Applied Evidence

Last month, we introduced you to 15-year-old Jane, a teenager whose once bubbly personality had in the last few months been reduced to a mood of quiet sadness. Her responses to your questions were muted, unenthusiastic. While Jane gets to school every day and can often shake off her down mood when she’s with friends, her responses to the Kutcher Adolescent Depression scale suggest that she’s struggling. You conclude that Jane is experiencing an episode of mild depressive disorder.

How would you manage Jane’s case? And what would you do if her symptoms worsened?

What’s the preference of patient and family?

Begin your initial management of a patient like Jane by considering the treatment preferences of the patient and her family, the severity and urgency of the case, the availability of mental health services, and your own comfort level with managing mental health disorders. A key conclusion of the GLAD-PC (GuideLines for Adolescent Depression in Primary Care) collaborative, described in Part 1 of this series, was that family physicians, alone or in collaboration with mental health professionals, are competent to manage adolescent depression.¹ You may or may not choose to manage a patient like Jane yourself, but even if you refer, your initial management provides an essential bridge until the patient and her family are seen by mental health professionals.

Your initial management should include the following:

• education
• a treatment plan
• safety planning.

Step 1: Educate patient and parents

Help your patient to better understand what it means to have depression. Describe the signs and symptoms that led to the diagnosis of depression and review the natural history of the illness, including the chronic nature of the disorder and its tendency to recur. Explain, too, the impact that depression can have on different areas of functioning, such as school performance and peer relationships, and then review the treatment options. You or someone on your staff can provide this patient education initially, but it is also critical to connect the family to specific community resources for additional education, advocacy, and peer support.¹

To do this effectively, you need to establish links with mental health resources in the community, including mental health service providers, as well as patients and families who have dealt with adolescent depression and are willing to serve as resources to other teens and their families. The GLAD-PC toolkit, available at www.gladpc.org, provides patient education handouts and links to reputable Web sites, advocacy organizations, and peer support groups. Additional online resources are listed in TABLE 1.

TABLE 1
Online resources

Step 2: Work out a treatment plan

Developing a treatment plan that the patient and her parents can accept is critical. A plan that includes psychotherapy with a mental health provider, for example, won’t be acceptable to some patients and parents. They may refuse to participate, or their underlying mistrust may affect the outcome of treatment.^2,3 Other families may reject any therapeutic approach that includes psychotropic drugs.

Expectations about the benefits of treatment influence outcomes significantly, so that, too, is a topic to explore as the treatment plan is worked out.^3,4 Finally, the plan should include agreed-upon goals of treatment. For Jane, planned goals might include getting back into gymnastics or trying out for the school play.

Step 3: Plan for safety

Suicidality, including ideation, behaviors, or attempts, is common among adolescents with depression.^5,6 In studies of completed suicide, more than 50% of the victims had a diagnosis of depression.⁵ To keep your patient safe, develop an emergency communication mechanism for handling increased suicidality or acute crises. If the patient’s risk is high, as shown by a clear plan or intent, immediate hospitalization may be necessary.

If you determine that inpatient treatment is not needed, you need to be sure that adequate adult supervision and support are available; that the teenager does not have access to potentially lethal medications, knives and other sharp objects, or firearms; and that both the patient and parents understand that drugs and alcohol weaken inhibitions. You need to set up a contingency plan with the family that includes checking in with you at reasonable intervals to assure the teen’s safety.⁵

Establishing a safety plan is especially important during the period of diagnosis and initial treatment, when suicide risk is highest.⁶ Confidentiality is the norm in adolescent medicine, but a patient like Jane must understand that you will breach confidentiality if that is necessary to keep her safe from harm.

Treatment options: When active support is best

Selecting the appropriate treatment modality for your patient hinges, of course, on the severity of the teen’s depression. (For more information on how to determine the severity of a depressive episode, see the first installment of this series, “Adolescent depression: Is your young patient suffering in silence?” J Fam Pract. 2009;58:187-192.)

When caring for a patient like Jane who is suffering from mild depression, consider providing active support and monitoring during 6 to 8 weekly or biweekly visits before recommending antidepressant medication or psychotherapy. This approach is also indicated when depressed patients or their parents refuse other treatments.⁷

Active support and monitoring may include education, frequent follow-up, a prescribed regimen of exercise and leisure activities, referral to a peer support group, and review of self-management goals. Other resources for active monitoring can be found in the GLAD-PC toolkit (available at www.gladpc.org). Evidence from randomized controlled trials (RCTs) shows that a sizable percentage of young people with depression respond to nondirective supportive therapy and regular symptom monitoring.⁷ Furthermore, emerging data from the research literature, expert opinion, and patient and family preferences indicate that active support and monitoring from family physicians is an important therapeutic strategy.^7,8

Is therapy needed—and if so, what kind?

Adolescents with moderate or severe depression or patients with mild depression whose symptoms do not improve with active support and monitoring alone will likely require treatment with one of the evidenced-based treatments, such as psychotherapy or antidepressants. Referral to a mental health provider for further assessment or treatment may also be required, depending on the training of the physician.^7,8 If so, you and the mental health provider will need to negotiate your roles and responsibilities for ongoing management, with the input and approval of the patient and family.

Both cognitive behavioral therapy (CBT) and interpersonal therapy (IPT) have been adapted to address major depressive disorder (MDD) in adolescents and have been shown to be effective in community as well as specialized settings.^9-11

CBT is time-limited and delivered individually or by 1 or 2 clinicians working with a group. Clinicians follow a manual to guide each session.¹² (A manual for therapists and a workbook for adolescents and parents can be downloaded from the Kaiser Permanente Center for Health Research Web site at http://www.kpchr.org/public/acwd/acwd.html.)

The focus of CBT is to change patients’ perception of themselves, their world, and others. CBT treats depression by identifying behavioral and cognitive patterns associated with depressive cycles. Examples of such patterns include the propensity to withdraw from pleasurable activities, or irritability that alienates family and friends just when the teenager needs them most. CBT helps teens identify these self-defeating patterns, encourages them to take part in activities they enjoy, helps develop or reactivate social skills important for maintaining positive social interactions, and helps teens to develop problem-solving strategies for resolving stressful situations.

CBT also aims to correct maladaptive beliefs associated with the patient’s depression. If, for instance, a patient believes she is worthless if she’s not accepted by the “popular” group at school, she is likely to become depressed and stay depressed as long as she is having difficulty connecting with her peers. CBT would help her examine that belief and learn to feel worthwhile even if she is not accepted by the “in” group. In general, CBT sessions are scheduled on a weekly basis for 12 to 16 weeks. In each session, the therapist and patient complete specific tasks and exercises that are provided in a CBT manual. There are also tasks for the patient to complete between sessions and review later with the therapist. CBT has been used in primary care with preliminary positive results.^13,14 However, the results of a recent RCT conducted in psychiatric settings demonstrated superior efficacy of combination therapy (fluoxetine and CBT) vs CBT alone.¹⁵

IPT for adolescents (IPT-A) is like CBT in that it is time-limited and clinicians are guided by a manual.¹⁶ A course of therapy can last anywhere from 12 to 16 sessions with optional maintenance treatment. The theoretical basis for IPT-A is the observed negative impact of depressive symptoms on interpersonal relationships, and the effect poor relationships have in causing and perpetuating depression. In deciding whether a patient may be suitable for IPT-A, you need to find out whether she would be willing to share her experiences of ongoing relationship conflicts with a therapist or therapeutic group. The relationship difficulties IPT-A is designed to help with arise from 1 of 4 sources: grief, fights with peers or family members (interpersonal disputes), transitions from one social surround to another (role transition), and friendlessness (interpersonal deficits).

IPT-A focuses on grief only when someone of significance to the patient has died. Therapy for teens who quarrel frequently with peers or family members is focused on interpersonal disputes, and this is the most common focus in IPT-A. A focus on role transition is called for when the teen’s social world has undergone a drastic change, such as a when a teen has moved to a new school or broken up with a boyfriend. Finally, therapy for a teen with no significant relationships outside the immediate family focuses on interpersonal deficits. In these cases, the goal of therapy is to increase social contact and help the patient build relationships. If your preliminary assessment identifies your patient’s difficulties as rooted in 1 of these 4 areas, IPT-A may be for her.

Because few family physicians are trained in CBT or IPT-A, most psychotherapy will be provided by mental health professionals. What you can provide is familiarity with available community mental health resources. To get to know the therapists in your community, you may want to reach out to a few of them and ask them the questions in TABLE 2. You may also want to share this list with parents who want to find their own therapist.

TABLE 2
6 questions to ask prospective therapists

Choose an antidepressant, monitor with care

Studies have shown that up to 42% of family physicians in the United States had recently prescribed selective serotonin reuptake inhibitors (SSRIs) for more than 1 adolescent under the age of 18.¹⁷ When the diagnosis of MDD without comorbid conditions is clear and the patient and family are amenable, you may want to prescribe an SSRI.^7,8

If you do, warn the patient and family that antidepressants can sometimes have adverse effects, including a switch from depressive to manic symptoms, signs of behavioral activation including agitation, hostility or restlessness, and suicidal ideation or behavior. If the patient can tolerate the medication without significant adverse effects, you need to prescribe the effective dose for at least 6 to 8 weeks to ensure an adequate trial.⁷

TABLE 3 provides some guidance for prescribing antidepressants for adolescents with depression.⁷ Among the antidepressants, only fluoxetine has been approved by the FDA for children and adolescents with depression. Fluoxetine is also the SSRI with the strongest evidence for efficacy in the adolescent population, as demonstrated in 4 RCTs.¹⁸ Two studies involving fluoxetine for depression have also shown efficacy in children as young as age 7 (range, 7-12 years).¹⁹

Effective dosages for antidepressants are lower for adolescents than for adults. Initiate medications at a low dose and increase in recommended increments every 2 weeks if no significant adverse effects emerge. With the exception of fluoxetine, SSRI medications must be discontinued slowly to minimize the risk of discontinuation effects.

Once treatment begins, you or a member of your staff will need to stay in touch with the patient and family to review their continued adherence to the treatment plan. An FDA black-box warning recommends observing for “clinical worsening, suicidality, and unusual changes in behavior” during initial visits or “at times of dose changes, either increases or decreases.” Develop a regular, frequent monitoring schedule with input from the teen and her (or his) parents to ensure compliance.^7,20

Make sure follow-up appointments are not missed, using flags in patient records or in the clinic schedule. The duration of treatment for teens with depression is yet to be determined through clinical trials. Most guidelines suggest drug therapy be continued at the same dosage for 6 to 12 months after symptoms resolve. Guidelines for the treatment of adolescent depression can be found at www.gladpc.org.

Keeping teenagers on an antidepressant regimen can be challenging, given the side effects, the amount of time it takes before they experience an improvement, and the lengthy duration of treatment. Families that know what to expect and are getting continuing support from you and others are most likely to stay with treatment for the duration.

TABLE 3
A guide to prescribing antidepressants for adolescents

What about Jane?

As the family’s physician, your initial management began with you educating Jane and her parents about mild depressive disorder and its likely course. You set up a series of weekly visits to monitor her symptoms and provide active support. You helped Jane find a peer support group and encouraged her to get back into gymnastics. You taught Jane and her family about the importance of keeping her safe while she is depressed, and they were cooperative about safety-proofing their home and setting up a plan to handle emergencies.

Jane’s depressive symptoms gradually ebbed, and she returned to her previous level of energy and social activity. You warned her and her family about the possibility that the disorder might recur, so they would be prepared.

Correspondence
Amy Cheung, MD, 33 Russell Street, 3rd Floor Tower, Toronto, Ontario, Canada MSS 2S1; [email protected]

Last month, we introduced you to 15-year-old Jane, a teenager whose once bubbly personality had in the last few months been reduced to a mood of quiet sadness. Her responses to your questions were muted, unenthusiastic. While Jane gets to school every day and can often shake off her down mood when she’s with friends, her responses to the Kutcher Adolescent Depression scale suggest that she’s struggling. You conclude that Jane is experiencing an episode of mild depressive disorder.

How would you manage Jane’s case? And what would you do if her symptoms worsened?

What’s the preference of patient and family?

Begin your initial management of a patient like Jane by considering the treatment preferences of the patient and her family, the severity and urgency of the case, the availability of mental health services, and your own comfort level with managing mental health disorders. A key conclusion of the GLAD-PC (GuideLines for Adolescent Depression in Primary Care) collaborative, described in Part 1 of this series, was that family physicians, alone or in collaboration with mental health professionals, are competent to manage adolescent depression.¹ You may or may not choose to manage a patient like Jane yourself, but even if you refer, your initial management provides an essential bridge until the patient and her family are seen by mental health professionals.

Your initial management should include the following:

• education
• a treatment plan
• safety planning.

Step 1: Educate patient and parents

Help your patient to better understand what it means to have depression. Describe the signs and symptoms that led to the diagnosis of depression and review the natural history of the illness, including the chronic nature of the disorder and its tendency to recur. Explain, too, the impact that depression can have on different areas of functioning, such as school performance and peer relationships, and then review the treatment options. You or someone on your staff can provide this patient education initially, but it is also critical to connect the family to specific community resources for additional education, advocacy, and peer support.¹

To do this effectively, you need to establish links with mental health resources in the community, including mental health service providers, as well as patients and families who have dealt with adolescent depression and are willing to serve as resources to other teens and their families. The GLAD-PC toolkit, available at www.gladpc.org, provides patient education handouts and links to reputable Web sites, advocacy organizations, and peer support groups. Additional online resources are listed in TABLE 1.

TABLE 1
Online resources

Step 2: Work out a treatment plan

Developing a treatment plan that the patient and her parents can accept is critical. A plan that includes psychotherapy with a mental health provider, for example, won’t be acceptable to some patients and parents. They may refuse to participate, or their underlying mistrust may affect the outcome of treatment.^2,3 Other families may reject any therapeutic approach that includes psychotropic drugs.

Expectations about the benefits of treatment influence outcomes significantly, so that, too, is a topic to explore as the treatment plan is worked out.^3,4 Finally, the plan should include agreed-upon goals of treatment. For Jane, planned goals might include getting back into gymnastics or trying out for the school play.

Step 3: Plan for safety

Suicidality, including ideation, behaviors, or attempts, is common among adolescents with depression.^5,6 In studies of completed suicide, more than 50% of the victims had a diagnosis of depression.⁵ To keep your patient safe, develop an emergency communication mechanism for handling increased suicidality or acute crises. If the patient’s risk is high, as shown by a clear plan or intent, immediate hospitalization may be necessary.

If you determine that inpatient treatment is not needed, you need to be sure that adequate adult supervision and support are available; that the teenager does not have access to potentially lethal medications, knives and other sharp objects, or firearms; and that both the patient and parents understand that drugs and alcohol weaken inhibitions. You need to set up a contingency plan with the family that includes checking in with you at reasonable intervals to assure the teen’s safety.⁵

Establishing a safety plan is especially important during the period of diagnosis and initial treatment, when suicide risk is highest.⁶ Confidentiality is the norm in adolescent medicine, but a patient like Jane must understand that you will breach confidentiality if that is necessary to keep her safe from harm.

Treatment options: When active support is best

Selecting the appropriate treatment modality for your patient hinges, of course, on the severity of the teen’s depression. (For more information on how to determine the severity of a depressive episode, see the first installment of this series, “Adolescent depression: Is your young patient suffering in silence?” J Fam Pract. 2009;58:187-192.)

When caring for a patient like Jane who is suffering from mild depression, consider providing active support and monitoring during 6 to 8 weekly or biweekly visits before recommending antidepressant medication or psychotherapy. This approach is also indicated when depressed patients or their parents refuse other treatments.⁷

Active support and monitoring may include education, frequent follow-up, a prescribed regimen of exercise and leisure activities, referral to a peer support group, and review of self-management goals. Other resources for active monitoring can be found in the GLAD-PC toolkit (available at www.gladpc.org). Evidence from randomized controlled trials (RCTs) shows that a sizable percentage of young people with depression respond to nondirective supportive therapy and regular symptom monitoring.⁷ Furthermore, emerging data from the research literature, expert opinion, and patient and family preferences indicate that active support and monitoring from family physicians is an important therapeutic strategy.^7,8

Is therapy needed—and if so, what kind?

Adolescents with moderate or severe depression or patients with mild depression whose symptoms do not improve with active support and monitoring alone will likely require treatment with one of the evidenced-based treatments, such as psychotherapy or antidepressants. Referral to a mental health provider for further assessment or treatment may also be required, depending on the training of the physician.^7,8 If so, you and the mental health provider will need to negotiate your roles and responsibilities for ongoing management, with the input and approval of the patient and family.

Both cognitive behavioral therapy (CBT) and interpersonal therapy (IPT) have been adapted to address major depressive disorder (MDD) in adolescents and have been shown to be effective in community as well as specialized settings.^9-11

CBT is time-limited and delivered individually or by 1 or 2 clinicians working with a group. Clinicians follow a manual to guide each session.¹² (A manual for therapists and a workbook for adolescents and parents can be downloaded from the Kaiser Permanente Center for Health Research Web site at http://www.kpchr.org/public/acwd/acwd.html.)

The focus of CBT is to change patients’ perception of themselves, their world, and others. CBT treats depression by identifying behavioral and cognitive patterns associated with depressive cycles. Examples of such patterns include the propensity to withdraw from pleasurable activities, or irritability that alienates family and friends just when the teenager needs them most. CBT helps teens identify these self-defeating patterns, encourages them to take part in activities they enjoy, helps develop or reactivate social skills important for maintaining positive social interactions, and helps teens to develop problem-solving strategies for resolving stressful situations.

CBT also aims to correct maladaptive beliefs associated with the patient’s depression. If, for instance, a patient believes she is worthless if she’s not accepted by the “popular” group at school, she is likely to become depressed and stay depressed as long as she is having difficulty connecting with her peers. CBT would help her examine that belief and learn to feel worthwhile even if she is not accepted by the “in” group. In general, CBT sessions are scheduled on a weekly basis for 12 to 16 weeks. In each session, the therapist and patient complete specific tasks and exercises that are provided in a CBT manual. There are also tasks for the patient to complete between sessions and review later with the therapist. CBT has been used in primary care with preliminary positive results.^13,14 However, the results of a recent RCT conducted in psychiatric settings demonstrated superior efficacy of combination therapy (fluoxetine and CBT) vs CBT alone.¹⁵

IPT for adolescents (IPT-A) is like CBT in that it is time-limited and clinicians are guided by a manual.¹⁶ A course of therapy can last anywhere from 12 to 16 sessions with optional maintenance treatment. The theoretical basis for IPT-A is the observed negative impact of depressive symptoms on interpersonal relationships, and the effect poor relationships have in causing and perpetuating depression. In deciding whether a patient may be suitable for IPT-A, you need to find out whether she would be willing to share her experiences of ongoing relationship conflicts with a therapist or therapeutic group. The relationship difficulties IPT-A is designed to help with arise from 1 of 4 sources: grief, fights with peers or family members (interpersonal disputes), transitions from one social surround to another (role transition), and friendlessness (interpersonal deficits).

IPT-A focuses on grief only when someone of significance to the patient has died. Therapy for teens who quarrel frequently with peers or family members is focused on interpersonal disputes, and this is the most common focus in IPT-A. A focus on role transition is called for when the teen’s social world has undergone a drastic change, such as a when a teen has moved to a new school or broken up with a boyfriend. Finally, therapy for a teen with no significant relationships outside the immediate family focuses on interpersonal deficits. In these cases, the goal of therapy is to increase social contact and help the patient build relationships. If your preliminary assessment identifies your patient’s difficulties as rooted in 1 of these 4 areas, IPT-A may be for her.

Because few family physicians are trained in CBT or IPT-A, most psychotherapy will be provided by mental health professionals. What you can provide is familiarity with available community mental health resources. To get to know the therapists in your community, you may want to reach out to a few of them and ask them the questions in TABLE 2. You may also want to share this list with parents who want to find their own therapist.

TABLE 2
6 questions to ask prospective therapists

Choose an antidepressant, monitor with care

Studies have shown that up to 42% of family physicians in the United States had recently prescribed selective serotonin reuptake inhibitors (SSRIs) for more than 1 adolescent under the age of 18.¹⁷ When the diagnosis of MDD without comorbid conditions is clear and the patient and family are amenable, you may want to prescribe an SSRI.^7,8

If you do, warn the patient and family that antidepressants can sometimes have adverse effects, including a switch from depressive to manic symptoms, signs of behavioral activation including agitation, hostility or restlessness, and suicidal ideation or behavior. If the patient can tolerate the medication without significant adverse effects, you need to prescribe the effective dose for at least 6 to 8 weeks to ensure an adequate trial.⁷

TABLE 3 provides some guidance for prescribing antidepressants for adolescents with depression.⁷ Among the antidepressants, only fluoxetine has been approved by the FDA for children and adolescents with depression. Fluoxetine is also the SSRI with the strongest evidence for efficacy in the adolescent population, as demonstrated in 4 RCTs.¹⁸ Two studies involving fluoxetine for depression have also shown efficacy in children as young as age 7 (range, 7-12 years).¹⁹

Effective dosages for antidepressants are lower for adolescents than for adults. Initiate medications at a low dose and increase in recommended increments every 2 weeks if no significant adverse effects emerge. With the exception of fluoxetine, SSRI medications must be discontinued slowly to minimize the risk of discontinuation effects.

Once treatment begins, you or a member of your staff will need to stay in touch with the patient and family to review their continued adherence to the treatment plan. An FDA black-box warning recommends observing for “clinical worsening, suicidality, and unusual changes in behavior” during initial visits or “at times of dose changes, either increases or decreases.” Develop a regular, frequent monitoring schedule with input from the teen and her (or his) parents to ensure compliance.^7,20

Make sure follow-up appointments are not missed, using flags in patient records or in the clinic schedule. The duration of treatment for teens with depression is yet to be determined through clinical trials. Most guidelines suggest drug therapy be continued at the same dosage for 6 to 12 months after symptoms resolve. Guidelines for the treatment of adolescent depression can be found at www.gladpc.org.

Keeping teenagers on an antidepressant regimen can be challenging, given the side effects, the amount of time it takes before they experience an improvement, and the lengthy duration of treatment. Families that know what to expect and are getting continuing support from you and others are most likely to stay with treatment for the duration.

TABLE 3
A guide to prescribing antidepressants for adolescents

What about Jane?

As the family’s physician, your initial management began with you educating Jane and her parents about mild depressive disorder and its likely course. You set up a series of weekly visits to monitor her symptoms and provide active support. You helped Jane find a peer support group and encouraged her to get back into gymnastics. You taught Jane and her family about the importance of keeping her safe while she is depressed, and they were cooperative about safety-proofing their home and setting up a plan to handle emergencies.

Jane’s depressive symptoms gradually ebbed, and she returned to her previous level of energy and social activity. You warned her and her family about the possibility that the disorder might recur, so they would be prepared.

Correspondence
Amy Cheung, MD, 33 Russell Street, 3rd Floor Tower, Toronto, Ontario, Canada MSS 2S1; [email protected]

Last month, we introduced you to 15-year-old Jane, a teenager whose once bubbly personality had in the last few months been reduced to a mood of quiet sadness. Her responses to your questions were muted, unenthusiastic. While Jane gets to school every day and can often shake off her down mood when she’s with friends, her responses to the Kutcher Adolescent Depression scale suggest that she’s struggling. You conclude that Jane is experiencing an episode of mild depressive disorder.

How would you manage Jane’s case? And what would you do if her symptoms worsened?

What’s the preference of patient and family?

Begin your initial management of a patient like Jane by considering the treatment preferences of the patient and her family, the severity and urgency of the case, the availability of mental health services, and your own comfort level with managing mental health disorders. A key conclusion of the GLAD-PC (GuideLines for Adolescent Depression in Primary Care) collaborative, described in Part 1 of this series, was that family physicians, alone or in collaboration with mental health professionals, are competent to manage adolescent depression.¹ You may or may not choose to manage a patient like Jane yourself, but even if you refer, your initial management provides an essential bridge until the patient and her family are seen by mental health professionals.

Your initial management should include the following:

• education
• a treatment plan
• safety planning.

Step 1: Educate patient and parents

Help your patient to better understand what it means to have depression. Describe the signs and symptoms that led to the diagnosis of depression and review the natural history of the illness, including the chronic nature of the disorder and its tendency to recur. Explain, too, the impact that depression can have on different areas of functioning, such as school performance and peer relationships, and then review the treatment options. You or someone on your staff can provide this patient education initially, but it is also critical to connect the family to specific community resources for additional education, advocacy, and peer support.¹

To do this effectively, you need to establish links with mental health resources in the community, including mental health service providers, as well as patients and families who have dealt with adolescent depression and are willing to serve as resources to other teens and their families. The GLAD-PC toolkit, available at www.gladpc.org, provides patient education handouts and links to reputable Web sites, advocacy organizations, and peer support groups. Additional online resources are listed in TABLE 1.

TABLE 1
Online resources

Step 2: Work out a treatment plan

Developing a treatment plan that the patient and her parents can accept is critical. A plan that includes psychotherapy with a mental health provider, for example, won’t be acceptable to some patients and parents. They may refuse to participate, or their underlying mistrust may affect the outcome of treatment.^2,3 Other families may reject any therapeutic approach that includes psychotropic drugs.

Expectations about the benefits of treatment influence outcomes significantly, so that, too, is a topic to explore as the treatment plan is worked out.^3,4 Finally, the plan should include agreed-upon goals of treatment. For Jane, planned goals might include getting back into gymnastics or trying out for the school play.

Step 3: Plan for safety

Suicidality, including ideation, behaviors, or attempts, is common among adolescents with depression.^5,6 In studies of completed suicide, more than 50% of the victims had a diagnosis of depression.⁵ To keep your patient safe, develop an emergency communication mechanism for handling increased suicidality or acute crises. If the patient’s risk is high, as shown by a clear plan or intent, immediate hospitalization may be necessary.

If you determine that inpatient treatment is not needed, you need to be sure that adequate adult supervision and support are available; that the teenager does not have access to potentially lethal medications, knives and other sharp objects, or firearms; and that both the patient and parents understand that drugs and alcohol weaken inhibitions. You need to set up a contingency plan with the family that includes checking in with you at reasonable intervals to assure the teen’s safety.⁵

Establishing a safety plan is especially important during the period of diagnosis and initial treatment, when suicide risk is highest.⁶ Confidentiality is the norm in adolescent medicine, but a patient like Jane must understand that you will breach confidentiality if that is necessary to keep her safe from harm.

Treatment options: When active support is best

Selecting the appropriate treatment modality for your patient hinges, of course, on the severity of the teen’s depression. (For more information on how to determine the severity of a depressive episode, see the first installment of this series, “Adolescent depression: Is your young patient suffering in silence?” J Fam Pract. 2009;58:187-192.)

When caring for a patient like Jane who is suffering from mild depression, consider providing active support and monitoring during 6 to 8 weekly or biweekly visits before recommending antidepressant medication or psychotherapy. This approach is also indicated when depressed patients or their parents refuse other treatments.⁷

Active support and monitoring may include education, frequent follow-up, a prescribed regimen of exercise and leisure activities, referral to a peer support group, and review of self-management goals. Other resources for active monitoring can be found in the GLAD-PC toolkit (available at www.gladpc.org). Evidence from randomized controlled trials (RCTs) shows that a sizable percentage of young people with depression respond to nondirective supportive therapy and regular symptom monitoring.⁷ Furthermore, emerging data from the research literature, expert opinion, and patient and family preferences indicate that active support and monitoring from family physicians is an important therapeutic strategy.^7,8

Is therapy needed—and if so, what kind?

Adolescents with moderate or severe depression or patients with mild depression whose symptoms do not improve with active support and monitoring alone will likely require treatment with one of the evidenced-based treatments, such as psychotherapy or antidepressants. Referral to a mental health provider for further assessment or treatment may also be required, depending on the training of the physician.^7,8 If so, you and the mental health provider will need to negotiate your roles and responsibilities for ongoing management, with the input and approval of the patient and family.

Both cognitive behavioral therapy (CBT) and interpersonal therapy (IPT) have been adapted to address major depressive disorder (MDD) in adolescents and have been shown to be effective in community as well as specialized settings.^9-11

CBT is time-limited and delivered individually or by 1 or 2 clinicians working with a group. Clinicians follow a manual to guide each session.¹² (A manual for therapists and a workbook for adolescents and parents can be downloaded from the Kaiser Permanente Center for Health Research Web site at http://www.kpchr.org/public/acwd/acwd.html.)

The focus of CBT is to change patients’ perception of themselves, their world, and others. CBT treats depression by identifying behavioral and cognitive patterns associated with depressive cycles. Examples of such patterns include the propensity to withdraw from pleasurable activities, or irritability that alienates family and friends just when the teenager needs them most. CBT helps teens identify these self-defeating patterns, encourages them to take part in activities they enjoy, helps develop or reactivate social skills important for maintaining positive social interactions, and helps teens to develop problem-solving strategies for resolving stressful situations.

CBT also aims to correct maladaptive beliefs associated with the patient’s depression. If, for instance, a patient believes she is worthless if she’s not accepted by the “popular” group at school, she is likely to become depressed and stay depressed as long as she is having difficulty connecting with her peers. CBT would help her examine that belief and learn to feel worthwhile even if she is not accepted by the “in” group. In general, CBT sessions are scheduled on a weekly basis for 12 to 16 weeks. In each session, the therapist and patient complete specific tasks and exercises that are provided in a CBT manual. There are also tasks for the patient to complete between sessions and review later with the therapist. CBT has been used in primary care with preliminary positive results.^13,14 However, the results of a recent RCT conducted in psychiatric settings demonstrated superior efficacy of combination therapy (fluoxetine and CBT) vs CBT alone.¹⁵

IPT for adolescents (IPT-A) is like CBT in that it is time-limited and clinicians are guided by a manual.¹⁶ A course of therapy can last anywhere from 12 to 16 sessions with optional maintenance treatment. The theoretical basis for IPT-A is the observed negative impact of depressive symptoms on interpersonal relationships, and the effect poor relationships have in causing and perpetuating depression. In deciding whether a patient may be suitable for IPT-A, you need to find out whether she would be willing to share her experiences of ongoing relationship conflicts with a therapist or therapeutic group. The relationship difficulties IPT-A is designed to help with arise from 1 of 4 sources: grief, fights with peers or family members (interpersonal disputes), transitions from one social surround to another (role transition), and friendlessness (interpersonal deficits).

IPT-A focuses on grief only when someone of significance to the patient has died. Therapy for teens who quarrel frequently with peers or family members is focused on interpersonal disputes, and this is the most common focus in IPT-A. A focus on role transition is called for when the teen’s social world has undergone a drastic change, such as a when a teen has moved to a new school or broken up with a boyfriend. Finally, therapy for a teen with no significant relationships outside the immediate family focuses on interpersonal deficits. In these cases, the goal of therapy is to increase social contact and help the patient build relationships. If your preliminary assessment identifies your patient’s difficulties as rooted in 1 of these 4 areas, IPT-A may be for her.

Because few family physicians are trained in CBT or IPT-A, most psychotherapy will be provided by mental health professionals. What you can provide is familiarity with available community mental health resources. To get to know the therapists in your community, you may want to reach out to a few of them and ask them the questions in TABLE 2. You may also want to share this list with parents who want to find their own therapist.

TABLE 2
6 questions to ask prospective therapists

Choose an antidepressant, monitor with care

Studies have shown that up to 42% of family physicians in the United States had recently prescribed selective serotonin reuptake inhibitors (SSRIs) for more than 1 adolescent under the age of 18.¹⁷ When the diagnosis of MDD without comorbid conditions is clear and the patient and family are amenable, you may want to prescribe an SSRI.^7,8

If you do, warn the patient and family that antidepressants can sometimes have adverse effects, including a switch from depressive to manic symptoms, signs of behavioral activation including agitation, hostility or restlessness, and suicidal ideation or behavior. If the patient can tolerate the medication without significant adverse effects, you need to prescribe the effective dose for at least 6 to 8 weeks to ensure an adequate trial.⁷

TABLE 3 provides some guidance for prescribing antidepressants for adolescents with depression.⁷ Among the antidepressants, only fluoxetine has been approved by the FDA for children and adolescents with depression. Fluoxetine is also the SSRI with the strongest evidence for efficacy in the adolescent population, as demonstrated in 4 RCTs.¹⁸ Two studies involving fluoxetine for depression have also shown efficacy in children as young as age 7 (range, 7-12 years).¹⁹

Effective dosages for antidepressants are lower for adolescents than for adults. Initiate medications at a low dose and increase in recommended increments every 2 weeks if no significant adverse effects emerge. With the exception of fluoxetine, SSRI medications must be discontinued slowly to minimize the risk of discontinuation effects.

Once treatment begins, you or a member of your staff will need to stay in touch with the patient and family to review their continued adherence to the treatment plan. An FDA black-box warning recommends observing for “clinical worsening, suicidality, and unusual changes in behavior” during initial visits or “at times of dose changes, either increases or decreases.” Develop a regular, frequent monitoring schedule with input from the teen and her (or his) parents to ensure compliance.^7,20

Make sure follow-up appointments are not missed, using flags in patient records or in the clinic schedule. The duration of treatment for teens with depression is yet to be determined through clinical trials. Most guidelines suggest drug therapy be continued at the same dosage for 6 to 12 months after symptoms resolve. Guidelines for the treatment of adolescent depression can be found at www.gladpc.org.

Keeping teenagers on an antidepressant regimen can be challenging, given the side effects, the amount of time it takes before they experience an improvement, and the lengthy duration of treatment. Families that know what to expect and are getting continuing support from you and others are most likely to stay with treatment for the duration.

TABLE 3
A guide to prescribing antidepressants for adolescents

What about Jane?

As the family’s physician, your initial management began with you educating Jane and her parents about mild depressive disorder and its likely course. You set up a series of weekly visits to monitor her symptoms and provide active support. You helped Jane find a peer support group and encouraged her to get back into gymnastics. You taught Jane and her family about the importance of keeping her safe while she is depressed, and they were cooperative about safety-proofing their home and setting up a plan to handle emergencies.

Jane’s depressive symptoms gradually ebbed, and she returned to her previous level of energy and social activity. You warned her and her family about the possibility that the disorder might recur, so they would be prepared.

Correspondence
Amy Cheung, MD, 33 Russell Street, 3rd Floor Tower, Toronto, Ontario, Canada MSS 2S1; [email protected]

Among adolescent women who use contraception, the injectable progestin-only depot-medroxyprogesterone acetate (DMPA, Depo-Provera) is second in popularity only to oral contraceptive pills.¹ A very real drawback with DMPA, however, is a resultant hypoestrogenic state that has been linked to lowered bone mineral density (BMD).

Although several studies have demonstrated a relationship between DMPA use and lower BMD among adults and adolescents (strength of recommendation [SOR]: B), many of them had small sample sizes and methodological flaws. Moreover, most studies have shown that BMD change is reversible after discontinuation of DMPA.

Experts recommend counseling young women about DMPA’s possible effects on bone. But they caution against limiting its use based on the insufficient research to date (SOR: C). Analysts estimate that the availability of DMPA has contributed significantly to decreased adolescent pregnancy rates in the United States over the last 10 years.² This article reports on a systematic review of the literature concerning DMPA and BMD.

Reason for concern

A 1991 study by Cundy et al³ was the first to examine the relationship between DMPA and BMD and found that DMPA users had significantly lower BMD than nonusers. DMPA delivers high doses of progestin and inhibits ovulation in most women. Consequently, DMPA can decrease serum estradiol levels. Low serum estradiol levels have also been linked to lower BMD levels in women who are in menopause or who have eating disorders.

Adolescence is a time of bone building. The chief reason for interest in the association between DMPA and decreased BMD is the potential risk of future osteoporosis and osteoporotic fractures for women using DMPA during adolescence. A mature woman’s BMD at any given time is related to her peak bone mass and subsequent rate of decline. Ninety percent of peak bone mass (the highest level of BMD achieved during one’s lifetime) is determined by age 18 in women.⁴ Between the ages of 18 and 30, women gain the last 10% of their maximum bone density. After age 30, bone resorption outpaces bone formation and women start to lose bone slowly.⁵ This decline continues until menopause, when women experience a more rapid decline in BMD related to sudden withdrawal of estrogen.

Factors that affect peak BMD. Several factors influence the level of peak bone mass a woman will reach—genetics, race, hormonal milieu, and lifestyle factors.^4,5 As for lifestyle, it’s been shown that both anorexia and the female athlete triad cause low estrogen levels, and the resultant loss of BMD may not be recovered.^6,7

Pregnancy, too, is known to be a state of increased bone turnover and resorption,^8,9 and pregnancy during adolescence may also negatively impact BMD. A small 2002 study compared teenagers who had been pregnant with age-matched controls who had not been pregnant, and found that hip bone density in the adolescent mothers was lower by approximately 10%.¹⁰

Use of bone-affecting medications by adolescents is worrisome because they are still building bone at a high rate.

What the literature tells us

Studies of adult women. Studies examining the relationship between DMPA use and BMD have yielded varying results ( TABLE 1 ). Most of them show that using DMPA over a course of 2 years decreases BMD by 5% to 10%. New users have the most significant decreases in BMD, suggesting the decline levels off after 2 years of use (SOR: B).^11-13 However, most early studies were cross-sectional and small, and thus had limited power to determine causality. In addition, these trials were not randomized, and they may have suffered from bias because treatment groups were volunteers.

Three recent prospective studies^12,14,15 found that bone density losses recover after discontinuation of DMPA. Kaunitz¹⁵ followed women for up to 2 years after DMPA discontinuation and found that BMD recovered almost completely (-0.2% at hip and -1.19% at lumbosacral [LS] spine at 2 years). However, only a small number of women were studied post-discontinuation for the full 2 years. Clark¹² followed women for up to 18 months after discontinuation and found that those who had used DMPA still had significantly lower BMD (-4.7% at the hip and -2.9% at the spine).

These studies established that bone density decreases with the initiation of DMPA, but none of them addressed the key issue of whether BMD remains at lower levels long term (ie, decades) and thereby increases future fracture risk.

Studies of adolescents. Fewer studies have examined the relationship between DMPA use and BMD in adolescents ( TABLE 2 ). Most available studies have small sample sizes and methodological limitations (high dropout rates, different age criteria, and significant differences in the comparison groups). In this population, DMPA seems to cause a mild decrease in BMD. There are not enough data to evaluate BMD recovery after DMPA discontinuation. Therefore, it is hard to extrapolate the information about BMD in an adolescent to future fracture risk.

One study examined serum estradiol levels and BMD in 22 adolescents ages 15 to 19 years who were new users of DMPA.¹⁶ Only 6 participants were still using DMPA at 1 year, and 4 used it throughout the 2 years of the study. The trend over 2 years was toward decreasing BMD. Serum estradiol levels were low, but were not correlated with BMD.

Another related study measured bone biochemical markers in 3 groups: 53 adolescents ages 12 to 18 starting DMPA; 165 adolescents starting oral contraceptive pills; and 152 adolescent women not using hormonal contraception.¹⁷ There was no relationship between bone biochemical markers and BMD at either the LS spine or the femoral neck.

TABLE 1
DMPA’s effect on BMD in adult women: What the studies reveal

TABLE 2
DMPA’s effect on BMD in adolescent women: What the studies reveal

Can estrogen therapy counteract DMPA’s effect?

If decreased BMD in women taking DMPA is due to low estradiol levels, it is logical that a trial of estradiol supplementation would mitigate the negative effect. Indeed, a bone-protective effect of supplemental estrogen therapy has been found in studies of young women with amenorrhea secondary to the female athlete triad. Similarly, in postmenopausal women with low serum estradiol levels, supplemental estrogen therapy helps maintain BMD.¹⁸

Two randomized trials have evaluated the use of supplemental estrogen on the adverse effects of DMPA on bone.^19,20 The trial by Cromer et al¹⁹ randomized 123 adolescent women ages 12 to 18 to receive either estrogen supplementation or placebo. They found that the participants in the estrogen group had BMD gains vs BMD losses among those in the placebo group over the 2-year period of the study (2.8% vs -1.8% at the LS spine, and 4.7% vs -5.1% at the femoral neck; P<.001 for both). The limitations to this study include a high dropout rate (53 participants had left by 24 months) and incomplete data collection due to early stoppage of the study.

Cundy et al²⁰ studied 38 adult women who had been on DMPA for at least 2 years and had below-average LS spine BMD. Nineteen women were randomized to receive estrogen supplementation and underwent bone density tests every 6 months; 19 women were also in the comparison placebo group. In the estrogen supplementation group, there was significant attenuation of lowering BMD that increased throughout the trial. However, only 26 subjects completed the 2-year study.

Limit DMPA use to 2 years? Experts disagree

The FDA, in 2004, placed a black box warning on DMPA: “Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk of osteoporotic fracture later in life. Depo-Provera Contraceptive Injection should be used as a long-term birth control method (eg, longer than 2 years) only if other birth-control methods are inadequate.”²¹ In light of these FDA guidelines, many practitioners have started limiting patients’ use of DMPA to 2 years.

The Society of Adolescent Medicine has produced clinical guidelines for treating adolescents who do well on DMPA for contraception (SOR: C, expert opinion).²² The guidelines recommend, among other things, that physicians:

• continue prescribing DMPA to adolescent girls needing contraception, while providing adequate explanation of benefits and potential risks.
• consider ordering a dual-energy x-ray absorptiometry (DEXA) scan to evaluate a patient’s risk.
• keep in mind that duration of use need not be restricted to 2 years.
• recommend 1300 mg calcium plus 400 IU vitamin D and daily exercise to all adolescents receiving DMPA.
• consider estrogen supplementation in those girls with osteopenia (or those at high risk of osteopenia who have not had a DEXA scan) who are otherwise doing well on DMPA and have no contraindication to estrogen.

The World Health Organization similarly published recommendations stating that no restriction should be placed on the use of DMPA due to bone effects (SOR: C, expert opinion).²³

Formulate a reasonable approach

As with any other potentially harmful medication, weigh the risks and benefits of DMPA for the individual patient. It is unclear whether BMD lost during DMPA use completely recovers or even what the time frame for that recovery is. Whether the potential risk for future fracture is increased is unknown, but it certainly is cause for concern. Discuss potential risks with any woman who wants to use DMPA for contraception. Routine calcium and vitamin D supplementation for women using DMPA may be helpful and is unlikely to be harmful.

There is not enough evidence to recommend for or against routine screening of BMD in long-term users of DMPA. Research should evaluate the efficacy of estrogen supplementation in women on prolonged DMPA. Long-term studies could provide more information regarding BMD recovery over several years.

Correspondence
Sarina Schrager, MD, MS, Department of Family Medicine, University of Wisconsin, 777 South Mills Street, Madison, WI 53715; [email protected]

Among adolescent women who use contraception, the injectable progestin-only depot-medroxyprogesterone acetate (DMPA, Depo-Provera) is second in popularity only to oral contraceptive pills.¹ A very real drawback with DMPA, however, is a resultant hypoestrogenic state that has been linked to lowered bone mineral density (BMD).

Although several studies have demonstrated a relationship between DMPA use and lower BMD among adults and adolescents (strength of recommendation [SOR]: B), many of them had small sample sizes and methodological flaws. Moreover, most studies have shown that BMD change is reversible after discontinuation of DMPA.

Experts recommend counseling young women about DMPA’s possible effects on bone. But they caution against limiting its use based on the insufficient research to date (SOR: C). Analysts estimate that the availability of DMPA has contributed significantly to decreased adolescent pregnancy rates in the United States over the last 10 years.² This article reports on a systematic review of the literature concerning DMPA and BMD.

Reason for concern

A 1991 study by Cundy et al³ was the first to examine the relationship between DMPA and BMD and found that DMPA users had significantly lower BMD than nonusers. DMPA delivers high doses of progestin and inhibits ovulation in most women. Consequently, DMPA can decrease serum estradiol levels. Low serum estradiol levels have also been linked to lower BMD levels in women who are in menopause or who have eating disorders.

Adolescence is a time of bone building. The chief reason for interest in the association between DMPA and decreased BMD is the potential risk of future osteoporosis and osteoporotic fractures for women using DMPA during adolescence. A mature woman’s BMD at any given time is related to her peak bone mass and subsequent rate of decline. Ninety percent of peak bone mass (the highest level of BMD achieved during one’s lifetime) is determined by age 18 in women.⁴ Between the ages of 18 and 30, women gain the last 10% of their maximum bone density. After age 30, bone resorption outpaces bone formation and women start to lose bone slowly.⁵ This decline continues until menopause, when women experience a more rapid decline in BMD related to sudden withdrawal of estrogen.

Factors that affect peak BMD. Several factors influence the level of peak bone mass a woman will reach—genetics, race, hormonal milieu, and lifestyle factors.^4,5 As for lifestyle, it’s been shown that both anorexia and the female athlete triad cause low estrogen levels, and the resultant loss of BMD may not be recovered.^6,7

Pregnancy, too, is known to be a state of increased bone turnover and resorption,^8,9 and pregnancy during adolescence may also negatively impact BMD. A small 2002 study compared teenagers who had been pregnant with age-matched controls who had not been pregnant, and found that hip bone density in the adolescent mothers was lower by approximately 10%.¹⁰

Use of bone-affecting medications by adolescents is worrisome because they are still building bone at a high rate.

What the literature tells us

Studies of adult women. Studies examining the relationship between DMPA use and BMD have yielded varying results ( TABLE 1 ). Most of them show that using DMPA over a course of 2 years decreases BMD by 5% to 10%. New users have the most significant decreases in BMD, suggesting the decline levels off after 2 years of use (SOR: B).^11-13 However, most early studies were cross-sectional and small, and thus had limited power to determine causality. In addition, these trials were not randomized, and they may have suffered from bias because treatment groups were volunteers.

Three recent prospective studies^12,14,15 found that bone density losses recover after discontinuation of DMPA. Kaunitz¹⁵ followed women for up to 2 years after DMPA discontinuation and found that BMD recovered almost completely (-0.2% at hip and -1.19% at lumbosacral [LS] spine at 2 years). However, only a small number of women were studied post-discontinuation for the full 2 years. Clark¹² followed women for up to 18 months after discontinuation and found that those who had used DMPA still had significantly lower BMD (-4.7% at the hip and -2.9% at the spine).

These studies established that bone density decreases with the initiation of DMPA, but none of them addressed the key issue of whether BMD remains at lower levels long term (ie, decades) and thereby increases future fracture risk.

Studies of adolescents. Fewer studies have examined the relationship between DMPA use and BMD in adolescents ( TABLE 2 ). Most available studies have small sample sizes and methodological limitations (high dropout rates, different age criteria, and significant differences in the comparison groups). In this population, DMPA seems to cause a mild decrease in BMD. There are not enough data to evaluate BMD recovery after DMPA discontinuation. Therefore, it is hard to extrapolate the information about BMD in an adolescent to future fracture risk.

One study examined serum estradiol levels and BMD in 22 adolescents ages 15 to 19 years who were new users of DMPA.¹⁶ Only 6 participants were still using DMPA at 1 year, and 4 used it throughout the 2 years of the study. The trend over 2 years was toward decreasing BMD. Serum estradiol levels were low, but were not correlated with BMD.

Another related study measured bone biochemical markers in 3 groups: 53 adolescents ages 12 to 18 starting DMPA; 165 adolescents starting oral contraceptive pills; and 152 adolescent women not using hormonal contraception.¹⁷ There was no relationship between bone biochemical markers and BMD at either the LS spine or the femoral neck.

TABLE 1
DMPA’s effect on BMD in adult women: What the studies reveal

TABLE 2
DMPA’s effect on BMD in adolescent women: What the studies reveal

Can estrogen therapy counteract DMPA’s effect?

If decreased BMD in women taking DMPA is due to low estradiol levels, it is logical that a trial of estradiol supplementation would mitigate the negative effect. Indeed, a bone-protective effect of supplemental estrogen therapy has been found in studies of young women with amenorrhea secondary to the female athlete triad. Similarly, in postmenopausal women with low serum estradiol levels, supplemental estrogen therapy helps maintain BMD.¹⁸

Two randomized trials have evaluated the use of supplemental estrogen on the adverse effects of DMPA on bone.^19,20 The trial by Cromer et al¹⁹ randomized 123 adolescent women ages 12 to 18 to receive either estrogen supplementation or placebo. They found that the participants in the estrogen group had BMD gains vs BMD losses among those in the placebo group over the 2-year period of the study (2.8% vs -1.8% at the LS spine, and 4.7% vs -5.1% at the femoral neck; P<.001 for both). The limitations to this study include a high dropout rate (53 participants had left by 24 months) and incomplete data collection due to early stoppage of the study.

Cundy et al²⁰ studied 38 adult women who had been on DMPA for at least 2 years and had below-average LS spine BMD. Nineteen women were randomized to receive estrogen supplementation and underwent bone density tests every 6 months; 19 women were also in the comparison placebo group. In the estrogen supplementation group, there was significant attenuation of lowering BMD that increased throughout the trial. However, only 26 subjects completed the 2-year study.

Limit DMPA use to 2 years? Experts disagree

The FDA, in 2004, placed a black box warning on DMPA: “Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk of osteoporotic fracture later in life. Depo-Provera Contraceptive Injection should be used as a long-term birth control method (eg, longer than 2 years) only if other birth-control methods are inadequate.”²¹ In light of these FDA guidelines, many practitioners have started limiting patients’ use of DMPA to 2 years.

The Society of Adolescent Medicine has produced clinical guidelines for treating adolescents who do well on DMPA for contraception (SOR: C, expert opinion).²² The guidelines recommend, among other things, that physicians:

• continue prescribing DMPA to adolescent girls needing contraception, while providing adequate explanation of benefits and potential risks.
• consider ordering a dual-energy x-ray absorptiometry (DEXA) scan to evaluate a patient’s risk.
• keep in mind that duration of use need not be restricted to 2 years.
• recommend 1300 mg calcium plus 400 IU vitamin D and daily exercise to all adolescents receiving DMPA.
• consider estrogen supplementation in those girls with osteopenia (or those at high risk of osteopenia who have not had a DEXA scan) who are otherwise doing well on DMPA and have no contraindication to estrogen.

The World Health Organization similarly published recommendations stating that no restriction should be placed on the use of DMPA due to bone effects (SOR: C, expert opinion).²³

Formulate a reasonable approach

As with any other potentially harmful medication, weigh the risks and benefits of DMPA for the individual patient. It is unclear whether BMD lost during DMPA use completely recovers or even what the time frame for that recovery is. Whether the potential risk for future fracture is increased is unknown, but it certainly is cause for concern. Discuss potential risks with any woman who wants to use DMPA for contraception. Routine calcium and vitamin D supplementation for women using DMPA may be helpful and is unlikely to be harmful.

There is not enough evidence to recommend for or against routine screening of BMD in long-term users of DMPA. Research should evaluate the efficacy of estrogen supplementation in women on prolonged DMPA. Long-term studies could provide more information regarding BMD recovery over several years.

Correspondence
Sarina Schrager, MD, MS, Department of Family Medicine, University of Wisconsin, 777 South Mills Street, Madison, WI 53715; [email protected]

Among adolescent women who use contraception, the injectable progestin-only depot-medroxyprogesterone acetate (DMPA, Depo-Provera) is second in popularity only to oral contraceptive pills.¹ A very real drawback with DMPA, however, is a resultant hypoestrogenic state that has been linked to lowered bone mineral density (BMD).

Although several studies have demonstrated a relationship between DMPA use and lower BMD among adults and adolescents (strength of recommendation [SOR]: B), many of them had small sample sizes and methodological flaws. Moreover, most studies have shown that BMD change is reversible after discontinuation of DMPA.

Experts recommend counseling young women about DMPA’s possible effects on bone. But they caution against limiting its use based on the insufficient research to date (SOR: C). Analysts estimate that the availability of DMPA has contributed significantly to decreased adolescent pregnancy rates in the United States over the last 10 years.² This article reports on a systematic review of the literature concerning DMPA and BMD.

Reason for concern

A 1991 study by Cundy et al³ was the first to examine the relationship between DMPA and BMD and found that DMPA users had significantly lower BMD than nonusers. DMPA delivers high doses of progestin and inhibits ovulation in most women. Consequently, DMPA can decrease serum estradiol levels. Low serum estradiol levels have also been linked to lower BMD levels in women who are in menopause or who have eating disorders.

Adolescence is a time of bone building. The chief reason for interest in the association between DMPA and decreased BMD is the potential risk of future osteoporosis and osteoporotic fractures for women using DMPA during adolescence. A mature woman’s BMD at any given time is related to her peak bone mass and subsequent rate of decline. Ninety percent of peak bone mass (the highest level of BMD achieved during one’s lifetime) is determined by age 18 in women.⁴ Between the ages of 18 and 30, women gain the last 10% of their maximum bone density. After age 30, bone resorption outpaces bone formation and women start to lose bone slowly.⁵ This decline continues until menopause, when women experience a more rapid decline in BMD related to sudden withdrawal of estrogen.

Factors that affect peak BMD. Several factors influence the level of peak bone mass a woman will reach—genetics, race, hormonal milieu, and lifestyle factors.^4,5 As for lifestyle, it’s been shown that both anorexia and the female athlete triad cause low estrogen levels, and the resultant loss of BMD may not be recovered.^6,7

Pregnancy, too, is known to be a state of increased bone turnover and resorption,^8,9 and pregnancy during adolescence may also negatively impact BMD. A small 2002 study compared teenagers who had been pregnant with age-matched controls who had not been pregnant, and found that hip bone density in the adolescent mothers was lower by approximately 10%.¹⁰

Use of bone-affecting medications by adolescents is worrisome because they are still building bone at a high rate.

What the literature tells us

Studies of adult women. Studies examining the relationship between DMPA use and BMD have yielded varying results ( TABLE 1 ). Most of them show that using DMPA over a course of 2 years decreases BMD by 5% to 10%. New users have the most significant decreases in BMD, suggesting the decline levels off after 2 years of use (SOR: B).^11-13 However, most early studies were cross-sectional and small, and thus had limited power to determine causality. In addition, these trials were not randomized, and they may have suffered from bias because treatment groups were volunteers.

Three recent prospective studies^12,14,15 found that bone density losses recover after discontinuation of DMPA. Kaunitz¹⁵ followed women for up to 2 years after DMPA discontinuation and found that BMD recovered almost completely (-0.2% at hip and -1.19% at lumbosacral [LS] spine at 2 years). However, only a small number of women were studied post-discontinuation for the full 2 years. Clark¹² followed women for up to 18 months after discontinuation and found that those who had used DMPA still had significantly lower BMD (-4.7% at the hip and -2.9% at the spine).

These studies established that bone density decreases with the initiation of DMPA, but none of them addressed the key issue of whether BMD remains at lower levels long term (ie, decades) and thereby increases future fracture risk.

Studies of adolescents. Fewer studies have examined the relationship between DMPA use and BMD in adolescents ( TABLE 2 ). Most available studies have small sample sizes and methodological limitations (high dropout rates, different age criteria, and significant differences in the comparison groups). In this population, DMPA seems to cause a mild decrease in BMD. There are not enough data to evaluate BMD recovery after DMPA discontinuation. Therefore, it is hard to extrapolate the information about BMD in an adolescent to future fracture risk.

One study examined serum estradiol levels and BMD in 22 adolescents ages 15 to 19 years who were new users of DMPA.¹⁶ Only 6 participants were still using DMPA at 1 year, and 4 used it throughout the 2 years of the study. The trend over 2 years was toward decreasing BMD. Serum estradiol levels were low, but were not correlated with BMD.

Another related study measured bone biochemical markers in 3 groups: 53 adolescents ages 12 to 18 starting DMPA; 165 adolescents starting oral contraceptive pills; and 152 adolescent women not using hormonal contraception.¹⁷ There was no relationship between bone biochemical markers and BMD at either the LS spine or the femoral neck.

TABLE 1
DMPA’s effect on BMD in adult women: What the studies reveal

TABLE 2
DMPA’s effect on BMD in adolescent women: What the studies reveal

Can estrogen therapy counteract DMPA’s effect?

If decreased BMD in women taking DMPA is due to low estradiol levels, it is logical that a trial of estradiol supplementation would mitigate the negative effect. Indeed, a bone-protective effect of supplemental estrogen therapy has been found in studies of young women with amenorrhea secondary to the female athlete triad. Similarly, in postmenopausal women with low serum estradiol levels, supplemental estrogen therapy helps maintain BMD.¹⁸

Two randomized trials have evaluated the use of supplemental estrogen on the adverse effects of DMPA on bone.^19,20 The trial by Cromer et al¹⁹ randomized 123 adolescent women ages 12 to 18 to receive either estrogen supplementation or placebo. They found that the participants in the estrogen group had BMD gains vs BMD losses among those in the placebo group over the 2-year period of the study (2.8% vs -1.8% at the LS spine, and 4.7% vs -5.1% at the femoral neck; P<.001 for both). The limitations to this study include a high dropout rate (53 participants had left by 24 months) and incomplete data collection due to early stoppage of the study.

Cundy et al²⁰ studied 38 adult women who had been on DMPA for at least 2 years and had below-average LS spine BMD. Nineteen women were randomized to receive estrogen supplementation and underwent bone density tests every 6 months; 19 women were also in the comparison placebo group. In the estrogen supplementation group, there was significant attenuation of lowering BMD that increased throughout the trial. However, only 26 subjects completed the 2-year study.

Limit DMPA use to 2 years? Experts disagree

The FDA, in 2004, placed a black box warning on DMPA: “Women who use Depo-Provera Contraceptive Injection may lose significant bone mineral density. Bone loss is greater with increasing duration of use and may not be completely reversible. It is unknown if use of Depo-Provera Contraceptive Injection during adolescence or early adulthood, a critical period of bone accretion, will reduce peak bone mass and increase the risk of osteoporotic fracture later in life. Depo-Provera Contraceptive Injection should be used as a long-term birth control method (eg, longer than 2 years) only if other birth-control methods are inadequate.”²¹ In light of these FDA guidelines, many practitioners have started limiting patients’ use of DMPA to 2 years.

The Society of Adolescent Medicine has produced clinical guidelines for treating adolescents who do well on DMPA for contraception (SOR: C, expert opinion).²² The guidelines recommend, among other things, that physicians:

• continue prescribing DMPA to adolescent girls needing contraception, while providing adequate explanation of benefits and potential risks.
• consider ordering a dual-energy x-ray absorptiometry (DEXA) scan to evaluate a patient’s risk.
• keep in mind that duration of use need not be restricted to 2 years.
• recommend 1300 mg calcium plus 400 IU vitamin D and daily exercise to all adolescents receiving DMPA.
• consider estrogen supplementation in those girls with osteopenia (or those at high risk of osteopenia who have not had a DEXA scan) who are otherwise doing well on DMPA and have no contraindication to estrogen.

The World Health Organization similarly published recommendations stating that no restriction should be placed on the use of DMPA due to bone effects (SOR: C, expert opinion).²³

Formulate a reasonable approach

As with any other potentially harmful medication, weigh the risks and benefits of DMPA for the individual patient. It is unclear whether BMD lost during DMPA use completely recovers or even what the time frame for that recovery is. Whether the potential risk for future fracture is increased is unknown, but it certainly is cause for concern. Discuss potential risks with any woman who wants to use DMPA for contraception. Routine calcium and vitamin D supplementation for women using DMPA may be helpful and is unlikely to be harmful.

There is not enough evidence to recommend for or against routine screening of BMD in long-term users of DMPA. Research should evaluate the efficacy of estrogen supplementation in women on prolonged DMPA. Long-term studies could provide more information regarding BMD recovery over several years.

Correspondence
Sarina Schrager, MD, MS, Department of Family Medicine, University of Wisconsin, 777 South Mills Street, Madison, WI 53715; [email protected]

The youngest Americans—those born in the year 2000 or thereafter—have more than a 1 in 3 lifetime risk of developing diabetes, according to the Centers for Disease Control and Prevention.¹ That estimate, coupled with the fact that more than 2 out of 3 adults and 1 in 6 children between the ages of 2 and 19 years are overweight,² would seem to indicate a need for widespread diabetes screening. But limited health care resources, a lack of evidence that mass screening improves outcomes, and differences among leading medical associations about whom and when to screen argue against it.

At the same time, widespread obesity is making the presentation of hyperglycemia more complex and the forms of diabetes harder to classify. Many cases don’t follow the classic patterns, in which type 1 (formerly called juvenile diabetes) virtually always emerges in childhood and type 2 (previously known as adult-onset diabetes) is strictly an adult disease. Our evolving understanding of diabetes has led researchers to focus on prediabetes (defined as impaired fasting glucose, impaired glucose tolerance, or both) and latent autoimmune diabetes in adults (LADA), a recently reported type 1 variant that some have labeled type 1.5.³

In the face of growing complexity, the US Preventive Services Task Force (USPSTF) last year upgraded its recommendation for screening for type 2 diabetes, and researchers have developed new risk calculation tools. We’ve taken a look at the changing clinical landscape and sorted through the latest evidence to help you make sense of the latest risk and diagnostic developments in diabetes care.

Screening for type 2: A look at guidelines

Type 2 diabetes accounts for approximately 90% of the cases you’ll see.^1,4,5 The American Diabetes Association (ADA) calls for routine screening, starting at 45 years of age and continuing every 3 years thereafter in the absence of risk. But for those who are overweight or obese and have 1 or more additional risk factors, screening is recommended at any age.⁵ In addition to a body mass index (BMI) ≥25, risks include physical inactivity, a first-degree relative with type 2 diabetes, blood pressure >135/80 mm Hg (or controlled with an antihypertensive), high-density lipoproteins (HDL) <35 mg/dL, triglycerides >250 mg/dL, polycystic ovary syndrome, impaired glucose tolerance or impaired fasting glucose, and acanthosis nigricans, a pigmented thickening of the skin folds of the neck (TABLE).^6,7 Patients with the metabolic syndrome—abdominal obesity (defined as a waist circumference of >40” in men and >35” in women) and ≥2 of the following: raised triglyceride levels, elevated blood pressure, elevated fasting plasma glucose, and reduced HDL cholesterol—are at especially high risk of both cardiovascular disease and type 2 diabetes.⁸

The ADA screening recommendations, however, are not based on prospective outcome studies, nor are they widely followed. Until recently, the USPSTF only recommended screening adults with hypertension and hyperlipidemia.

In 2008, after an assessment of new findings and research updates, the USPSTF revised its recommendation: The task force now calls for screening asymptomatic adults with sustained blood pressure >135/80 mm Hg—regardless of lipid profile.⁷ For patients with diabetes and hypertension, the USPSTF concluded, evidence shows that early intervention—including lowering blood pressure below conventional targets—can prevent long-term adverse outcomes of diabetes and reduce the risk of cardiovascular events.

Although mass screening remains controversial, regular assessment of risk factors and targeting individuals with established risk is clearly indicated (PATIENT HANDOUT). The importance of early detection was highlighted by the United Kingdom Prospective Diabetes Study, in which approximately half of the patients with newly diagnosed type 2 diabetes already had evidence of complications.⁹

TABLE
Type 1, type 2, and gestational diabetes: Diagnostic clues

Validated risk calculators can boost detection rates

In an attempt to improve detection rates of type 2 diabetes and prediabetes, researchers in both the United States and the United Kingdom recently developed easy-to-use risk calculation tools. The Diabetes Risk Calculator (available at http://www.diabetes.org/food-nutrition-lifestyle/lifestyle-prevention/risk-test.jsp), published in 2008, was validated with findings from the Third National Health and Nutrition Survey.¹⁰ The calculator uses answers to questions about age, waist circumference, history of gestational diabetes mellitus (GDM), height, race/ethnicity, hypertension, family history, and exercise to determine whether an individual is at high risk for undetected diabetes. The tool has a low positive predictive value (14%), but a negative predictive value >99%.¹⁰

The QDScore Diabetes Risk Calculator (www.qdscore.org), another new tool, is designed to estimate an individual’s 10-year risk of developing type 2 diabetes.¹¹ The program, which calculates risk based on answers to questions about family history of diabetes, patient history of cardiovascular disease, smoking, treatment for hypertension, BMI, ethnicity, and steroid use, was validated with data collected from 2.5 million patients in practices throughout England and Wales. The screening tool showed a high degree of discrimination in reflecting differences in disease prevalence related to ethnic and socioeconomic risk factors.¹¹

Pinning down a type 2 (or prediabetes) diagnosis

The ADA, American Association of Clinical Endocrinologists (AACE), USPSTF, and World Health Organization/International Diabetes Federation agree on the diagnostic criteria for type 2 diabetes: a fasting glucose >126 mg/dL, a random plasma glucose ≥200 mg/dL (that must be confirmed on a subsequent day), or both.^5,7,12,13 Patient history, risk factors, and additional laboratory tests can help clinicians distinguish between type 1 and type 2 diabetes.

An oral glucose tolerance test (OGTT) is also an option for diagnosis, but time and scheduling difficulties limit the routine use of this test in primary care. Hemoglobin A1c is not recommended as a diagnostic test because of a lack of standardization.¹

Prediabetes and type 2 risk. One in 4 (25.9%) US adults 20 years of age or older and more than 1 in 3 (35.9%) of those 60 years of age or older have prediabetes,¹⁴ defined as impaired fasting glucose (100-125 mg/dL), impaired glucose tolerance (2-hour glucose test results of 140-199 mg/dL), or both. Prediabetes increases the risk of developing type 2 diabetes by an estimated 30% over a 4-year period,¹⁵ and 70% over 30 years,¹⁶ although lifestyle interventions can substantially lower the risk. In a recently released consensus statement, an AACE task force noted that in addition to the increased risk of type 2 diabetes, patients with prediabetes face a greater risk of macrovascular complications.¹⁷

Type 2 in kids can be mistaken for type 1

As childhood obesity has surged, type 2 diabetes has been diagnosed at an increasingly early age—even in children younger than 10 years.¹⁸ Minority youth, primarily African Americans, Hispanics, and Asians/Pacific Islanders, are at increased risk.¹⁴ Symptoms can be insidious in children and adolescents and easily missed or mistaken for type 1 diabetes, in part because type 2 diabetes is still relatively rare in this age group.¹⁹

Preteens at risk. In a recent study of BMI and metabolic syndrome risk factors in 8- to 14-year-olds, however, researchers concluded that children who are overweight in early adolescence may be at risk for type 2 diabetes as well as cardiovascular disease before they reach their teens.²⁰ There is evidence of a genetic predisposition for type 2 diabetes and defects of β-cell function,^5,21 and family history, in addition to weight, is an important consideration in identifying type 2 diabetes in young patients.

Although young adults with type 1 and type 2 diabetes can present with similar symptoms, there may be certain clues to a type 2 diagnosis. Acanthosis nigricans, which is related to insulin resistance and occurs most frequently in obese adolescents, points to a type 2 diagnosis. Increased insulin and C-peptide levels are indicators of type 2 diabetes. Low levels are not necessarily an indication of type 1, however, because patients with type 2 diabetes may have low levels of insulin and C-peptide because of glucose toxicity and lipotoxicity at the time of diagnosis.²² Treatment with insulin may be necessary until glucose toxicity resolves.

Type 1 diabetes: Beyond childhood

Approximately 5% to 10% of patients with diabetes have type 1, which is defined as idiopathic or cellular immune-mediated autoimmune β-cell destruction.⁵ The rate of destruction is variable—it generally progresses more rapidly in infants and children than in adults. Some people with type 1 diabetes retain residual β-cell function, but have little or no insulin secretion; this manifests as a low or undetectable level of serum C-peptide.

Most cases of type 1 diabetes are diagnosed in patients younger than 18 years. But type 1 diabetes is increasingly recognized as a disorder that also develops in early adulthood, usually before the age of 40.

Arriving at a type 1 diagnosis

Patients with type 1 diabetes often present with modest hyperglycemia, but may rapidly progress to severe hyperglycemia and diabetic ketoacidosis (DKA) when infection or other physical stressors occur.

While screening for autoantibodies in asymptomatic individuals is not recommended,⁵ patients with blood glucose levels ≥200 mg/dL and symptoms of polydipsia, polyuria, and polyphagia who do not meet the profile for type 2 diabetes may be candidates for additional laboratory work. Approximately 85% to 90% of patients with type 1 diabetes will have antibodies to islet cells or glutamic acid decarboxylase (GAD).^5,23

Even without antibody testing, there are distinguishing characteristics that help support a type 1 diagnosis. As a general rule, individuals who develop type 1 diabetes—especially children—are not obese, although patients usually gain weight over time. In addition, many patients with type 1 diabetes have an auto-immune disease, such as celiac or Graves’ disease, hypothyroidism, adrenal anemia, or pernicious anemia; and a first-degree relative with type 1 diabetes. DKA, with acute symptoms of polydipsia and/or polyuria and recent, unintentional weight loss, is suggestive of—but not definitive for—type 1 diabetes.

A recently validated type 1 risk calculator may be particularly useful for screening patients who have a sibling, parent, or child with type 1 diabetes. Using age, BMI, C-peptide concentration, and OGTT results, the algorithm was highly predictive of type 1 diabetes in family members of patients who tested positive for islet cell antibodies.²⁴

Patient doesn’t “fit” type 1 or 2? Consider LADA

LADA, a gradual, progressive form of type 1 diabetes, can be difficult to identify. Circulating GAD or islet cell antibodies are present, but patients don’t have an absolute need for insulin at the time of diagnosis. Thus, they’re often thought to have type 2 diabetes.²⁵ Individuals with LADA show no signs of insulin resistance, however, and over time, β cells decline and insulin usually becomes necessary.

There are no universal recommendations for testing for LADA. Rather, the diagnosis should be considered in those who don’t fit the classic profile for type 1 or type 2 diabetes,²⁶ but have some of the following features:

• age <50 years
• acute symptoms of polydipsia, polyuria, and/or unintentional weight loss
• BMI <25
• a personal history of autoimmune disease
• a family history of autoimmune disease.²⁷

A prospective analysis found that the majority of LADA patients had at least 2 of these distinguishing characteristics.²⁸ Other recent research found heterogeneity among patients with LADA. Noting that not all patients with LADA become insulin-dependent, researchers concluded that the need for insulin is linked to the degree of autoimmunity and β-cell failure.²⁹

When GDM complicates prenatal care

Any degree of carbohydrate intolerance that is first recognized during pregnancy is classified as GDM, whether or not the condition resolves after delivery. A GDM diagnosis does not preclude the possibility of undiagnosed type 2 diabetes or prediabetes, or (rarely) type 1 diabetes.

Approximately 7% of all pregnancies in the United States are complicated by GDM, totaling more than 200,000 cases annually.⁵ The rate of GDM is in direct proportion to the prevalence of type 2 diabetes in the population in question, and ranges from 1% to 14%. GDM is the diagnosis in nearly 90% of pregnancies complicated by diabetes.⁵

The GDM screening controversy

Screening for GDM—whether it should be done universally or selectively on the basis of risk factors—is highly controversial. The USPSTF maintains that there is insufficient evidence to recommend for or against screening women with no history of GDM. The American College of Obstetricians and Gynecologists (ACOG)³⁰ and ADA⁵ recommend selective screening based on patient history, clinical presentation, and, possibly, prior impaired glucose test results or other abnormal laboratory values. AACE calls for universal screening of pregnant women, starting at 20 weeks for high-risk individuals and between 24 and 28 weeks for those at low risk.¹²

Identifying patients at risk. Maternal age (>25 years), obesity (BMI ≥30), prior GDM or delivery of a large-forgestational-age infant, belonging to a high-risk ethnic group, glycosuria, history of glucose resistance or glucose tolerance, and a first-degree relative with diabetes (TABLE) are risk factors for GDM. Women at high risk—those who meet all or most of these criteria—should undergo early screening: at the first prenatal visit, according to ACOG;³⁰ upon confirmation of pregnancy (ADA);⁵ at 20 weeks’ gestation (AACE);¹² or between 24 and 28 weeks’ gestation (USPSTF).⁷ ADA and ACOG recommend a 2-stage approach, starting with a 50-g 1-hour OGTT and following up with a 100-g 3-hour OGTT if the first test results are not definitive.^5,30 Testing for patients at average risk—which includes any pregnant woman with even a single risk factor, such as being older than 25 years—should be done between 24 and 28 weeks’ gestation, according to ACOG and ADA; testing is not required for women who are <25 years, have a normal body weight, and no other risk factors.

GDM screening in primary care. Because most women fit the criteria for average or high risk,³¹ family physicians may find universal screening to be more practical than individual risk assessment. Universal screening is associated with favorable outcomes,³² but screening limited to those at high and average risk also has evidence to support it. In a study of 25,118 deliveries, only 4% of women with GDM were missed by the exclusion of low-risk patients.³³

In the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, researchers tracked 25,505 women from 9 countries and found a continuous relationship between the risk of macrosomia and the rise in maternal glucose levels.³⁴ The impact on the developing fetus of varying degrees of glucose was studied after a 75-g 2-hour OGTT. The risk of macrosomia increased with fasting blood glucose >75 mg/dL, 1-hour glucose levels >105 mg/dL, and 2-hour glucose concentration >90 mg/dL.³⁵ The most compelling results for adverse effects were associated with fasting glucose levels, rather than glucose tolerance tests.

2 abnormal results needed for a GDM diagnosis

In the absence of unequivocal hyperglycemia, there are 2 diagnostic standards for GDM: The Carpenter-Coustan Conversion and the National Diabetes Data Group Conversion. The Carpenter-Coustan Conversion uses lower glucose values for fasting (≥95 mg/dL) and subsequent 1-, 2-, and 3-hour levels (≥180, 155, and 140 mg/dL, respectively) and is more widely used. But expert opinion also supports the National Diabetes Data Group Conversion criteria (fasting plasma glucose, ≥105 mg/dL; ≥190, 165, and 145 mg/dL for 1-, 2-, and 3-hour OGTT, respectively), and there are no data from clinical trials to prove the superiority of either standard.³⁰

Both sets of standards require 2 or more thresholds to be met or exceeded for a GDM diagnosis. Women with only 1 abnormal value should be monitored carefully, however, as they, too, may be at increased risk for macrosomia and other morbidities.³⁰

Postpartum follow-up. Obtain a fasting glucose reading or perform an OGTT around the time of the postpartum checkup for any patient who was diagnosed with GDM. ACOG recommends using an OGTT to more accurately diagnose type 2 diabetes or prediabetes in these patients, who are at significantly elevated risk.³⁰

Acknowledgement

The authors wish to thank Carol Hildebrandt, a research assistant with no potential conflict of interest, for her help with this manuscript.

Correspondence
Julienne K. Kirk, PharmD, CDE, Department of Family and Community Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1084; [email protected]

The youngest Americans—those born in the year 2000 or thereafter—have more than a 1 in 3 lifetime risk of developing diabetes, according to the Centers for Disease Control and Prevention.¹ That estimate, coupled with the fact that more than 2 out of 3 adults and 1 in 6 children between the ages of 2 and 19 years are overweight,² would seem to indicate a need for widespread diabetes screening. But limited health care resources, a lack of evidence that mass screening improves outcomes, and differences among leading medical associations about whom and when to screen argue against it.

At the same time, widespread obesity is making the presentation of hyperglycemia more complex and the forms of diabetes harder to classify. Many cases don’t follow the classic patterns, in which type 1 (formerly called juvenile diabetes) virtually always emerges in childhood and type 2 (previously known as adult-onset diabetes) is strictly an adult disease. Our evolving understanding of diabetes has led researchers to focus on prediabetes (defined as impaired fasting glucose, impaired glucose tolerance, or both) and latent autoimmune diabetes in adults (LADA), a recently reported type 1 variant that some have labeled type 1.5.³

In the face of growing complexity, the US Preventive Services Task Force (USPSTF) last year upgraded its recommendation for screening for type 2 diabetes, and researchers have developed new risk calculation tools. We’ve taken a look at the changing clinical landscape and sorted through the latest evidence to help you make sense of the latest risk and diagnostic developments in diabetes care.

Screening for type 2: A look at guidelines

Type 2 diabetes accounts for approximately 90% of the cases you’ll see.^1,4,5 The American Diabetes Association (ADA) calls for routine screening, starting at 45 years of age and continuing every 3 years thereafter in the absence of risk. But for those who are overweight or obese and have 1 or more additional risk factors, screening is recommended at any age.⁵ In addition to a body mass index (BMI) ≥25, risks include physical inactivity, a first-degree relative with type 2 diabetes, blood pressure >135/80 mm Hg (or controlled with an antihypertensive), high-density lipoproteins (HDL) <35 mg/dL, triglycerides >250 mg/dL, polycystic ovary syndrome, impaired glucose tolerance or impaired fasting glucose, and acanthosis nigricans, a pigmented thickening of the skin folds of the neck (TABLE).^6,7 Patients with the metabolic syndrome—abdominal obesity (defined as a waist circumference of >40” in men and >35” in women) and ≥2 of the following: raised triglyceride levels, elevated blood pressure, elevated fasting plasma glucose, and reduced HDL cholesterol—are at especially high risk of both cardiovascular disease and type 2 diabetes.⁸

The ADA screening recommendations, however, are not based on prospective outcome studies, nor are they widely followed. Until recently, the USPSTF only recommended screening adults with hypertension and hyperlipidemia.

In 2008, after an assessment of new findings and research updates, the USPSTF revised its recommendation: The task force now calls for screening asymptomatic adults with sustained blood pressure >135/80 mm Hg—regardless of lipid profile.⁷ For patients with diabetes and hypertension, the USPSTF concluded, evidence shows that early intervention—including lowering blood pressure below conventional targets—can prevent long-term adverse outcomes of diabetes and reduce the risk of cardiovascular events.

Although mass screening remains controversial, regular assessment of risk factors and targeting individuals with established risk is clearly indicated (PATIENT HANDOUT). The importance of early detection was highlighted by the United Kingdom Prospective Diabetes Study, in which approximately half of the patients with newly diagnosed type 2 diabetes already had evidence of complications.⁹

TABLE
Type 1, type 2, and gestational diabetes: Diagnostic clues

Validated risk calculators can boost detection rates

In an attempt to improve detection rates of type 2 diabetes and prediabetes, researchers in both the United States and the United Kingdom recently developed easy-to-use risk calculation tools. The Diabetes Risk Calculator (available at http://www.diabetes.org/food-nutrition-lifestyle/lifestyle-prevention/risk-test.jsp), published in 2008, was validated with findings from the Third National Health and Nutrition Survey.¹⁰ The calculator uses answers to questions about age, waist circumference, history of gestational diabetes mellitus (GDM), height, race/ethnicity, hypertension, family history, and exercise to determine whether an individual is at high risk for undetected diabetes. The tool has a low positive predictive value (14%), but a negative predictive value >99%.¹⁰

The QDScore Diabetes Risk Calculator (www.qdscore.org), another new tool, is designed to estimate an individual’s 10-year risk of developing type 2 diabetes.¹¹ The program, which calculates risk based on answers to questions about family history of diabetes, patient history of cardiovascular disease, smoking, treatment for hypertension, BMI, ethnicity, and steroid use, was validated with data collected from 2.5 million patients in practices throughout England and Wales. The screening tool showed a high degree of discrimination in reflecting differences in disease prevalence related to ethnic and socioeconomic risk factors.¹¹

Pinning down a type 2 (or prediabetes) diagnosis

The ADA, American Association of Clinical Endocrinologists (AACE), USPSTF, and World Health Organization/International Diabetes Federation agree on the diagnostic criteria for type 2 diabetes: a fasting glucose >126 mg/dL, a random plasma glucose ≥200 mg/dL (that must be confirmed on a subsequent day), or both.^5,7,12,13 Patient history, risk factors, and additional laboratory tests can help clinicians distinguish between type 1 and type 2 diabetes.

An oral glucose tolerance test (OGTT) is also an option for diagnosis, but time and scheduling difficulties limit the routine use of this test in primary care. Hemoglobin A1c is not recommended as a diagnostic test because of a lack of standardization.¹

Prediabetes and type 2 risk. One in 4 (25.9%) US adults 20 years of age or older and more than 1 in 3 (35.9%) of those 60 years of age or older have prediabetes,¹⁴ defined as impaired fasting glucose (100-125 mg/dL), impaired glucose tolerance (2-hour glucose test results of 140-199 mg/dL), or both. Prediabetes increases the risk of developing type 2 diabetes by an estimated 30% over a 4-year period,¹⁵ and 70% over 30 years,¹⁶ although lifestyle interventions can substantially lower the risk. In a recently released consensus statement, an AACE task force noted that in addition to the increased risk of type 2 diabetes, patients with prediabetes face a greater risk of macrovascular complications.¹⁷

Type 2 in kids can be mistaken for type 1

As childhood obesity has surged, type 2 diabetes has been diagnosed at an increasingly early age—even in children younger than 10 years.¹⁸ Minority youth, primarily African Americans, Hispanics, and Asians/Pacific Islanders, are at increased risk.¹⁴ Symptoms can be insidious in children and adolescents and easily missed or mistaken for type 1 diabetes, in part because type 2 diabetes is still relatively rare in this age group.¹⁹

Preteens at risk. In a recent study of BMI and metabolic syndrome risk factors in 8- to 14-year-olds, however, researchers concluded that children who are overweight in early adolescence may be at risk for type 2 diabetes as well as cardiovascular disease before they reach their teens.²⁰ There is evidence of a genetic predisposition for type 2 diabetes and defects of β-cell function,^5,21 and family history, in addition to weight, is an important consideration in identifying type 2 diabetes in young patients.

Although young adults with type 1 and type 2 diabetes can present with similar symptoms, there may be certain clues to a type 2 diagnosis. Acanthosis nigricans, which is related to insulin resistance and occurs most frequently in obese adolescents, points to a type 2 diagnosis. Increased insulin and C-peptide levels are indicators of type 2 diabetes. Low levels are not necessarily an indication of type 1, however, because patients with type 2 diabetes may have low levels of insulin and C-peptide because of glucose toxicity and lipotoxicity at the time of diagnosis.²² Treatment with insulin may be necessary until glucose toxicity resolves.

Type 1 diabetes: Beyond childhood

Approximately 5% to 10% of patients with diabetes have type 1, which is defined as idiopathic or cellular immune-mediated autoimmune β-cell destruction.⁵ The rate of destruction is variable—it generally progresses more rapidly in infants and children than in adults. Some people with type 1 diabetes retain residual β-cell function, but have little or no insulin secretion; this manifests as a low or undetectable level of serum C-peptide.

Most cases of type 1 diabetes are diagnosed in patients younger than 18 years. But type 1 diabetes is increasingly recognized as a disorder that also develops in early adulthood, usually before the age of 40.

Arriving at a type 1 diagnosis

Patients with type 1 diabetes often present with modest hyperglycemia, but may rapidly progress to severe hyperglycemia and diabetic ketoacidosis (DKA) when infection or other physical stressors occur.

While screening for autoantibodies in asymptomatic individuals is not recommended,⁵ patients with blood glucose levels ≥200 mg/dL and symptoms of polydipsia, polyuria, and polyphagia who do not meet the profile for type 2 diabetes may be candidates for additional laboratory work. Approximately 85% to 90% of patients with type 1 diabetes will have antibodies to islet cells or glutamic acid decarboxylase (GAD).^5,23

Even without antibody testing, there are distinguishing characteristics that help support a type 1 diagnosis. As a general rule, individuals who develop type 1 diabetes—especially children—are not obese, although patients usually gain weight over time. In addition, many patients with type 1 diabetes have an auto-immune disease, such as celiac or Graves’ disease, hypothyroidism, adrenal anemia, or pernicious anemia; and a first-degree relative with type 1 diabetes. DKA, with acute symptoms of polydipsia and/or polyuria and recent, unintentional weight loss, is suggestive of—but not definitive for—type 1 diabetes.

A recently validated type 1 risk calculator may be particularly useful for screening patients who have a sibling, parent, or child with type 1 diabetes. Using age, BMI, C-peptide concentration, and OGTT results, the algorithm was highly predictive of type 1 diabetes in family members of patients who tested positive for islet cell antibodies.²⁴

Patient doesn’t “fit” type 1 or 2? Consider LADA

LADA, a gradual, progressive form of type 1 diabetes, can be difficult to identify. Circulating GAD or islet cell antibodies are present, but patients don’t have an absolute need for insulin at the time of diagnosis. Thus, they’re often thought to have type 2 diabetes.²⁵ Individuals with LADA show no signs of insulin resistance, however, and over time, β cells decline and insulin usually becomes necessary.

There are no universal recommendations for testing for LADA. Rather, the diagnosis should be considered in those who don’t fit the classic profile for type 1 or type 2 diabetes,²⁶ but have some of the following features:

• age <50 years
• acute symptoms of polydipsia, polyuria, and/or unintentional weight loss
• BMI <25
• a personal history of autoimmune disease
• a family history of autoimmune disease.²⁷

A prospective analysis found that the majority of LADA patients had at least 2 of these distinguishing characteristics.²⁸ Other recent research found heterogeneity among patients with LADA. Noting that not all patients with LADA become insulin-dependent, researchers concluded that the need for insulin is linked to the degree of autoimmunity and β-cell failure.²⁹

When GDM complicates prenatal care

Any degree of carbohydrate intolerance that is first recognized during pregnancy is classified as GDM, whether or not the condition resolves after delivery. A GDM diagnosis does not preclude the possibility of undiagnosed type 2 diabetes or prediabetes, or (rarely) type 1 diabetes.

Approximately 7% of all pregnancies in the United States are complicated by GDM, totaling more than 200,000 cases annually.⁵ The rate of GDM is in direct proportion to the prevalence of type 2 diabetes in the population in question, and ranges from 1% to 14%. GDM is the diagnosis in nearly 90% of pregnancies complicated by diabetes.⁵

The GDM screening controversy

Screening for GDM—whether it should be done universally or selectively on the basis of risk factors—is highly controversial. The USPSTF maintains that there is insufficient evidence to recommend for or against screening women with no history of GDM. The American College of Obstetricians and Gynecologists (ACOG)³⁰ and ADA⁵ recommend selective screening based on patient history, clinical presentation, and, possibly, prior impaired glucose test results or other abnormal laboratory values. AACE calls for universal screening of pregnant women, starting at 20 weeks for high-risk individuals and between 24 and 28 weeks for those at low risk.¹²

Identifying patients at risk. Maternal age (>25 years), obesity (BMI ≥30), prior GDM or delivery of a large-forgestational-age infant, belonging to a high-risk ethnic group, glycosuria, history of glucose resistance or glucose tolerance, and a first-degree relative with diabetes (TABLE) are risk factors for GDM. Women at high risk—those who meet all or most of these criteria—should undergo early screening: at the first prenatal visit, according to ACOG;³⁰ upon confirmation of pregnancy (ADA);⁵ at 20 weeks’ gestation (AACE);¹² or between 24 and 28 weeks’ gestation (USPSTF).⁷ ADA and ACOG recommend a 2-stage approach, starting with a 50-g 1-hour OGTT and following up with a 100-g 3-hour OGTT if the first test results are not definitive.^5,30 Testing for patients at average risk—which includes any pregnant woman with even a single risk factor, such as being older than 25 years—should be done between 24 and 28 weeks’ gestation, according to ACOG and ADA; testing is not required for women who are <25 years, have a normal body weight, and no other risk factors.

GDM screening in primary care. Because most women fit the criteria for average or high risk,³¹ family physicians may find universal screening to be more practical than individual risk assessment. Universal screening is associated with favorable outcomes,³² but screening limited to those at high and average risk also has evidence to support it. In a study of 25,118 deliveries, only 4% of women with GDM were missed by the exclusion of low-risk patients.³³

In the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, researchers tracked 25,505 women from 9 countries and found a continuous relationship between the risk of macrosomia and the rise in maternal glucose levels.³⁴ The impact on the developing fetus of varying degrees of glucose was studied after a 75-g 2-hour OGTT. The risk of macrosomia increased with fasting blood glucose >75 mg/dL, 1-hour glucose levels >105 mg/dL, and 2-hour glucose concentration >90 mg/dL.³⁵ The most compelling results for adverse effects were associated with fasting glucose levels, rather than glucose tolerance tests.

2 abnormal results needed for a GDM diagnosis

In the absence of unequivocal hyperglycemia, there are 2 diagnostic standards for GDM: The Carpenter-Coustan Conversion and the National Diabetes Data Group Conversion. The Carpenter-Coustan Conversion uses lower glucose values for fasting (≥95 mg/dL) and subsequent 1-, 2-, and 3-hour levels (≥180, 155, and 140 mg/dL, respectively) and is more widely used. But expert opinion also supports the National Diabetes Data Group Conversion criteria (fasting plasma glucose, ≥105 mg/dL; ≥190, 165, and 145 mg/dL for 1-, 2-, and 3-hour OGTT, respectively), and there are no data from clinical trials to prove the superiority of either standard.³⁰

Both sets of standards require 2 or more thresholds to be met or exceeded for a GDM diagnosis. Women with only 1 abnormal value should be monitored carefully, however, as they, too, may be at increased risk for macrosomia and other morbidities.³⁰

Postpartum follow-up. Obtain a fasting glucose reading or perform an OGTT around the time of the postpartum checkup for any patient who was diagnosed with GDM. ACOG recommends using an OGTT to more accurately diagnose type 2 diabetes or prediabetes in these patients, who are at significantly elevated risk.³⁰

Acknowledgement

The authors wish to thank Carol Hildebrandt, a research assistant with no potential conflict of interest, for her help with this manuscript.

Correspondence
Julienne K. Kirk, PharmD, CDE, Department of Family and Community Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1084; [email protected]

The youngest Americans—those born in the year 2000 or thereafter—have more than a 1 in 3 lifetime risk of developing diabetes, according to the Centers for Disease Control and Prevention.¹ That estimate, coupled with the fact that more than 2 out of 3 adults and 1 in 6 children between the ages of 2 and 19 years are overweight,² would seem to indicate a need for widespread diabetes screening. But limited health care resources, a lack of evidence that mass screening improves outcomes, and differences among leading medical associations about whom and when to screen argue against it.

At the same time, widespread obesity is making the presentation of hyperglycemia more complex and the forms of diabetes harder to classify. Many cases don’t follow the classic patterns, in which type 1 (formerly called juvenile diabetes) virtually always emerges in childhood and type 2 (previously known as adult-onset diabetes) is strictly an adult disease. Our evolving understanding of diabetes has led researchers to focus on prediabetes (defined as impaired fasting glucose, impaired glucose tolerance, or both) and latent autoimmune diabetes in adults (LADA), a recently reported type 1 variant that some have labeled type 1.5.³

In the face of growing complexity, the US Preventive Services Task Force (USPSTF) last year upgraded its recommendation for screening for type 2 diabetes, and researchers have developed new risk calculation tools. We’ve taken a look at the changing clinical landscape and sorted through the latest evidence to help you make sense of the latest risk and diagnostic developments in diabetes care.

Screening for type 2: A look at guidelines

Type 2 diabetes accounts for approximately 90% of the cases you’ll see.^1,4,5 The American Diabetes Association (ADA) calls for routine screening, starting at 45 years of age and continuing every 3 years thereafter in the absence of risk. But for those who are overweight or obese and have 1 or more additional risk factors, screening is recommended at any age.⁵ In addition to a body mass index (BMI) ≥25, risks include physical inactivity, a first-degree relative with type 2 diabetes, blood pressure >135/80 mm Hg (or controlled with an antihypertensive), high-density lipoproteins (HDL) <35 mg/dL, triglycerides >250 mg/dL, polycystic ovary syndrome, impaired glucose tolerance or impaired fasting glucose, and acanthosis nigricans, a pigmented thickening of the skin folds of the neck (TABLE).^6,7 Patients with the metabolic syndrome—abdominal obesity (defined as a waist circumference of >40” in men and >35” in women) and ≥2 of the following: raised triglyceride levels, elevated blood pressure, elevated fasting plasma glucose, and reduced HDL cholesterol—are at especially high risk of both cardiovascular disease and type 2 diabetes.⁸

The ADA screening recommendations, however, are not based on prospective outcome studies, nor are they widely followed. Until recently, the USPSTF only recommended screening adults with hypertension and hyperlipidemia.

In 2008, after an assessment of new findings and research updates, the USPSTF revised its recommendation: The task force now calls for screening asymptomatic adults with sustained blood pressure >135/80 mm Hg—regardless of lipid profile.⁷ For patients with diabetes and hypertension, the USPSTF concluded, evidence shows that early intervention—including lowering blood pressure below conventional targets—can prevent long-term adverse outcomes of diabetes and reduce the risk of cardiovascular events.

Although mass screening remains controversial, regular assessment of risk factors and targeting individuals with established risk is clearly indicated (PATIENT HANDOUT). The importance of early detection was highlighted by the United Kingdom Prospective Diabetes Study, in which approximately half of the patients with newly diagnosed type 2 diabetes already had evidence of complications.⁹

TABLE
Type 1, type 2, and gestational diabetes: Diagnostic clues

Validated risk calculators can boost detection rates

In an attempt to improve detection rates of type 2 diabetes and prediabetes, researchers in both the United States and the United Kingdom recently developed easy-to-use risk calculation tools. The Diabetes Risk Calculator (available at http://www.diabetes.org/food-nutrition-lifestyle/lifestyle-prevention/risk-test.jsp), published in 2008, was validated with findings from the Third National Health and Nutrition Survey.¹⁰ The calculator uses answers to questions about age, waist circumference, history of gestational diabetes mellitus (GDM), height, race/ethnicity, hypertension, family history, and exercise to determine whether an individual is at high risk for undetected diabetes. The tool has a low positive predictive value (14%), but a negative predictive value >99%.¹⁰

The QDScore Diabetes Risk Calculator (www.qdscore.org), another new tool, is designed to estimate an individual’s 10-year risk of developing type 2 diabetes.¹¹ The program, which calculates risk based on answers to questions about family history of diabetes, patient history of cardiovascular disease, smoking, treatment for hypertension, BMI, ethnicity, and steroid use, was validated with data collected from 2.5 million patients in practices throughout England and Wales. The screening tool showed a high degree of discrimination in reflecting differences in disease prevalence related to ethnic and socioeconomic risk factors.¹¹

Pinning down a type 2 (or prediabetes) diagnosis

The ADA, American Association of Clinical Endocrinologists (AACE), USPSTF, and World Health Organization/International Diabetes Federation agree on the diagnostic criteria for type 2 diabetes: a fasting glucose >126 mg/dL, a random plasma glucose ≥200 mg/dL (that must be confirmed on a subsequent day), or both.^5,7,12,13 Patient history, risk factors, and additional laboratory tests can help clinicians distinguish between type 1 and type 2 diabetes.

An oral glucose tolerance test (OGTT) is also an option for diagnosis, but time and scheduling difficulties limit the routine use of this test in primary care. Hemoglobin A1c is not recommended as a diagnostic test because of a lack of standardization.¹

Prediabetes and type 2 risk. One in 4 (25.9%) US adults 20 years of age or older and more than 1 in 3 (35.9%) of those 60 years of age or older have prediabetes,¹⁴ defined as impaired fasting glucose (100-125 mg/dL), impaired glucose tolerance (2-hour glucose test results of 140-199 mg/dL), or both. Prediabetes increases the risk of developing type 2 diabetes by an estimated 30% over a 4-year period,¹⁵ and 70% over 30 years,¹⁶ although lifestyle interventions can substantially lower the risk. In a recently released consensus statement, an AACE task force noted that in addition to the increased risk of type 2 diabetes, patients with prediabetes face a greater risk of macrovascular complications.¹⁷

Type 2 in kids can be mistaken for type 1

As childhood obesity has surged, type 2 diabetes has been diagnosed at an increasingly early age—even in children younger than 10 years.¹⁸ Minority youth, primarily African Americans, Hispanics, and Asians/Pacific Islanders, are at increased risk.¹⁴ Symptoms can be insidious in children and adolescents and easily missed or mistaken for type 1 diabetes, in part because type 2 diabetes is still relatively rare in this age group.¹⁹

Preteens at risk. In a recent study of BMI and metabolic syndrome risk factors in 8- to 14-year-olds, however, researchers concluded that children who are overweight in early adolescence may be at risk for type 2 diabetes as well as cardiovascular disease before they reach their teens.²⁰ There is evidence of a genetic predisposition for type 2 diabetes and defects of β-cell function,^5,21 and family history, in addition to weight, is an important consideration in identifying type 2 diabetes in young patients.

Although young adults with type 1 and type 2 diabetes can present with similar symptoms, there may be certain clues to a type 2 diagnosis. Acanthosis nigricans, which is related to insulin resistance and occurs most frequently in obese adolescents, points to a type 2 diagnosis. Increased insulin and C-peptide levels are indicators of type 2 diabetes. Low levels are not necessarily an indication of type 1, however, because patients with type 2 diabetes may have low levels of insulin and C-peptide because of glucose toxicity and lipotoxicity at the time of diagnosis.²² Treatment with insulin may be necessary until glucose toxicity resolves.

Type 1 diabetes: Beyond childhood

Approximately 5% to 10% of patients with diabetes have type 1, which is defined as idiopathic or cellular immune-mediated autoimmune β-cell destruction.⁵ The rate of destruction is variable—it generally progresses more rapidly in infants and children than in adults. Some people with type 1 diabetes retain residual β-cell function, but have little or no insulin secretion; this manifests as a low or undetectable level of serum C-peptide.

Most cases of type 1 diabetes are diagnosed in patients younger than 18 years. But type 1 diabetes is increasingly recognized as a disorder that also develops in early adulthood, usually before the age of 40.

Arriving at a type 1 diagnosis

Patients with type 1 diabetes often present with modest hyperglycemia, but may rapidly progress to severe hyperglycemia and diabetic ketoacidosis (DKA) when infection or other physical stressors occur.

While screening for autoantibodies in asymptomatic individuals is not recommended,⁵ patients with blood glucose levels ≥200 mg/dL and symptoms of polydipsia, polyuria, and polyphagia who do not meet the profile for type 2 diabetes may be candidates for additional laboratory work. Approximately 85% to 90% of patients with type 1 diabetes will have antibodies to islet cells or glutamic acid decarboxylase (GAD).^5,23

Even without antibody testing, there are distinguishing characteristics that help support a type 1 diagnosis. As a general rule, individuals who develop type 1 diabetes—especially children—are not obese, although patients usually gain weight over time. In addition, many patients with type 1 diabetes have an auto-immune disease, such as celiac or Graves’ disease, hypothyroidism, adrenal anemia, or pernicious anemia; and a first-degree relative with type 1 diabetes. DKA, with acute symptoms of polydipsia and/or polyuria and recent, unintentional weight loss, is suggestive of—but not definitive for—type 1 diabetes.

A recently validated type 1 risk calculator may be particularly useful for screening patients who have a sibling, parent, or child with type 1 diabetes. Using age, BMI, C-peptide concentration, and OGTT results, the algorithm was highly predictive of type 1 diabetes in family members of patients who tested positive for islet cell antibodies.²⁴

Patient doesn’t “fit” type 1 or 2? Consider LADA

LADA, a gradual, progressive form of type 1 diabetes, can be difficult to identify. Circulating GAD or islet cell antibodies are present, but patients don’t have an absolute need for insulin at the time of diagnosis. Thus, they’re often thought to have type 2 diabetes.²⁵ Individuals with LADA show no signs of insulin resistance, however, and over time, β cells decline and insulin usually becomes necessary.

There are no universal recommendations for testing for LADA. Rather, the diagnosis should be considered in those who don’t fit the classic profile for type 1 or type 2 diabetes,²⁶ but have some of the following features:

• age <50 years
• acute symptoms of polydipsia, polyuria, and/or unintentional weight loss
• BMI <25
• a personal history of autoimmune disease
• a family history of autoimmune disease.²⁷

A prospective analysis found that the majority of LADA patients had at least 2 of these distinguishing characteristics.²⁸ Other recent research found heterogeneity among patients with LADA. Noting that not all patients with LADA become insulin-dependent, researchers concluded that the need for insulin is linked to the degree of autoimmunity and β-cell failure.²⁹

When GDM complicates prenatal care

Any degree of carbohydrate intolerance that is first recognized during pregnancy is classified as GDM, whether or not the condition resolves after delivery. A GDM diagnosis does not preclude the possibility of undiagnosed type 2 diabetes or prediabetes, or (rarely) type 1 diabetes.

Approximately 7% of all pregnancies in the United States are complicated by GDM, totaling more than 200,000 cases annually.⁵ The rate of GDM is in direct proportion to the prevalence of type 2 diabetes in the population in question, and ranges from 1% to 14%. GDM is the diagnosis in nearly 90% of pregnancies complicated by diabetes.⁵

The GDM screening controversy

Screening for GDM—whether it should be done universally or selectively on the basis of risk factors—is highly controversial. The USPSTF maintains that there is insufficient evidence to recommend for or against screening women with no history of GDM. The American College of Obstetricians and Gynecologists (ACOG)³⁰ and ADA⁵ recommend selective screening based on patient history, clinical presentation, and, possibly, prior impaired glucose test results or other abnormal laboratory values. AACE calls for universal screening of pregnant women, starting at 20 weeks for high-risk individuals and between 24 and 28 weeks for those at low risk.¹²

Identifying patients at risk. Maternal age (>25 years), obesity (BMI ≥30), prior GDM or delivery of a large-forgestational-age infant, belonging to a high-risk ethnic group, glycosuria, history of glucose resistance or glucose tolerance, and a first-degree relative with diabetes (TABLE) are risk factors for GDM. Women at high risk—those who meet all or most of these criteria—should undergo early screening: at the first prenatal visit, according to ACOG;³⁰ upon confirmation of pregnancy (ADA);⁵ at 20 weeks’ gestation (AACE);¹² or between 24 and 28 weeks’ gestation (USPSTF).⁷ ADA and ACOG recommend a 2-stage approach, starting with a 50-g 1-hour OGTT and following up with a 100-g 3-hour OGTT if the first test results are not definitive.^5,30 Testing for patients at average risk—which includes any pregnant woman with even a single risk factor, such as being older than 25 years—should be done between 24 and 28 weeks’ gestation, according to ACOG and ADA; testing is not required for women who are <25 years, have a normal body weight, and no other risk factors.

GDM screening in primary care. Because most women fit the criteria for average or high risk,³¹ family physicians may find universal screening to be more practical than individual risk assessment. Universal screening is associated with favorable outcomes,³² but screening limited to those at high and average risk also has evidence to support it. In a study of 25,118 deliveries, only 4% of women with GDM were missed by the exclusion of low-risk patients.³³

In the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, researchers tracked 25,505 women from 9 countries and found a continuous relationship between the risk of macrosomia and the rise in maternal glucose levels.³⁴ The impact on the developing fetus of varying degrees of glucose was studied after a 75-g 2-hour OGTT. The risk of macrosomia increased with fasting blood glucose >75 mg/dL, 1-hour glucose levels >105 mg/dL, and 2-hour glucose concentration >90 mg/dL.³⁵ The most compelling results for adverse effects were associated with fasting glucose levels, rather than glucose tolerance tests.

2 abnormal results needed for a GDM diagnosis

In the absence of unequivocal hyperglycemia, there are 2 diagnostic standards for GDM: The Carpenter-Coustan Conversion and the National Diabetes Data Group Conversion. The Carpenter-Coustan Conversion uses lower glucose values for fasting (≥95 mg/dL) and subsequent 1-, 2-, and 3-hour levels (≥180, 155, and 140 mg/dL, respectively) and is more widely used. But expert opinion also supports the National Diabetes Data Group Conversion criteria (fasting plasma glucose, ≥105 mg/dL; ≥190, 165, and 145 mg/dL for 1-, 2-, and 3-hour OGTT, respectively), and there are no data from clinical trials to prove the superiority of either standard.³⁰

Both sets of standards require 2 or more thresholds to be met or exceeded for a GDM diagnosis. Women with only 1 abnormal value should be monitored carefully, however, as they, too, may be at increased risk for macrosomia and other morbidities.³⁰

Postpartum follow-up. Obtain a fasting glucose reading or perform an OGTT around the time of the postpartum checkup for any patient who was diagnosed with GDM. ACOG recommends using an OGTT to more accurately diagnose type 2 diabetes or prediabetes in these patients, who are at significantly elevated risk.³⁰

Acknowledgement

The authors wish to thank Carol Hildebrandt, a research assistant with no potential conflict of interest, for her help with this manuscript.

Correspondence
Julienne K. Kirk, PharmD, CDE, Department of Family and Community Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1084; [email protected]

By age 60, more than half of men have histopathologic benign prostatic hyperplasia (BPH).¹ And, given the publicity BPH is receiving today, it’s quite possible that those who are experiencing symptoms will be less reticent to discuss it than before.

So what does the evidence tell us about how to best manage these patients? Specifically, do you know what the minimal assessment is for those who are experiencing symptoms? When might advanced testing methods be helpful?

Furthermore, among men who are now 50 years old, the expected lifetime incidence for any type of surgical intervention for BPH is approximately 35%.² What are the first-line treatments available to these patients? Who might be a candidate for combination drug therapy? Are herbal preparations worth considering? When might surgery be a first choice?

These questions underscore the importance of a proper primary care framework for evaluating and treating BPH, which we can develop based on a consensus guideline released by the American Urological Association (AUA)¹ and on more recent research.

Assessing symptoms: 2 tools can help

Symptoms of BPH can include urinary frequency, nocturia, urgency, hesitancy, weak or intermittent urine stream, straining to void, and a sensation of incomplete voiding.¹ Each patient experiences a unique constellation of these symptoms. Using a urinary symptom scoring system can help define the severity of BPH and be useful in monitoring the success of subsequent therapy. Available instruments for this purpose include the AUA’s 7-question Symptom Index for BPH (http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=bph) and the International Prostate Symptom Score, which adds an eighth question to the AUA list to gauge the extent to which symptoms bother a patient (http://www.usli.net/uro/Forms/ipss.pdf).^1-5 If the patient is unclear about the pattern of his symptoms, consider asking him to keep a voiding diary.

Ruling out other causes of BPH-like symptoms

TABLE 1 lists the differential diagnoses of obstructive urinary symptoms, otherwise known as lower urinary tract symptoms (LUTS).

Look for clues in the history. Ask the patient whether he uses medications known to cause obstructive urinary symptoms—tricyclic antidepressants, first-generation antihistamines, anticholinergic agents, diuretics, narcotics, and decongestants. Does he have any first-degree relatives with prostate cancer? If the answer is yes, how young was he when the cancer was diagnosed?

Focus your examination. Perform a digital rectal examination (DRE) to check prostate size and to detect palpable nodules, induration, or irregularities associated with malignancy or infection. An enlarged prostate is commonly found on rectal examination; however, the degree of hypertrophy does not necessarily correlate with the degree of obstruction or the severity of symptoms. Any irregularity suggestive of cancer requires that you talk to your patient about his preferences for further investigation.⁶

Conduct a neurologic exam to check mental status, gait, lower extremity strength, and anal sphincter tone to assess for conditions that could cause a neurogenic bladder.

TABLE 1
Lower urinary tract symptoms are also seen with these disorders³¹

Consider these tests. Urinary tract infection (UTI) or bladder cancer may produce symptoms similar to those of BPH. For any patient who has LUTS, perform a urinalysis to screen for infection or hematuria. If a UTI is found, treat it and re-evaluate the patient. If you detect microscopic hematuria, do a further work-up to rule out bladder cancer. If DRE findings are suggestive of prostate cancer, you’ll need an ultrasound-guided biopsy and histological examination to make the diagnosis.

Optional tests in the work-up of LUTS include urinary flow rate measurements, post-void residual urine measurements, and pressure flow studies. These tests may be informative if the diagnosis is unclear based on the history and physical exam or when patients do not respond to initial therapy. Ultrasonography, intravenous pyelography, filling cystometrography, and cystoscopy are not routinely recommended for the evaluation of suspected BPH. However, they may be helpful if a patient has a complex medical history (eg, neurologic disorder or other disease known to affect bladder function, or prior failure of BPH therapy), or if he wants to pursue invasive therapy.¹

Talk to your patient about the controversial PSA test. Measuring serum prostate-specific antigen (PSA) levels to screen for prostate cancer is controversial, even for patients with LUTS. Although PSA testing can effectively detect prostate cancer in its early pathologic stages, researchers continue to investigate whether early detection significantly improves outcomes. Quite recently, 2 studies demonstrated that the test saves few lives;^7,8 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent 1 death from prostate cancer.

A subset of detected cancers appears to be clinically significant, but many cancers will not progress during a patient’s lifetime.^3,5 The United States Preventive Services Task Force (USPSTF) has concluded that the evidence is insufficient to recommend for or against routine prostate cancer screening due to the uncertainty of the balance of potential benefits (reduction of prostate cancer morbidity and mortality) and risks (false-positive results, unnecessary biopsies, and possible complications) of treatment for early disease.^9-12 Furthermore, in its 2008 update, the USPSTF specifically recommended against screening for prostate cancer in men 75 years of age and older.

The American Cancer Society says that discouraging or not offering testing is inappropriate: Men who ask their physicians to make the decision on their behalf should be tested.⁹ A 2006 Cochrane review of this topic found only 2 eligible randomized trials, both of which had high risk of bias. They concluded that insufficient high-quality evidence exists to support or refute the use of any screening for prostate cancer in any patient population, including those with BPH.¹³

Given this conflicting advice, discuss the benefits and limitations of screening with your patient before deciding whether or not to test.

What is the optimal Approach to treatment?

Patients who are not bothered by their urinary symptoms—even those with moderate to severe symptom scores—can be managed with watchful waiting. Because of the cost and frequent side effects of medications for BPH, these patients generally will not benefit from drug therapy.^3,5,14,15 However, follow-up monitoring is important, because the severity of BPH can change even without treatment.

Even if patients with moderate or severe AUA symptom scores are not bothered by their symptoms, inform them of appropriate treatment options.³ When urinary obstruction symptoms from BPH significantly interfere with daily living and sleep activities, treatment is justified.¹

Medical management, yes, but which option?

Medical therapies are not as effective as surgical intervention,¹⁶ but they often provide adequate symptom relief and cause fewer, less severe, and less permanent adverse effects than surgery. Initiate treatment with medical therapy if (1) the patient is bothered by his symptoms, (2) no significant urinary obstruction exists, and (3) you have followed the patient’s preference for prostate cancer evaluation. TABLE 2 lists prescription medications for the treatment of BPH.

Nonselective α-adrenergic blockers, such as doxazosin and terazosin, reduce prostatic smooth muscle tone, thereby improving urinary flow. A Cochrane systematic review and a subsequent large randomized trial found terazosin to be superior to placebo in improving urinary flow and decreasing symptoms in men with BPH.^16,17

Selective α-adrenergic blockers, such as alfuzosin and tamsulosin, are highly selective α-1_A-adrenergic antagonists. They are believed to be as effective as the nonselective agents, and patients may experience fewer side effects than with nonselective agents.^1,18 However, these drugs are considerably more expensive than their nonselective counterparts.

5-α Reductase inhibitors, such as finasteride and dutasteride, are more effective than placebo for patients with LUTS associated with demonstrable prostate enlargement. In a Cochrane review and subsequent large randomized trial, finasteride proved inferior to terazosin.^16,17 However, finasteride reduces the progression to urinary obstruction and the need for invasive therapy; terazosin does not.¹⁷ Finasteride achieves this effect by reducing prostatic volume by about 20% over 3 to 6 months of treatment.

Finasteride decreases PSA levels by 40% to 50%. If you conduct PSA screening for prostate cancer in a patient taking finasteride, double the PSA level before comparing it with age-related norms. Handled this way, PSA screening will not lose its sensitivity or specificity for the diagnosis of prostate cancer.¹⁹

Though a 5-mg daily regimen of finasteride reduces the overall risk of prostate cancer from 24.4% to 18.4%, it increases the risk of high-grade disease associated with higher mortality from 5.1% to 6.4%. Warn patients of this risk.²⁰

Combining an α-adrenergic blocker and 5-α reductase inhibitor. Combination therapy is appropriate and effective for patients with LUTS associated with demonstrable prostate enlargement for whom monotherapy has failed.⁹ Taken together, a 5-α reductase inhibitor and a nonselective α-1_A-adrenergic blocker alleviate symptoms more effectively than either drug can do alone.^21,22 The incidence of most adverse drug reactions with the combination is similar to the baseline risk for each drug. However, ejaculatory abnormalities are reported in 7% of patients in the combination therapy group vs 2% or less in the monotherapy groups. Discontinuation rates for combination therapy are comparable to those in the nonselective α-adrenergic blocker group.²² The adverse effect profile of combining selective α-adrenergic blockers with 5-α reductase inhibitors has not been reported; however, the combination is often used in practice.

For patients to make an informed decision about treatment, discuss with them the common adverse reactions from these agents (TABLE 2) and the need for long-term daily therapy. Also give the patient a reasonable estimate of the risk of his retention symptoms progressing.

TABLE 2
BPH medications: How they compare

Complementary medicine: Information is still limited

Herbal or complementary medicines are used worldwide to treat BPH. These products are not regulated by the US Food and Drug Administration (FDA), and therefore no standardized formulation or dosing exists. Although a few substances appear to have some positive effects, high-quality clinical trials on clinical outcomes are lacking.

The AUA guideline does not recommend the use of phytotherapy.¹ Despite this, many patients—and any number of physicians—turn to phytotherapy to treat LUTS associated with BPH.

Some patients turn to phytotherapy without their physician’s knowledge, so it’s important to ask whether they are using any herbal preparations. Agents currently used include saw palmetto, African plum, South African star grass, and Cernilton.

Saw palmetto (Serenoa repens) has been used by more than 2 million men in the United States. In 2006, Bent et al conducted a rigorously designed double-blinded trial in which 225 men older than 49 years with moderate-to-severe symptoms of BPH were treated for 1 year with saw palmetto extract (160 mg twice a day) or placebo.²³ Saw palmetto did not ameliorate the symptoms of BPH. In contrast, a Cochrane systematic review last updated in 2002 asserted that this substance caused mild-to-moderate reductions in urologic symptoms and flow measures when given to men with symptomatic BPH.²⁴ Long-term efficacy and safety of this product are unknown. Given the efficacy of saw palmetto, it is a reasonable option for men who prefer a nonprescription product to treat symptoms of BPH.

African plum (Pygeum africanum) is more effective than placebo in reducing symptoms of BPH and has few side effects, based on poorly designed small studies.^25,26 Comparative data with finasteride or the α-adrenergic blockers are lacking.

South African star grass (Hypoxis rooperi and certain species of Pinus and Picea) contain beta-sitosterols and are sources for phytotherapeutic treatments for BPH. A systematic review analyzed the effects of beta-sitosterols in men and found improved urinary symptom scores and flow measures (n=519; 4 randomized, controlled, double-blind trials; duration, 4-26 weeks).²⁷ Their long-term effectiveness and safety are not known.

Cernilton, prepared from the ryegrass pollen Secale cereale, is marketed for the treatment of BPH. A Cochrane systematic review demonstrated that comparative trials lacked a proven active control. Available evidence suggests that short-term use of cernilton is well tolerated and modestly decreases overall urologic symptoms, including nocturia. Additional randomized placebo and active-controlled trials are needed to evaluate the long-term clinical effectiveness and safety of Cernilton.²⁸

Acupuncture was not effective in treating LUTS in men in randomized controlled (single-blinded) trials.²⁹

When patients don’t respond to medical treatment

Surgery is recommended for patients who have not responded to medical treatment, who have refractory retention with a failed attempt at catheter removal, or who experience recurrent UTIs, persistent hematuria, bladder stones, or renal insufficiency.³ In addition, surgery can be the initial treatment choice for patients with high AUA symptom scores who opt for this intervention and are good operative candidates.

The specific surgical approach (open or endoscopic; electrocautery or laser) are technical decisions based on the patient’s prostate size, the individual surgeon’s judgment, and the patient’s comorbidities.^1,30 For patients who are not surgical candidates, treatment with intermittent catheterization, an indwelling catheter, or a stent is recommended.

Acknowledgements

The authors thank Jen Creer, MA, of Edit Rx, LLC, for her assistance in the preparation of this manuscript. The University of Nebraska Medical Center, with which both authors were previously affiliated, funded this writing assistance.

Correspondence
Drew M. Keister, MD, Lehigh Valley Health Network, PO Box 7017, Allentown, PA 18105-7017; [email protected]

By age 60, more than half of men have histopathologic benign prostatic hyperplasia (BPH).¹ And, given the publicity BPH is receiving today, it’s quite possible that those who are experiencing symptoms will be less reticent to discuss it than before.

So what does the evidence tell us about how to best manage these patients? Specifically, do you know what the minimal assessment is for those who are experiencing symptoms? When might advanced testing methods be helpful?

Furthermore, among men who are now 50 years old, the expected lifetime incidence for any type of surgical intervention for BPH is approximately 35%.² What are the first-line treatments available to these patients? Who might be a candidate for combination drug therapy? Are herbal preparations worth considering? When might surgery be a first choice?

These questions underscore the importance of a proper primary care framework for evaluating and treating BPH, which we can develop based on a consensus guideline released by the American Urological Association (AUA)¹ and on more recent research.

Assessing symptoms: 2 tools can help

Symptoms of BPH can include urinary frequency, nocturia, urgency, hesitancy, weak or intermittent urine stream, straining to void, and a sensation of incomplete voiding.¹ Each patient experiences a unique constellation of these symptoms. Using a urinary symptom scoring system can help define the severity of BPH and be useful in monitoring the success of subsequent therapy. Available instruments for this purpose include the AUA’s 7-question Symptom Index for BPH (http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=bph) and the International Prostate Symptom Score, which adds an eighth question to the AUA list to gauge the extent to which symptoms bother a patient (http://www.usli.net/uro/Forms/ipss.pdf).^1-5 If the patient is unclear about the pattern of his symptoms, consider asking him to keep a voiding diary.

Ruling out other causes of BPH-like symptoms

TABLE 1 lists the differential diagnoses of obstructive urinary symptoms, otherwise known as lower urinary tract symptoms (LUTS).

Look for clues in the history. Ask the patient whether he uses medications known to cause obstructive urinary symptoms—tricyclic antidepressants, first-generation antihistamines, anticholinergic agents, diuretics, narcotics, and decongestants. Does he have any first-degree relatives with prostate cancer? If the answer is yes, how young was he when the cancer was diagnosed?

Focus your examination. Perform a digital rectal examination (DRE) to check prostate size and to detect palpable nodules, induration, or irregularities associated with malignancy or infection. An enlarged prostate is commonly found on rectal examination; however, the degree of hypertrophy does not necessarily correlate with the degree of obstruction or the severity of symptoms. Any irregularity suggestive of cancer requires that you talk to your patient about his preferences for further investigation.⁶

Conduct a neurologic exam to check mental status, gait, lower extremity strength, and anal sphincter tone to assess for conditions that could cause a neurogenic bladder.

TABLE 1
Lower urinary tract symptoms are also seen with these disorders³¹

Consider these tests. Urinary tract infection (UTI) or bladder cancer may produce symptoms similar to those of BPH. For any patient who has LUTS, perform a urinalysis to screen for infection or hematuria. If a UTI is found, treat it and re-evaluate the patient. If you detect microscopic hematuria, do a further work-up to rule out bladder cancer. If DRE findings are suggestive of prostate cancer, you’ll need an ultrasound-guided biopsy and histological examination to make the diagnosis.

Optional tests in the work-up of LUTS include urinary flow rate measurements, post-void residual urine measurements, and pressure flow studies. These tests may be informative if the diagnosis is unclear based on the history and physical exam or when patients do not respond to initial therapy. Ultrasonography, intravenous pyelography, filling cystometrography, and cystoscopy are not routinely recommended for the evaluation of suspected BPH. However, they may be helpful if a patient has a complex medical history (eg, neurologic disorder or other disease known to affect bladder function, or prior failure of BPH therapy), or if he wants to pursue invasive therapy.¹

Talk to your patient about the controversial PSA test. Measuring serum prostate-specific antigen (PSA) levels to screen for prostate cancer is controversial, even for patients with LUTS. Although PSA testing can effectively detect prostate cancer in its early pathologic stages, researchers continue to investigate whether early detection significantly improves outcomes. Quite recently, 2 studies demonstrated that the test saves few lives;^7,8 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent 1 death from prostate cancer.

A subset of detected cancers appears to be clinically significant, but many cancers will not progress during a patient’s lifetime.^3,5 The United States Preventive Services Task Force (USPSTF) has concluded that the evidence is insufficient to recommend for or against routine prostate cancer screening due to the uncertainty of the balance of potential benefits (reduction of prostate cancer morbidity and mortality) and risks (false-positive results, unnecessary biopsies, and possible complications) of treatment for early disease.^9-12 Furthermore, in its 2008 update, the USPSTF specifically recommended against screening for prostate cancer in men 75 years of age and older.

The American Cancer Society says that discouraging or not offering testing is inappropriate: Men who ask their physicians to make the decision on their behalf should be tested.⁹ A 2006 Cochrane review of this topic found only 2 eligible randomized trials, both of which had high risk of bias. They concluded that insufficient high-quality evidence exists to support or refute the use of any screening for prostate cancer in any patient population, including those with BPH.¹³

Given this conflicting advice, discuss the benefits and limitations of screening with your patient before deciding whether or not to test.

What is the optimal Approach to treatment?

Patients who are not bothered by their urinary symptoms—even those with moderate to severe symptom scores—can be managed with watchful waiting. Because of the cost and frequent side effects of medications for BPH, these patients generally will not benefit from drug therapy.^3,5,14,15 However, follow-up monitoring is important, because the severity of BPH can change even without treatment.

Even if patients with moderate or severe AUA symptom scores are not bothered by their symptoms, inform them of appropriate treatment options.³ When urinary obstruction symptoms from BPH significantly interfere with daily living and sleep activities, treatment is justified.¹

Medical management, yes, but which option?

Medical therapies are not as effective as surgical intervention,¹⁶ but they often provide adequate symptom relief and cause fewer, less severe, and less permanent adverse effects than surgery. Initiate treatment with medical therapy if (1) the patient is bothered by his symptoms, (2) no significant urinary obstruction exists, and (3) you have followed the patient’s preference for prostate cancer evaluation. TABLE 2 lists prescription medications for the treatment of BPH.

Nonselective α-adrenergic blockers, such as doxazosin and terazosin, reduce prostatic smooth muscle tone, thereby improving urinary flow. A Cochrane systematic review and a subsequent large randomized trial found terazosin to be superior to placebo in improving urinary flow and decreasing symptoms in men with BPH.^16,17

Selective α-adrenergic blockers, such as alfuzosin and tamsulosin, are highly selective α-1_A-adrenergic antagonists. They are believed to be as effective as the nonselective agents, and patients may experience fewer side effects than with nonselective agents.^1,18 However, these drugs are considerably more expensive than their nonselective counterparts.

5-α Reductase inhibitors, such as finasteride and dutasteride, are more effective than placebo for patients with LUTS associated with demonstrable prostate enlargement. In a Cochrane review and subsequent large randomized trial, finasteride proved inferior to terazosin.^16,17 However, finasteride reduces the progression to urinary obstruction and the need for invasive therapy; terazosin does not.¹⁷ Finasteride achieves this effect by reducing prostatic volume by about 20% over 3 to 6 months of treatment.

Finasteride decreases PSA levels by 40% to 50%. If you conduct PSA screening for prostate cancer in a patient taking finasteride, double the PSA level before comparing it with age-related norms. Handled this way, PSA screening will not lose its sensitivity or specificity for the diagnosis of prostate cancer.¹⁹

Though a 5-mg daily regimen of finasteride reduces the overall risk of prostate cancer from 24.4% to 18.4%, it increases the risk of high-grade disease associated with higher mortality from 5.1% to 6.4%. Warn patients of this risk.²⁰

Combining an α-adrenergic blocker and 5-α reductase inhibitor. Combination therapy is appropriate and effective for patients with LUTS associated with demonstrable prostate enlargement for whom monotherapy has failed.⁹ Taken together, a 5-α reductase inhibitor and a nonselective α-1_A-adrenergic blocker alleviate symptoms more effectively than either drug can do alone.^21,22 The incidence of most adverse drug reactions with the combination is similar to the baseline risk for each drug. However, ejaculatory abnormalities are reported in 7% of patients in the combination therapy group vs 2% or less in the monotherapy groups. Discontinuation rates for combination therapy are comparable to those in the nonselective α-adrenergic blocker group.²² The adverse effect profile of combining selective α-adrenergic blockers with 5-α reductase inhibitors has not been reported; however, the combination is often used in practice.

For patients to make an informed decision about treatment, discuss with them the common adverse reactions from these agents (TABLE 2) and the need for long-term daily therapy. Also give the patient a reasonable estimate of the risk of his retention symptoms progressing.

TABLE 2
BPH medications: How they compare

Complementary medicine: Information is still limited

Herbal or complementary medicines are used worldwide to treat BPH. These products are not regulated by the US Food and Drug Administration (FDA), and therefore no standardized formulation or dosing exists. Although a few substances appear to have some positive effects, high-quality clinical trials on clinical outcomes are lacking.

The AUA guideline does not recommend the use of phytotherapy.¹ Despite this, many patients—and any number of physicians—turn to phytotherapy to treat LUTS associated with BPH.

Some patients turn to phytotherapy without their physician’s knowledge, so it’s important to ask whether they are using any herbal preparations. Agents currently used include saw palmetto, African plum, South African star grass, and Cernilton.

Saw palmetto (Serenoa repens) has been used by more than 2 million men in the United States. In 2006, Bent et al conducted a rigorously designed double-blinded trial in which 225 men older than 49 years with moderate-to-severe symptoms of BPH were treated for 1 year with saw palmetto extract (160 mg twice a day) or placebo.²³ Saw palmetto did not ameliorate the symptoms of BPH. In contrast, a Cochrane systematic review last updated in 2002 asserted that this substance caused mild-to-moderate reductions in urologic symptoms and flow measures when given to men with symptomatic BPH.²⁴ Long-term efficacy and safety of this product are unknown. Given the efficacy of saw palmetto, it is a reasonable option for men who prefer a nonprescription product to treat symptoms of BPH.

African plum (Pygeum africanum) is more effective than placebo in reducing symptoms of BPH and has few side effects, based on poorly designed small studies.^25,26 Comparative data with finasteride or the α-adrenergic blockers are lacking.

South African star grass (Hypoxis rooperi and certain species of Pinus and Picea) contain beta-sitosterols and are sources for phytotherapeutic treatments for BPH. A systematic review analyzed the effects of beta-sitosterols in men and found improved urinary symptom scores and flow measures (n=519; 4 randomized, controlled, double-blind trials; duration, 4-26 weeks).²⁷ Their long-term effectiveness and safety are not known.

Cernilton, prepared from the ryegrass pollen Secale cereale, is marketed for the treatment of BPH. A Cochrane systematic review demonstrated that comparative trials lacked a proven active control. Available evidence suggests that short-term use of cernilton is well tolerated and modestly decreases overall urologic symptoms, including nocturia. Additional randomized placebo and active-controlled trials are needed to evaluate the long-term clinical effectiveness and safety of Cernilton.²⁸

Acupuncture was not effective in treating LUTS in men in randomized controlled (single-blinded) trials.²⁹

When patients don’t respond to medical treatment

Surgery is recommended for patients who have not responded to medical treatment, who have refractory retention with a failed attempt at catheter removal, or who experience recurrent UTIs, persistent hematuria, bladder stones, or renal insufficiency.³ In addition, surgery can be the initial treatment choice for patients with high AUA symptom scores who opt for this intervention and are good operative candidates.

The specific surgical approach (open or endoscopic; electrocautery or laser) are technical decisions based on the patient’s prostate size, the individual surgeon’s judgment, and the patient’s comorbidities.^1,30 For patients who are not surgical candidates, treatment with intermittent catheterization, an indwelling catheter, or a stent is recommended.

Acknowledgements

The authors thank Jen Creer, MA, of Edit Rx, LLC, for her assistance in the preparation of this manuscript. The University of Nebraska Medical Center, with which both authors were previously affiliated, funded this writing assistance.

Correspondence
Drew M. Keister, MD, Lehigh Valley Health Network, PO Box 7017, Allentown, PA 18105-7017; [email protected]

By age 60, more than half of men have histopathologic benign prostatic hyperplasia (BPH).¹ And, given the publicity BPH is receiving today, it’s quite possible that those who are experiencing symptoms will be less reticent to discuss it than before.

So what does the evidence tell us about how to best manage these patients? Specifically, do you know what the minimal assessment is for those who are experiencing symptoms? When might advanced testing methods be helpful?

Furthermore, among men who are now 50 years old, the expected lifetime incidence for any type of surgical intervention for BPH is approximately 35%.² What are the first-line treatments available to these patients? Who might be a candidate for combination drug therapy? Are herbal preparations worth considering? When might surgery be a first choice?

These questions underscore the importance of a proper primary care framework for evaluating and treating BPH, which we can develop based on a consensus guideline released by the American Urological Association (AUA)¹ and on more recent research.

Assessing symptoms: 2 tools can help

Symptoms of BPH can include urinary frequency, nocturia, urgency, hesitancy, weak or intermittent urine stream, straining to void, and a sensation of incomplete voiding.¹ Each patient experiences a unique constellation of these symptoms. Using a urinary symptom scoring system can help define the severity of BPH and be useful in monitoring the success of subsequent therapy. Available instruments for this purpose include the AUA’s 7-question Symptom Index for BPH (http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=bph) and the International Prostate Symptom Score, which adds an eighth question to the AUA list to gauge the extent to which symptoms bother a patient (http://www.usli.net/uro/Forms/ipss.pdf).^1-5 If the patient is unclear about the pattern of his symptoms, consider asking him to keep a voiding diary.

Ruling out other causes of BPH-like symptoms

TABLE 1 lists the differential diagnoses of obstructive urinary symptoms, otherwise known as lower urinary tract symptoms (LUTS).

Look for clues in the history. Ask the patient whether he uses medications known to cause obstructive urinary symptoms—tricyclic antidepressants, first-generation antihistamines, anticholinergic agents, diuretics, narcotics, and decongestants. Does he have any first-degree relatives with prostate cancer? If the answer is yes, how young was he when the cancer was diagnosed?

Focus your examination. Perform a digital rectal examination (DRE) to check prostate size and to detect palpable nodules, induration, or irregularities associated with malignancy or infection. An enlarged prostate is commonly found on rectal examination; however, the degree of hypertrophy does not necessarily correlate with the degree of obstruction or the severity of symptoms. Any irregularity suggestive of cancer requires that you talk to your patient about his preferences for further investigation.⁶

Conduct a neurologic exam to check mental status, gait, lower extremity strength, and anal sphincter tone to assess for conditions that could cause a neurogenic bladder.

TABLE 1
Lower urinary tract symptoms are also seen with these disorders³¹

Consider these tests. Urinary tract infection (UTI) or bladder cancer may produce symptoms similar to those of BPH. For any patient who has LUTS, perform a urinalysis to screen for infection or hematuria. If a UTI is found, treat it and re-evaluate the patient. If you detect microscopic hematuria, do a further work-up to rule out bladder cancer. If DRE findings are suggestive of prostate cancer, you’ll need an ultrasound-guided biopsy and histological examination to make the diagnosis.

Optional tests in the work-up of LUTS include urinary flow rate measurements, post-void residual urine measurements, and pressure flow studies. These tests may be informative if the diagnosis is unclear based on the history and physical exam or when patients do not respond to initial therapy. Ultrasonography, intravenous pyelography, filling cystometrography, and cystoscopy are not routinely recommended for the evaluation of suspected BPH. However, they may be helpful if a patient has a complex medical history (eg, neurologic disorder or other disease known to affect bladder function, or prior failure of BPH therapy), or if he wants to pursue invasive therapy.¹

Talk to your patient about the controversial PSA test. Measuring serum prostate-specific antigen (PSA) levels to screen for prostate cancer is controversial, even for patients with LUTS. Although PSA testing can effectively detect prostate cancer in its early pathologic stages, researchers continue to investigate whether early detection significantly improves outcomes. Quite recently, 2 studies demonstrated that the test saves few lives;^7,8 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent 1 death from prostate cancer.

A subset of detected cancers appears to be clinically significant, but many cancers will not progress during a patient’s lifetime.^3,5 The United States Preventive Services Task Force (USPSTF) has concluded that the evidence is insufficient to recommend for or against routine prostate cancer screening due to the uncertainty of the balance of potential benefits (reduction of prostate cancer morbidity and mortality) and risks (false-positive results, unnecessary biopsies, and possible complications) of treatment for early disease.^9-12 Furthermore, in its 2008 update, the USPSTF specifically recommended against screening for prostate cancer in men 75 years of age and older.

The American Cancer Society says that discouraging or not offering testing is inappropriate: Men who ask their physicians to make the decision on their behalf should be tested.⁹ A 2006 Cochrane review of this topic found only 2 eligible randomized trials, both of which had high risk of bias. They concluded that insufficient high-quality evidence exists to support or refute the use of any screening for prostate cancer in any patient population, including those with BPH.¹³

Given this conflicting advice, discuss the benefits and limitations of screening with your patient before deciding whether or not to test.

What is the optimal Approach to treatment?

Patients who are not bothered by their urinary symptoms—even those with moderate to severe symptom scores—can be managed with watchful waiting. Because of the cost and frequent side effects of medications for BPH, these patients generally will not benefit from drug therapy.^3,5,14,15 However, follow-up monitoring is important, because the severity of BPH can change even without treatment.

Even if patients with moderate or severe AUA symptom scores are not bothered by their symptoms, inform them of appropriate treatment options.³ When urinary obstruction symptoms from BPH significantly interfere with daily living and sleep activities, treatment is justified.¹

Medical management, yes, but which option?

Medical therapies are not as effective as surgical intervention,¹⁶ but they often provide adequate symptom relief and cause fewer, less severe, and less permanent adverse effects than surgery. Initiate treatment with medical therapy if (1) the patient is bothered by his symptoms, (2) no significant urinary obstruction exists, and (3) you have followed the patient’s preference for prostate cancer evaluation. TABLE 2 lists prescription medications for the treatment of BPH.

Nonselective α-adrenergic blockers, such as doxazosin and terazosin, reduce prostatic smooth muscle tone, thereby improving urinary flow. A Cochrane systematic review and a subsequent large randomized trial found terazosin to be superior to placebo in improving urinary flow and decreasing symptoms in men with BPH.^16,17

Selective α-adrenergic blockers, such as alfuzosin and tamsulosin, are highly selective α-1_A-adrenergic antagonists. They are believed to be as effective as the nonselective agents, and patients may experience fewer side effects than with nonselective agents.^1,18 However, these drugs are considerably more expensive than their nonselective counterparts.

5-α Reductase inhibitors, such as finasteride and dutasteride, are more effective than placebo for patients with LUTS associated with demonstrable prostate enlargement. In a Cochrane review and subsequent large randomized trial, finasteride proved inferior to terazosin.^16,17 However, finasteride reduces the progression to urinary obstruction and the need for invasive therapy; terazosin does not.¹⁷ Finasteride achieves this effect by reducing prostatic volume by about 20% over 3 to 6 months of treatment.

Finasteride decreases PSA levels by 40% to 50%. If you conduct PSA screening for prostate cancer in a patient taking finasteride, double the PSA level before comparing it with age-related norms. Handled this way, PSA screening will not lose its sensitivity or specificity for the diagnosis of prostate cancer.¹⁹

Though a 5-mg daily regimen of finasteride reduces the overall risk of prostate cancer from 24.4% to 18.4%, it increases the risk of high-grade disease associated with higher mortality from 5.1% to 6.4%. Warn patients of this risk.²⁰

Combining an α-adrenergic blocker and 5-α reductase inhibitor. Combination therapy is appropriate and effective for patients with LUTS associated with demonstrable prostate enlargement for whom monotherapy has failed.⁹ Taken together, a 5-α reductase inhibitor and a nonselective α-1_A-adrenergic blocker alleviate symptoms more effectively than either drug can do alone.^21,22 The incidence of most adverse drug reactions with the combination is similar to the baseline risk for each drug. However, ejaculatory abnormalities are reported in 7% of patients in the combination therapy group vs 2% or less in the monotherapy groups. Discontinuation rates for combination therapy are comparable to those in the nonselective α-adrenergic blocker group.²² The adverse effect profile of combining selective α-adrenergic blockers with 5-α reductase inhibitors has not been reported; however, the combination is often used in practice.

For patients to make an informed decision about treatment, discuss with them the common adverse reactions from these agents (TABLE 2) and the need for long-term daily therapy. Also give the patient a reasonable estimate of the risk of his retention symptoms progressing.

TABLE 2
BPH medications: How they compare

Complementary medicine: Information is still limited

Herbal or complementary medicines are used worldwide to treat BPH. These products are not regulated by the US Food and Drug Administration (FDA), and therefore no standardized formulation or dosing exists. Although a few substances appear to have some positive effects, high-quality clinical trials on clinical outcomes are lacking.

The AUA guideline does not recommend the use of phytotherapy.¹ Despite this, many patients—and any number of physicians—turn to phytotherapy to treat LUTS associated with BPH.

Some patients turn to phytotherapy without their physician’s knowledge, so it’s important to ask whether they are using any herbal preparations. Agents currently used include saw palmetto, African plum, South African star grass, and Cernilton.

Saw palmetto (Serenoa repens) has been used by more than 2 million men in the United States. In 2006, Bent et al conducted a rigorously designed double-blinded trial in which 225 men older than 49 years with moderate-to-severe symptoms of BPH were treated for 1 year with saw palmetto extract (160 mg twice a day) or placebo.²³ Saw palmetto did not ameliorate the symptoms of BPH. In contrast, a Cochrane systematic review last updated in 2002 asserted that this substance caused mild-to-moderate reductions in urologic symptoms and flow measures when given to men with symptomatic BPH.²⁴ Long-term efficacy and safety of this product are unknown. Given the efficacy of saw palmetto, it is a reasonable option for men who prefer a nonprescription product to treat symptoms of BPH.

African plum (Pygeum africanum) is more effective than placebo in reducing symptoms of BPH and has few side effects, based on poorly designed small studies.^25,26 Comparative data with finasteride or the α-adrenergic blockers are lacking.

South African star grass (Hypoxis rooperi and certain species of Pinus and Picea) contain beta-sitosterols and are sources for phytotherapeutic treatments for BPH. A systematic review analyzed the effects of beta-sitosterols in men and found improved urinary symptom scores and flow measures (n=519; 4 randomized, controlled, double-blind trials; duration, 4-26 weeks).²⁷ Their long-term effectiveness and safety are not known.

Cernilton, prepared from the ryegrass pollen Secale cereale, is marketed for the treatment of BPH. A Cochrane systematic review demonstrated that comparative trials lacked a proven active control. Available evidence suggests that short-term use of cernilton is well tolerated and modestly decreases overall urologic symptoms, including nocturia. Additional randomized placebo and active-controlled trials are needed to evaluate the long-term clinical effectiveness and safety of Cernilton.²⁸

Acupuncture was not effective in treating LUTS in men in randomized controlled (single-blinded) trials.²⁹

When patients don’t respond to medical treatment

Surgery is recommended for patients who have not responded to medical treatment, who have refractory retention with a failed attempt at catheter removal, or who experience recurrent UTIs, persistent hematuria, bladder stones, or renal insufficiency.³ In addition, surgery can be the initial treatment choice for patients with high AUA symptom scores who opt for this intervention and are good operative candidates.

The specific surgical approach (open or endoscopic; electrocautery or laser) are technical decisions based on the patient’s prostate size, the individual surgeon’s judgment, and the patient’s comorbidities.^1,30 For patients who are not surgical candidates, treatment with intermittent catheterization, an indwelling catheter, or a stent is recommended.

Acknowledgements

The authors thank Jen Creer, MA, of Edit Rx, LLC, for her assistance in the preparation of this manuscript. The University of Nebraska Medical Center, with which both authors were previously affiliated, funded this writing assistance.

Correspondence
Drew M. Keister, MD, Lehigh Valley Health Network, PO Box 7017, Allentown, PA 18105-7017; [email protected]

When Mary J,* an overweight 47-year-old Caucasian woman, came in for an annual physical examination, she appeared to be in good health. She denied any recent illness, and reported that an oral contraceptive was the only medication she was taking. The patient’s only complaint: She was having difficulty losing weight despite complying with a low-calorie diet and exercise regimen for the last 6 months. Her comments prompted her physician (CC) to order a thyroid-stimulating hormone (TSH) test to rule out hypothyroidism.

The test showed a TSH of 0.2 mIU/L (normal range is 0.35-5.0 mIU/L). Her physician ordered retesting a week later and this time, Mary’s TSH was normal (1.99 mIU/L). The laboratory report also showed elevated free triiodothyronine (T₃) of 8.1 pmol/L (normal range 2.6-5.7 pmol/L) and free thyroxine (T₄) >70 pmol/L (normal, 10-20 pmol/L); negative antithyroid peroxidase and antithyroglobulin antibodies; normal complete blood count, calcium, and alkaline phosphatase; and low levels of thyroglobulin. The patient had no symptoms and no personal or family history of thyroid disease. She also denied taking thyroid medications.

* The patient’s name has been changed to protect her privacy.

In search of an explanation

On examination, her physician found no significant thyroid enlargement or tenderness. However, the patient’s thyroid was somewhat boggy on palpation. There was no exopthalmos or pretibial myxedema. Mary’s blood pressure was 144/98 mm Hg (with no prior history of hypertension), her heart rate was 84, and she was afebrile. Her physician found no obvious tremors, hyperdynamic apex, or hyperreflexia on physical exam.

To rule out laboratory error from the second set of tests, her physician ordered yet another round of blood work. A diagnosis of hyperthyroidism was confirmed by elevated T₄ (>70 pmol/L) and T₃ (6.2 pmol/L). As in the previous test, the patient’s TSH was in the normal range (1.54 mIU/L).

Detailed questioning solves the mystery

At follow-up, the patient was again asked about exogenous thyroid intake, which she had initially denied. After further questioning about what she was ingesting, Mary acknowledged that she had been taking Pu Erh—a European dietary supplement marketed as a means of increasing metabolism to help with weight loss—3 times daily for more than 3 months. She hadn’t mentioned it before because it hadn’t occurred to her to question its safety.

Her physician advised her to discontinue the supplement immediately, and to have her blood work retested in a month. Within 5 weeks, all her lab values returned to normal. (For more on lab values, see “Investigating thyroid dysfunction: What to test for” on page 205. )

TABLE
Investigating thyroid dysfunction: What to test for

Natural does not=safe

With an ever-increasing overweight population, there is growing concern about the misuse of diet aids. It is important for patients to be cautious when using dietary supplements because of the lack of regulation and standardization. Yet such products are often marketed as “natural,” which may be interpreted as an assurance of safety.¹ Family physicians can play a crucial role in primary prevention by inquiring about the use of over-the-counter substances including “natural” herbal supplements and dietary aids, advising patients of the risks associated with their use, and being alert to potentially dangerous side effects.

Thyrotoxicosis factitia: An exogenous cause

Thyroid hyperactivity can occur when excessive quantities of thyroid hormone are ingested. The excessive intake may be associated with treatment for hypothyroidism, or, as in Mary’s case, may be linked to overuse (or abuse) of a diet aid in an attempt to lose weight.² Often, the condition can be traced to an iodine-containing substance such as kelp—a widely used dietary aid that we’ll discuss in greater detail in a bit.

Iodide is an inorganic salt that is absorbed through the gastrointestinal mucosa and transported to the thyroid gland, where it is trapped and concentrated for thyroid hormone synthesis.³ Consuming large quantities of foods or other products that contain iodine—such as iodized salt, shellfish, cough syrups, multivitamins, or medications such as amiodarone and interferon alpha, as well as kelp—can cause hyperthyroidism.

What’s in that weight-loss aid?

Pu Erh, the dietary supplement Mary was taking, was not available for analysis; it was purchased in Poland and the patient had exhausted her supply by the time her physician told her to stop taking it. Each capsule contains 400 mg of red tea extract with 15 mcg chromium, according to the label.

Red tea and chromium. There are no reports associating red tea with thyroid dysfunction, but chromium is a popular weight-loss supplement whose efficacy and long-term safety are uncertain.⁴ It is unlikely that Mary’s hyperthyroidism was associated with chromium in-take, however, as multivitamins often contain 100 mcg of chromium—nearly 7 times the quantity in each Pu Erh capsule—with no reported thyroid side effects.

Did the supplement contain a thyroid extract? It’s possible, of course, that the supplement contained a thyroid extract, which would explain the resolution of symptoms after Mary stopped taking it. But without analysis of the product, we can’t be sure. Our suspicion, of course, is that it did.

Another possible, but unlikely, explanation. Theoretically, the fluctuating TSH could have been related to silent or subacute thyroiditis, in which T₄ can remain elevated for 1 to 3 months. The fact that Mary had no history of cold or flu symptoms in the month preceding the initial TSH was inconsistent with this alternative diagnosis, however. Painless thyroiditis is also unlikely, as it is autoimmune in origin and the patient’s antithyroid antibodies were negative. The low thyroglobulin level supported an exogenous cause of hyperthyroidism.

Other supplements and thyroid dysfunction

Mary’s presentation is a single case indicating a possible link between a weight-loss supplement and asymptomatic hyperthyroidism—a clinically important condition that may be associated with disorders such as paroxysmal atrial fibrillation and osteoporosis. This is only one of a number of case reports of patients taking dietary supplements who have developed thyroid dysfunction.

Kelp. Long used as a dietary supplement, especially in Asia, kelp has been linked to thyroid dysfunction. One case report describes a 72-year-old woman with a history of thyroid disease having typical symptoms of hyperthyroidism while ingesting 4 to 6 kelp tablets daily for 1 year. Her TSH concentration was low, while total T₃ and T₄ levels were high. After discontinuing the kelp tablets, the hyperthyroidism resolved, and thyroid function tests returned to normal.⁵ Another report describes an instance of probable transient hyperthyroidism in a patient taking kelp in 2 different diet supplements.⁶

Tiratricol (Triac), a substance that has weak thyromimetic effects, resulted in a case of documented hyperthyroidism secondary to its use.¹

Other reports. In Japan, the weight-reducing herbal medicines, Dream Shape and Ever Youth, became available in 2000. Twelve patients subsequently developed thyrotoxicosis after taking these herbal medicines, both of which were found to contain triiodothyronine and thyroxine.⁷

As early as 1986, researchers have described several patients who developed thyrotoxicosis from Enzo-Caps, a nonprescription diet aid manufactured in Peru. The product was touted as “a natural food product of papaya, garlic, and kelp” to assist with weight reduction. Researchers obtained the supplement for biochemical analysis and found that it had been adulterated with thyroid hormones, which led to thyrotoxicosis factitia.²

Patients in the report complained of palpitations, weakness, fatigue, headache, diaphoresis, irritability, and nervousness, and had elevated serum T₃ and T₄ levels. Thyroglobulin levels were not determined, but would have been useful in differentiating thyrotoxicosis factitia from hyperthyroxinemia (Graves’ disease, thyroiditis, nodular goiter).²

These reports, as well as our own experience, leave little doubt as to the importance of asking pointed questions about all prescription and nonprescription products a patient is taking. As we can attest, a little persistence goes a long way when it comes to identifying that agent your patient didn’t think was worth mentioning.

Correspondence
Taryn Taylor, MD, CCFP, Bruyere Family Medicine Center, University of Ottawa, 206 Monterey Drive, Ottawa, Ontario, Canada K2H 7A8; [email protected]

When Mary J,* an overweight 47-year-old Caucasian woman, came in for an annual physical examination, she appeared to be in good health. She denied any recent illness, and reported that an oral contraceptive was the only medication she was taking. The patient’s only complaint: She was having difficulty losing weight despite complying with a low-calorie diet and exercise regimen for the last 6 months. Her comments prompted her physician (CC) to order a thyroid-stimulating hormone (TSH) test to rule out hypothyroidism.

The test showed a TSH of 0.2 mIU/L (normal range is 0.35-5.0 mIU/L). Her physician ordered retesting a week later and this time, Mary’s TSH was normal (1.99 mIU/L). The laboratory report also showed elevated free triiodothyronine (T₃) of 8.1 pmol/L (normal range 2.6-5.7 pmol/L) and free thyroxine (T₄) >70 pmol/L (normal, 10-20 pmol/L); negative antithyroid peroxidase and antithyroglobulin antibodies; normal complete blood count, calcium, and alkaline phosphatase; and low levels of thyroglobulin. The patient had no symptoms and no personal or family history of thyroid disease. She also denied taking thyroid medications.

* The patient’s name has been changed to protect her privacy.

In search of an explanation

On examination, her physician found no significant thyroid enlargement or tenderness. However, the patient’s thyroid was somewhat boggy on palpation. There was no exopthalmos or pretibial myxedema. Mary’s blood pressure was 144/98 mm Hg (with no prior history of hypertension), her heart rate was 84, and she was afebrile. Her physician found no obvious tremors, hyperdynamic apex, or hyperreflexia on physical exam.

To rule out laboratory error from the second set of tests, her physician ordered yet another round of blood work. A diagnosis of hyperthyroidism was confirmed by elevated T₄ (>70 pmol/L) and T₃ (6.2 pmol/L). As in the previous test, the patient’s TSH was in the normal range (1.54 mIU/L).

Detailed questioning solves the mystery

At follow-up, the patient was again asked about exogenous thyroid intake, which she had initially denied. After further questioning about what she was ingesting, Mary acknowledged that she had been taking Pu Erh—a European dietary supplement marketed as a means of increasing metabolism to help with weight loss—3 times daily for more than 3 months. She hadn’t mentioned it before because it hadn’t occurred to her to question its safety.

Her physician advised her to discontinue the supplement immediately, and to have her blood work retested in a month. Within 5 weeks, all her lab values returned to normal. (For more on lab values, see “Investigating thyroid dysfunction: What to test for” on page 205. )

TABLE
Investigating thyroid dysfunction: What to test for

Natural does not=safe

With an ever-increasing overweight population, there is growing concern about the misuse of diet aids. It is important for patients to be cautious when using dietary supplements because of the lack of regulation and standardization. Yet such products are often marketed as “natural,” which may be interpreted as an assurance of safety.¹ Family physicians can play a crucial role in primary prevention by inquiring about the use of over-the-counter substances including “natural” herbal supplements and dietary aids, advising patients of the risks associated with their use, and being alert to potentially dangerous side effects.

Thyrotoxicosis factitia: An exogenous cause

Thyroid hyperactivity can occur when excessive quantities of thyroid hormone are ingested. The excessive intake may be associated with treatment for hypothyroidism, or, as in Mary’s case, may be linked to overuse (or abuse) of a diet aid in an attempt to lose weight.² Often, the condition can be traced to an iodine-containing substance such as kelp—a widely used dietary aid that we’ll discuss in greater detail in a bit.

Iodide is an inorganic salt that is absorbed through the gastrointestinal mucosa and transported to the thyroid gland, where it is trapped and concentrated for thyroid hormone synthesis.³ Consuming large quantities of foods or other products that contain iodine—such as iodized salt, shellfish, cough syrups, multivitamins, or medications such as amiodarone and interferon alpha, as well as kelp—can cause hyperthyroidism.

What’s in that weight-loss aid?

Pu Erh, the dietary supplement Mary was taking, was not available for analysis; it was purchased in Poland and the patient had exhausted her supply by the time her physician told her to stop taking it. Each capsule contains 400 mg of red tea extract with 15 mcg chromium, according to the label.

Red tea and chromium. There are no reports associating red tea with thyroid dysfunction, but chromium is a popular weight-loss supplement whose efficacy and long-term safety are uncertain.⁴ It is unlikely that Mary’s hyperthyroidism was associated with chromium in-take, however, as multivitamins often contain 100 mcg of chromium—nearly 7 times the quantity in each Pu Erh capsule—with no reported thyroid side effects.

Did the supplement contain a thyroid extract? It’s possible, of course, that the supplement contained a thyroid extract, which would explain the resolution of symptoms after Mary stopped taking it. But without analysis of the product, we can’t be sure. Our suspicion, of course, is that it did.

Another possible, but unlikely, explanation. Theoretically, the fluctuating TSH could have been related to silent or subacute thyroiditis, in which T₄ can remain elevated for 1 to 3 months. The fact that Mary had no history of cold or flu symptoms in the month preceding the initial TSH was inconsistent with this alternative diagnosis, however. Painless thyroiditis is also unlikely, as it is autoimmune in origin and the patient’s antithyroid antibodies were negative. The low thyroglobulin level supported an exogenous cause of hyperthyroidism.

Other supplements and thyroid dysfunction

Mary’s presentation is a single case indicating a possible link between a weight-loss supplement and asymptomatic hyperthyroidism—a clinically important condition that may be associated with disorders such as paroxysmal atrial fibrillation and osteoporosis. This is only one of a number of case reports of patients taking dietary supplements who have developed thyroid dysfunction.

Kelp. Long used as a dietary supplement, especially in Asia, kelp has been linked to thyroid dysfunction. One case report describes a 72-year-old woman with a history of thyroid disease having typical symptoms of hyperthyroidism while ingesting 4 to 6 kelp tablets daily for 1 year. Her TSH concentration was low, while total T₃ and T₄ levels were high. After discontinuing the kelp tablets, the hyperthyroidism resolved, and thyroid function tests returned to normal.⁵ Another report describes an instance of probable transient hyperthyroidism in a patient taking kelp in 2 different diet supplements.⁶

Tiratricol (Triac), a substance that has weak thyromimetic effects, resulted in a case of documented hyperthyroidism secondary to its use.¹

Other reports. In Japan, the weight-reducing herbal medicines, Dream Shape and Ever Youth, became available in 2000. Twelve patients subsequently developed thyrotoxicosis after taking these herbal medicines, both of which were found to contain triiodothyronine and thyroxine.⁷

As early as 1986, researchers have described several patients who developed thyrotoxicosis from Enzo-Caps, a nonprescription diet aid manufactured in Peru. The product was touted as “a natural food product of papaya, garlic, and kelp” to assist with weight reduction. Researchers obtained the supplement for biochemical analysis and found that it had been adulterated with thyroid hormones, which led to thyrotoxicosis factitia.²

Patients in the report complained of palpitations, weakness, fatigue, headache, diaphoresis, irritability, and nervousness, and had elevated serum T₃ and T₄ levels. Thyroglobulin levels were not determined, but would have been useful in differentiating thyrotoxicosis factitia from hyperthyroxinemia (Graves’ disease, thyroiditis, nodular goiter).²

These reports, as well as our own experience, leave little doubt as to the importance of asking pointed questions about all prescription and nonprescription products a patient is taking. As we can attest, a little persistence goes a long way when it comes to identifying that agent your patient didn’t think was worth mentioning.

Correspondence
Taryn Taylor, MD, CCFP, Bruyere Family Medicine Center, University of Ottawa, 206 Monterey Drive, Ottawa, Ontario, Canada K2H 7A8; [email protected]

When Mary J,* an overweight 47-year-old Caucasian woman, came in for an annual physical examination, she appeared to be in good health. She denied any recent illness, and reported that an oral contraceptive was the only medication she was taking. The patient’s only complaint: She was having difficulty losing weight despite complying with a low-calorie diet and exercise regimen for the last 6 months. Her comments prompted her physician (CC) to order a thyroid-stimulating hormone (TSH) test to rule out hypothyroidism.

The test showed a TSH of 0.2 mIU/L (normal range is 0.35-5.0 mIU/L). Her physician ordered retesting a week later and this time, Mary’s TSH was normal (1.99 mIU/L). The laboratory report also showed elevated free triiodothyronine (T₃) of 8.1 pmol/L (normal range 2.6-5.7 pmol/L) and free thyroxine (T₄) >70 pmol/L (normal, 10-20 pmol/L); negative antithyroid peroxidase and antithyroglobulin antibodies; normal complete blood count, calcium, and alkaline phosphatase; and low levels of thyroglobulin. The patient had no symptoms and no personal or family history of thyroid disease. She also denied taking thyroid medications.

* The patient’s name has been changed to protect her privacy.

In search of an explanation

On examination, her physician found no significant thyroid enlargement or tenderness. However, the patient’s thyroid was somewhat boggy on palpation. There was no exopthalmos or pretibial myxedema. Mary’s blood pressure was 144/98 mm Hg (with no prior history of hypertension), her heart rate was 84, and she was afebrile. Her physician found no obvious tremors, hyperdynamic apex, or hyperreflexia on physical exam.

To rule out laboratory error from the second set of tests, her physician ordered yet another round of blood work. A diagnosis of hyperthyroidism was confirmed by elevated T₄ (>70 pmol/L) and T₃ (6.2 pmol/L). As in the previous test, the patient’s TSH was in the normal range (1.54 mIU/L).

Detailed questioning solves the mystery

At follow-up, the patient was again asked about exogenous thyroid intake, which she had initially denied. After further questioning about what she was ingesting, Mary acknowledged that she had been taking Pu Erh—a European dietary supplement marketed as a means of increasing metabolism to help with weight loss—3 times daily for more than 3 months. She hadn’t mentioned it before because it hadn’t occurred to her to question its safety.

Her physician advised her to discontinue the supplement immediately, and to have her blood work retested in a month. Within 5 weeks, all her lab values returned to normal. (For more on lab values, see “Investigating thyroid dysfunction: What to test for” on page 205. )

TABLE
Investigating thyroid dysfunction: What to test for

Natural does not=safe

With an ever-increasing overweight population, there is growing concern about the misuse of diet aids. It is important for patients to be cautious when using dietary supplements because of the lack of regulation and standardization. Yet such products are often marketed as “natural,” which may be interpreted as an assurance of safety.¹ Family physicians can play a crucial role in primary prevention by inquiring about the use of over-the-counter substances including “natural” herbal supplements and dietary aids, advising patients of the risks associated with their use, and being alert to potentially dangerous side effects.

Thyrotoxicosis factitia: An exogenous cause

Thyroid hyperactivity can occur when excessive quantities of thyroid hormone are ingested. The excessive intake may be associated with treatment for hypothyroidism, or, as in Mary’s case, may be linked to overuse (or abuse) of a diet aid in an attempt to lose weight.² Often, the condition can be traced to an iodine-containing substance such as kelp—a widely used dietary aid that we’ll discuss in greater detail in a bit.

Iodide is an inorganic salt that is absorbed through the gastrointestinal mucosa and transported to the thyroid gland, where it is trapped and concentrated for thyroid hormone synthesis.³ Consuming large quantities of foods or other products that contain iodine—such as iodized salt, shellfish, cough syrups, multivitamins, or medications such as amiodarone and interferon alpha, as well as kelp—can cause hyperthyroidism.

What’s in that weight-loss aid?

Pu Erh, the dietary supplement Mary was taking, was not available for analysis; it was purchased in Poland and the patient had exhausted her supply by the time her physician told her to stop taking it. Each capsule contains 400 mg of red tea extract with 15 mcg chromium, according to the label.

Red tea and chromium. There are no reports associating red tea with thyroid dysfunction, but chromium is a popular weight-loss supplement whose efficacy and long-term safety are uncertain.⁴ It is unlikely that Mary’s hyperthyroidism was associated with chromium in-take, however, as multivitamins often contain 100 mcg of chromium—nearly 7 times the quantity in each Pu Erh capsule—with no reported thyroid side effects.

Did the supplement contain a thyroid extract? It’s possible, of course, that the supplement contained a thyroid extract, which would explain the resolution of symptoms after Mary stopped taking it. But without analysis of the product, we can’t be sure. Our suspicion, of course, is that it did.

Another possible, but unlikely, explanation. Theoretically, the fluctuating TSH could have been related to silent or subacute thyroiditis, in which T₄ can remain elevated for 1 to 3 months. The fact that Mary had no history of cold or flu symptoms in the month preceding the initial TSH was inconsistent with this alternative diagnosis, however. Painless thyroiditis is also unlikely, as it is autoimmune in origin and the patient’s antithyroid antibodies were negative. The low thyroglobulin level supported an exogenous cause of hyperthyroidism.

Other supplements and thyroid dysfunction

Mary’s presentation is a single case indicating a possible link between a weight-loss supplement and asymptomatic hyperthyroidism—a clinically important condition that may be associated with disorders such as paroxysmal atrial fibrillation and osteoporosis. This is only one of a number of case reports of patients taking dietary supplements who have developed thyroid dysfunction.

Kelp. Long used as a dietary supplement, especially in Asia, kelp has been linked to thyroid dysfunction. One case report describes a 72-year-old woman with a history of thyroid disease having typical symptoms of hyperthyroidism while ingesting 4 to 6 kelp tablets daily for 1 year. Her TSH concentration was low, while total T₃ and T₄ levels were high. After discontinuing the kelp tablets, the hyperthyroidism resolved, and thyroid function tests returned to normal.⁵ Another report describes an instance of probable transient hyperthyroidism in a patient taking kelp in 2 different diet supplements.⁶

Tiratricol (Triac), a substance that has weak thyromimetic effects, resulted in a case of documented hyperthyroidism secondary to its use.¹

Other reports. In Japan, the weight-reducing herbal medicines, Dream Shape and Ever Youth, became available in 2000. Twelve patients subsequently developed thyrotoxicosis after taking these herbal medicines, both of which were found to contain triiodothyronine and thyroxine.⁷

As early as 1986, researchers have described several patients who developed thyrotoxicosis from Enzo-Caps, a nonprescription diet aid manufactured in Peru. The product was touted as “a natural food product of papaya, garlic, and kelp” to assist with weight reduction. Researchers obtained the supplement for biochemical analysis and found that it had been adulterated with thyroid hormones, which led to thyrotoxicosis factitia.²

Patients in the report complained of palpitations, weakness, fatigue, headache, diaphoresis, irritability, and nervousness, and had elevated serum T₃ and T₄ levels. Thyroglobulin levels were not determined, but would have been useful in differentiating thyrotoxicosis factitia from hyperthyroxinemia (Graves’ disease, thyroiditis, nodular goiter).²

These reports, as well as our own experience, leave little doubt as to the importance of asking pointed questions about all prescription and nonprescription products a patient is taking. As we can attest, a little persistence goes a long way when it comes to identifying that agent your patient didn’t think was worth mentioning.

Correspondence
Taryn Taylor, MD, CCFP, Bruyere Family Medicine Center, University of Ottawa, 206 Monterey Drive, Ottawa, Ontario, Canada K2H 7A8; [email protected]

As family physicians, we’re accustomed to seeing patients shortly before they’re scheduled for surgery—in the office, the hospital, or other settings. But not all preoperative (preop) visits are created equal in terms of the level of care, the coding, and the documentation required. Test your knowledge:

1. A preop evaluation can be coded as a consultation visit if a request for the evaluation was initiated by:
   1. a surgeon.
   2. a patient or patient’s family member.
   3. physician self-referral.
   4. all of the above.
2. The best reason to code a preop evaluation as a consultation is:
   1. more accurate Current Procedural Terminology Evaluation and Management (CPT E/M) coding.
   2. more accurate diagnostic coding per the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) system.
   3. reimbursement is (usually) better.
   4. all of the above.
3. For outpatient consults for established patients, 2 out of the 3 key components of an encounter must be provided and documented.
   1. True.
   2. False.
4. The correct way to report the primary diagnosis for a preop consultation is to use:
   1. the ICD-9-CM code for the patient’s acute or chronic medical condition that will likely be a concern in the perioperative period (eg, diabetes mellitus, coronary artery disease).
   2. the ICD-9-CM code for the acute or chronic condition for which the patient requires surgery (eg, osteoarthritis for an elective joint replacement, or cholelithiasis for a laparoscopic cholecystectomy).
   3. V codes V72.81-V72.84 (preop exams).
   4. none of the above.
5. A comprehensive level of examination is required for:
   1. a level 4 office consultation.
   2. a level 3 inpatient consultation.
   3. a level 4 established patient office visit.
   4. none of the above.
6. Preop consultations conducted in the hospital setting should be coded using inpatient consultation codes.
   1. True.
   2. False.
   3. It depends.

QUESTION 1: When can a preop evaluation be coded as a consultation?

Answer: A When a surgeon requests the consult. Here’s why.

A consultation is defined as a type of service provided by a physician whose opinion or advice regarding evaluation and/or management of a specific problem is requested by another physician, or other appropriate source. In order to qualify as a consultation—CPT E/M codes 99241-99245 for outpatients and 99251-99255 for inpatients (TABLE 1)—the evaluation must be requested by any of the following:¹

• a physician
• physician assistant
• nurse practitioner
• chiropractor
• physical therapist
• occupational therapist
• speech-language pathologist
• psychologist
• social worker
• lawyer
• insurance company.

If the consultation is mandated by a third-party payer, use modifier -32 to report it.

If the preop encounter does not meet this requirement, use the customary E/M codes instead.

The physician providing the consult must clearly document the request from the surgeon or other source in the medical record.¹ Our office satisfies this requirement by using a form that is faxed to the surgeon’s office at the time the preop visit is scheduled. The surgeon completes and signs the form (sometimes with a little prodding from our office staff) and faxes it back. The signed form is affixed to the patient’s chart and available at the time of the consultation visit.

TABLE 1
Consultation codes: The right way to use them