while malignant catatonia can be complicated by medical morbidity or death.⁴ The long-term prognosis generally depends on the underlying cause of catatonia.⁵

Bottom Line

Much more common than many clinicians realize, catatonia can be overlooked because symptoms can mimic or overlap with features of an underlying medical or neurologic disorder. Suspect catatonia when one of these illnesses has an unexpected course or an inadequate treatment response. Be alert to characteristic changes in behavior and speech. A benzodiazepine challenge can be used to diagnose and begin treatment of catatonia. Consider electroconvulsive therapy sooner rather than later, especially for severely ill patients.

Related Resources

• Gibson RC, Walcott G. Benzodiazepines for catatonia in people with schizophrenia and other serious mental illnesses. Cochrane Database Syst Rev. 2008;(4):CD006570. 
• Newcastle University. Catatonia. https://youtu.be/_s1lzxHRO4U.

Drug Brand Names

Amantadine • Symmetrel
Amobarbital • Amytal
Aripiprazole • Abilify
Azithromycin • Zithromax
Baclofen • Lioresal
Benztropine • Cogentin
Carbamazepine • Carbatrol, Tegretol
Carbidopa/levodopa • Sinemet
Ciprofloxacin • Cipro
Clozapine • Clozaril
Dantrolene • Dantrium
Dexamethasone • Decadron
Dextromethorphan/quinidine • Neudexta
Diazepam • Valium
Disulfiram • Antabuse
Flumazenil • Romazicon
Fluoxetine • Prozac
Fluvoxamine • Luvox
Levetiracetam • Keppra
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Memantine • Namenda
Methylphenidate • Ritalin
Minocycline • Minocin
Olanzapine • Zyprexa
Risperidone • Risperdal
Succinylcholine • Anectine
Topiramate • Topamax
Trihexyphenidyl • Artane
Valproate • Depakote
Ziprasidone • Geodon
Zolpidem • Ambien