Applied Evidence

CASE A 28-year-old woman, gravida 4, para 3, requested medical termination of her pregnancy at approximately 7 weeks’ gestation. She was given intramuscular methotrexate 50 mg/m² and oral misoprostol 400 mcg. Nine weeks later, she presented at our primary care clinic complaining of mild pelvic pain. Given her history, we ordered transvaginal ultrasound, which showed a viable pregnancy with an average ultrasound age of 16 weeks’ gestation and grossly normal fetal anatomy. We counseled the patient regarding the risks associated with maintaining the pregnancy after exposure to methotrexate, and she and her husband elected to proceed with the pregnancy.

Throughout the pregnancy, a perinatologist conducted serial 2-dimensional ultrasounds. At 30 weeks’ gestation, ultrasound revealed mild hydrocephalus but yielded poor visualization of the kidneys, heart, and spine. A repeat ultrasound at 34 weeks demonstrated unchanged hydrocephalus and normal fetal anatomy with appropriate interval growth. A fetal echocardiogram in utero showed no cardiac anomalies. At 39 weeks, the patient underwent induction of labor due to severe oligohydramnios. A viable female infant weighing 2456 g was delivered by spontaneous vaginal delivery, with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively.

The infant was small for her gestational age. Her hands had 4 digits each, including the thumb (FIGURE 1A). The upper extremities were shorter than expected in relation to the infant’s torso and were locked in 90 degrees of flexion at the elbow (FIGURE 1B). Her lower extremities were both normal in length, but her left ankle joint was everted with considerable laxity at the tibiotalar joint. The infant’s mandible deviated to the right. An ultrasound of her head showed dilation of the lateral ventricle, consistent with nonobstructive hydrocephalus. A skeletal survey revealed bilateral radial-humeral synostosis at approximately 90 degrees of flexion. The second day after birth, the infant was transferred to a tertiary medical facility for further evaluation by pediatric subspecialists.

A pediatric orthopedic surgeon noted bilateral hip dysplasia and fitted the infant for a Pavlik harness. Ultrasound of the spine identified a dysmorphic sacrum with a thickened conus medullaris ending at the level of L2-L3, with increased risk for a tethered spinal cord. To correct the hydrocephalus, a neurosurgeon recommended intervention in the neonatal period. The parents were counseled to expect some degree of developmental disability, and karyotyping was performed to rule out potential genetically linked syndromes.

FIGURE 1

Methotrexate exposure led to these congenital anomalies

Methotrexate exposure at 7 weeks’ gestation resulted in this child having 4 digits on each hand (A), shortened arms locked in 90 degrees of flexion at the elbow, and an everted left ankle joint (B).

Risks associated with methotrexate

In the 1960s, methotrexate was commonly used as an abortifacient.¹ Its use for that purpose became rare, however, after multiple reports from the 1950s to the 1970s of congenital malformations in infants exposed to the drug in utero, either inadvertently or after attempted abortion.¹ In the 1990s, its use increased again in conjunction with misoprostol, primarily for medical management of suspected ectopic pregnancies and less often for elective terminations. Use of the combination resulted in fewer reports of congenital anomalies.¹

The failure rate of medical abortion using methotrexate varies. In 1999, one study reported an 8% failure rate when methotrexate was used with misoprostol.² In 2004, methotrexate alone led to a failure rate of 31% in medical termination of early pregnancy.³ In 2005, another study of methotrexate and misoprostol used in combination for elective termination reported a failure rate of 2% to 10%.⁴

Risk is not always foreseen

Methotrexate is widely used to treat such conditions as neoplastic disease and autoimmune disorders. Unintended exposure of a fetus to methotrexate is a very real possibility when the drug is used to treat a mother’s rheumatoid arthritis, psoriasis, or systemic lupus erythematosus. Methotrexate is a folic acid antagonist that produces its most teratogenic effects between 6 and 8 weeks postconception.⁴ Anomalies associated with methotrexate exposure include skull defects, central nervous system abnormalities, limb defects, gastrointestinal and cardiopulmonary defects, developmental delay, and cognitive impairment.⁴ Even at low doses and with short-term exposure, methotrexate can cause substantial fetal anomalies. In 2002, a woman who was unknowingly 3.5 weeks pregnant used oral methotrexate 7.5 mg/d for 2 days to treat her psoriasis.⁵ During a fetal anatomy sonogram at 18 weeks’ gestation, multiple anomalies were noted and later confirmed at fetopsy.

A meta-analysis on the safety of methotrexate in treating rheumatoid arthritis concluded that, for doses typical in this setting, data were lacking regarding the safety and risks of the drug during conception, pregnancy, and lactation.⁶ The review said that rheumatologists should discourage patients from continuing methotrexate if they wish to become pregnant, and that any continuing pregnancy should be closely monitored.⁶

The exact malformation rate after in utero exposure to methotrexate is unknown.⁷ Kozlowski et al reported 10 pregnancies in which the fetus was exposed to low-dose methotrexate (5 mg orally every week) for the treatment of rheumatoid arthritis.⁸ Five of the pregnancies were carried to term and the newborns exhibited no abnormalities, thus illustrating the drug’s variability for teratogenicity. The risk is real, however, and methotrexate can remain in human tissue for up to 8 months, thereby putting a fetus at risk for exposure even after a mother has discontinued the drug.²

The importance of primary care counsel

Incidental exposure. Inform any pregnant patient who has used methotrexate of the potential for congenital anomalies. The capacity to make educated decisions about elective termination of pregnancy requires a full disclosure of risks. In particular, ultrasound may not identify teratogenic effects from methotrexate exposure, and antenatal diagnosis of congenital anomalies is uncommon.⁹ Diagnosis is usually made at delivery. Thorough counseling on this point is imperative to prevent a false reassurance of having a normal fetus.

Did medical termination fail? Despite methotrexate’s widespread use for pregnancy termination, insufficient published data exist to guide the counseling of patients who have experienced a failed termination. Nevertheless, primary care physicians are often called on to counsel such patients.

Only about half of women who undergo a medical termination procedure attend follow-up visits with the abortion provider.¹⁰ One reason is the distance some patients travel and the associated costs. A 2000 report showed that 87% of counties in the United States lack even a single abortion provider, and that approximately 25% of women travel 50 miles or more for their abortions.¹¹

Financial hardship leads some women to opt for continuing a pregnancy after a failed elective termination.¹ That was the case with our patient. When she began experiencing pelvic pain after the termination procedure, she did not return to the abortion clinic, but instead sought guidance from her primary care physician at our medical center. After learning that she was 16 weeks pregnant, she opted to proceed with the pregnancy because she couldn’t afford a second elective termination.

Primary care involvement makes sense for other reasons as well. Protocols requiring in-person follow-up appointments after elective termination may not make the best use of the medical system.¹⁰ The high proportion of “no shows” can lead to scheduling difficulties and reduce a provider’s availability to perform abortions. This in turn would lead to a loss of income for the provider and could possibly increase the total cost of medical care.

One proposed solution has been to teach women how to recognize the signs and symptoms of a successful abortion or possible complications. However, a study of methotrexate-misoprostol abortion in the United States showed that women were often unable to assess whether they had successfully aborted.¹⁰ Of 50 women, 28 thought they had aborted by day 9, and 13 of those (46%) were still pregnant.¹⁰ A patient’s overestimation of her ability to make such judgments is thought to be another reason for the low follow-up rates post termination.

When termination is performed—regardless of the modality used—it is imperative to confirm that it was successful. Primary care providers, who are usually accessible and offer cost-effective care, can provide such confirmation. In addition, primary care physicians may need to address the psychological stress caused by elective termination.

CASE A 28-year-old woman, gravida 4, para 3, requested medical termination of her pregnancy at approximately 7 weeks’ gestation. She was given intramuscular methotrexate 50 mg/m² and oral misoprostol 400 mcg. Nine weeks later, she presented at our primary care clinic complaining of mild pelvic pain. Given her history, we ordered transvaginal ultrasound, which showed a viable pregnancy with an average ultrasound age of 16 weeks’ gestation and grossly normal fetal anatomy. We counseled the patient regarding the risks associated with maintaining the pregnancy after exposure to methotrexate, and she and her husband elected to proceed with the pregnancy.

Throughout the pregnancy, a perinatologist conducted serial 2-dimensional ultrasounds. At 30 weeks’ gestation, ultrasound revealed mild hydrocephalus but yielded poor visualization of the kidneys, heart, and spine. A repeat ultrasound at 34 weeks demonstrated unchanged hydrocephalus and normal fetal anatomy with appropriate interval growth. A fetal echocardiogram in utero showed no cardiac anomalies. At 39 weeks, the patient underwent induction of labor due to severe oligohydramnios. A viable female infant weighing 2456 g was delivered by spontaneous vaginal delivery, with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively.

The infant was small for her gestational age. Her hands had 4 digits each, including the thumb (FIGURE 1A). The upper extremities were shorter than expected in relation to the infant’s torso and were locked in 90 degrees of flexion at the elbow (FIGURE 1B). Her lower extremities were both normal in length, but her left ankle joint was everted with considerable laxity at the tibiotalar joint. The infant’s mandible deviated to the right. An ultrasound of her head showed dilation of the lateral ventricle, consistent with nonobstructive hydrocephalus. A skeletal survey revealed bilateral radial-humeral synostosis at approximately 90 degrees of flexion. The second day after birth, the infant was transferred to a tertiary medical facility for further evaluation by pediatric subspecialists.

A pediatric orthopedic surgeon noted bilateral hip dysplasia and fitted the infant for a Pavlik harness. Ultrasound of the spine identified a dysmorphic sacrum with a thickened conus medullaris ending at the level of L2-L3, with increased risk for a tethered spinal cord. To correct the hydrocephalus, a neurosurgeon recommended intervention in the neonatal period. The parents were counseled to expect some degree of developmental disability, and karyotyping was performed to rule out potential genetically linked syndromes.

FIGURE 1

Methotrexate exposure led to these congenital anomalies

Methotrexate exposure at 7 weeks’ gestation resulted in this child having 4 digits on each hand (A), shortened arms locked in 90 degrees of flexion at the elbow, and an everted left ankle joint (B).

Risks associated with methotrexate

In the 1960s, methotrexate was commonly used as an abortifacient.¹ Its use for that purpose became rare, however, after multiple reports from the 1950s to the 1970s of congenital malformations in infants exposed to the drug in utero, either inadvertently or after attempted abortion.¹ In the 1990s, its use increased again in conjunction with misoprostol, primarily for medical management of suspected ectopic pregnancies and less often for elective terminations. Use of the combination resulted in fewer reports of congenital anomalies.¹

The failure rate of medical abortion using methotrexate varies. In 1999, one study reported an 8% failure rate when methotrexate was used with misoprostol.² In 2004, methotrexate alone led to a failure rate of 31% in medical termination of early pregnancy.³ In 2005, another study of methotrexate and misoprostol used in combination for elective termination reported a failure rate of 2% to 10%.⁴

Risk is not always foreseen

Methotrexate is widely used to treat such conditions as neoplastic disease and autoimmune disorders. Unintended exposure of a fetus to methotrexate is a very real possibility when the drug is used to treat a mother’s rheumatoid arthritis, psoriasis, or systemic lupus erythematosus. Methotrexate is a folic acid antagonist that produces its most teratogenic effects between 6 and 8 weeks postconception.⁴ Anomalies associated with methotrexate exposure include skull defects, central nervous system abnormalities, limb defects, gastrointestinal and cardiopulmonary defects, developmental delay, and cognitive impairment.⁴ Even at low doses and with short-term exposure, methotrexate can cause substantial fetal anomalies. In 2002, a woman who was unknowingly 3.5 weeks pregnant used oral methotrexate 7.5 mg/d for 2 days to treat her psoriasis.⁵ During a fetal anatomy sonogram at 18 weeks’ gestation, multiple anomalies were noted and later confirmed at fetopsy.

A meta-analysis on the safety of methotrexate in treating rheumatoid arthritis concluded that, for doses typical in this setting, data were lacking regarding the safety and risks of the drug during conception, pregnancy, and lactation.⁶ The review said that rheumatologists should discourage patients from continuing methotrexate if they wish to become pregnant, and that any continuing pregnancy should be closely monitored.⁶

The exact malformation rate after in utero exposure to methotrexate is unknown.⁷ Kozlowski et al reported 10 pregnancies in which the fetus was exposed to low-dose methotrexate (5 mg orally every week) for the treatment of rheumatoid arthritis.⁸ Five of the pregnancies were carried to term and the newborns exhibited no abnormalities, thus illustrating the drug’s variability for teratogenicity. The risk is real, however, and methotrexate can remain in human tissue for up to 8 months, thereby putting a fetus at risk for exposure even after a mother has discontinued the drug.²

The importance of primary care counsel

Incidental exposure. Inform any pregnant patient who has used methotrexate of the potential for congenital anomalies. The capacity to make educated decisions about elective termination of pregnancy requires a full disclosure of risks. In particular, ultrasound may not identify teratogenic effects from methotrexate exposure, and antenatal diagnosis of congenital anomalies is uncommon.⁹ Diagnosis is usually made at delivery. Thorough counseling on this point is imperative to prevent a false reassurance of having a normal fetus.

Did medical termination fail? Despite methotrexate’s widespread use for pregnancy termination, insufficient published data exist to guide the counseling of patients who have experienced a failed termination. Nevertheless, primary care physicians are often called on to counsel such patients.

Only about half of women who undergo a medical termination procedure attend follow-up visits with the abortion provider.¹⁰ One reason is the distance some patients travel and the associated costs. A 2000 report showed that 87% of counties in the United States lack even a single abortion provider, and that approximately 25% of women travel 50 miles or more for their abortions.¹¹

Financial hardship leads some women to opt for continuing a pregnancy after a failed elective termination.¹ That was the case with our patient. When she began experiencing pelvic pain after the termination procedure, she did not return to the abortion clinic, but instead sought guidance from her primary care physician at our medical center. After learning that she was 16 weeks pregnant, she opted to proceed with the pregnancy because she couldn’t afford a second elective termination.

Primary care involvement makes sense for other reasons as well. Protocols requiring in-person follow-up appointments after elective termination may not make the best use of the medical system.¹⁰ The high proportion of “no shows” can lead to scheduling difficulties and reduce a provider’s availability to perform abortions. This in turn would lead to a loss of income for the provider and could possibly increase the total cost of medical care.

One proposed solution has been to teach women how to recognize the signs and symptoms of a successful abortion or possible complications. However, a study of methotrexate-misoprostol abortion in the United States showed that women were often unable to assess whether they had successfully aborted.¹⁰ Of 50 women, 28 thought they had aborted by day 9, and 13 of those (46%) were still pregnant.¹⁰ A patient’s overestimation of her ability to make such judgments is thought to be another reason for the low follow-up rates post termination.

When termination is performed—regardless of the modality used—it is imperative to confirm that it was successful. Primary care providers, who are usually accessible and offer cost-effective care, can provide such confirmation. In addition, primary care physicians may need to address the psychological stress caused by elective termination.

CASE A 28-year-old woman, gravida 4, para 3, requested medical termination of her pregnancy at approximately 7 weeks’ gestation. She was given intramuscular methotrexate 50 mg/m² and oral misoprostol 400 mcg. Nine weeks later, she presented at our primary care clinic complaining of mild pelvic pain. Given her history, we ordered transvaginal ultrasound, which showed a viable pregnancy with an average ultrasound age of 16 weeks’ gestation and grossly normal fetal anatomy. We counseled the patient regarding the risks associated with maintaining the pregnancy after exposure to methotrexate, and she and her husband elected to proceed with the pregnancy.

Throughout the pregnancy, a perinatologist conducted serial 2-dimensional ultrasounds. At 30 weeks’ gestation, ultrasound revealed mild hydrocephalus but yielded poor visualization of the kidneys, heart, and spine. A repeat ultrasound at 34 weeks demonstrated unchanged hydrocephalus and normal fetal anatomy with appropriate interval growth. A fetal echocardiogram in utero showed no cardiac anomalies. At 39 weeks, the patient underwent induction of labor due to severe oligohydramnios. A viable female infant weighing 2456 g was delivered by spontaneous vaginal delivery, with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively.

The infant was small for her gestational age. Her hands had 4 digits each, including the thumb (FIGURE 1A). The upper extremities were shorter than expected in relation to the infant’s torso and were locked in 90 degrees of flexion at the elbow (FIGURE 1B). Her lower extremities were both normal in length, but her left ankle joint was everted with considerable laxity at the tibiotalar joint. The infant’s mandible deviated to the right. An ultrasound of her head showed dilation of the lateral ventricle, consistent with nonobstructive hydrocephalus. A skeletal survey revealed bilateral radial-humeral synostosis at approximately 90 degrees of flexion. The second day after birth, the infant was transferred to a tertiary medical facility for further evaluation by pediatric subspecialists.

A pediatric orthopedic surgeon noted bilateral hip dysplasia and fitted the infant for a Pavlik harness. Ultrasound of the spine identified a dysmorphic sacrum with a thickened conus medullaris ending at the level of L2-L3, with increased risk for a tethered spinal cord. To correct the hydrocephalus, a neurosurgeon recommended intervention in the neonatal period. The parents were counseled to expect some degree of developmental disability, and karyotyping was performed to rule out potential genetically linked syndromes.

FIGURE 1

Methotrexate exposure led to these congenital anomalies

Methotrexate exposure at 7 weeks’ gestation resulted in this child having 4 digits on each hand (A), shortened arms locked in 90 degrees of flexion at the elbow, and an everted left ankle joint (B).

Risks associated with methotrexate

In the 1960s, methotrexate was commonly used as an abortifacient.¹ Its use for that purpose became rare, however, after multiple reports from the 1950s to the 1970s of congenital malformations in infants exposed to the drug in utero, either inadvertently or after attempted abortion.¹ In the 1990s, its use increased again in conjunction with misoprostol, primarily for medical management of suspected ectopic pregnancies and less often for elective terminations. Use of the combination resulted in fewer reports of congenital anomalies.¹

The failure rate of medical abortion using methotrexate varies. In 1999, one study reported an 8% failure rate when methotrexate was used with misoprostol.² In 2004, methotrexate alone led to a failure rate of 31% in medical termination of early pregnancy.³ In 2005, another study of methotrexate and misoprostol used in combination for elective termination reported a failure rate of 2% to 10%.⁴

Risk is not always foreseen

Methotrexate is widely used to treat such conditions as neoplastic disease and autoimmune disorders. Unintended exposure of a fetus to methotrexate is a very real possibility when the drug is used to treat a mother’s rheumatoid arthritis, psoriasis, or systemic lupus erythematosus. Methotrexate is a folic acid antagonist that produces its most teratogenic effects between 6 and 8 weeks postconception.⁴ Anomalies associated with methotrexate exposure include skull defects, central nervous system abnormalities, limb defects, gastrointestinal and cardiopulmonary defects, developmental delay, and cognitive impairment.⁴ Even at low doses and with short-term exposure, methotrexate can cause substantial fetal anomalies. In 2002, a woman who was unknowingly 3.5 weeks pregnant used oral methotrexate 7.5 mg/d for 2 days to treat her psoriasis.⁵ During a fetal anatomy sonogram at 18 weeks’ gestation, multiple anomalies were noted and later confirmed at fetopsy.

A meta-analysis on the safety of methotrexate in treating rheumatoid arthritis concluded that, for doses typical in this setting, data were lacking regarding the safety and risks of the drug during conception, pregnancy, and lactation.⁶ The review said that rheumatologists should discourage patients from continuing methotrexate if they wish to become pregnant, and that any continuing pregnancy should be closely monitored.⁶

The exact malformation rate after in utero exposure to methotrexate is unknown.⁷ Kozlowski et al reported 10 pregnancies in which the fetus was exposed to low-dose methotrexate (5 mg orally every week) for the treatment of rheumatoid arthritis.⁸ Five of the pregnancies were carried to term and the newborns exhibited no abnormalities, thus illustrating the drug’s variability for teratogenicity. The risk is real, however, and methotrexate can remain in human tissue for up to 8 months, thereby putting a fetus at risk for exposure even after a mother has discontinued the drug.²

The importance of primary care counsel

Incidental exposure. Inform any pregnant patient who has used methotrexate of the potential for congenital anomalies. The capacity to make educated decisions about elective termination of pregnancy requires a full disclosure of risks. In particular, ultrasound may not identify teratogenic effects from methotrexate exposure, and antenatal diagnosis of congenital anomalies is uncommon.⁹ Diagnosis is usually made at delivery. Thorough counseling on this point is imperative to prevent a false reassurance of having a normal fetus.

Did medical termination fail? Despite methotrexate’s widespread use for pregnancy termination, insufficient published data exist to guide the counseling of patients who have experienced a failed termination. Nevertheless, primary care physicians are often called on to counsel such patients.

Only about half of women who undergo a medical termination procedure attend follow-up visits with the abortion provider.¹⁰ One reason is the distance some patients travel and the associated costs. A 2000 report showed that 87% of counties in the United States lack even a single abortion provider, and that approximately 25% of women travel 50 miles or more for their abortions.¹¹

Financial hardship leads some women to opt for continuing a pregnancy after a failed elective termination.¹ That was the case with our patient. When she began experiencing pelvic pain after the termination procedure, she did not return to the abortion clinic, but instead sought guidance from her primary care physician at our medical center. After learning that she was 16 weeks pregnant, she opted to proceed with the pregnancy because she couldn’t afford a second elective termination.

Primary care involvement makes sense for other reasons as well. Protocols requiring in-person follow-up appointments after elective termination may not make the best use of the medical system.¹⁰ The high proportion of “no shows” can lead to scheduling difficulties and reduce a provider’s availability to perform abortions. This in turn would lead to a loss of income for the provider and could possibly increase the total cost of medical care.

One proposed solution has been to teach women how to recognize the signs and symptoms of a successful abortion or possible complications. However, a study of methotrexate-misoprostol abortion in the United States showed that women were often unable to assess whether they had successfully aborted.¹⁰ Of 50 women, 28 thought they had aborted by day 9, and 13 of those (46%) were still pregnant.¹⁰ A patient’s overestimation of her ability to make such judgments is thought to be another reason for the low follow-up rates post termination.

When termination is performed—regardless of the modality used—it is imperative to confirm that it was successful. Primary care providers, who are usually accessible and offer cost-effective care, can provide such confirmation. In addition, primary care physicians may need to address the psychological stress caused by elective termination.

A 42-year-old man with type 2 diabetes mellitus and hypertension was referred to our clinic for assessment of mixed hyperlipidemia found on routine investigation. Results of our physical examination were unremarkable. The patient had no xanthomatous deposits. His family history was strongly positive for type 2 diabetes. His medications included ramipril, glyburide, and hydrochlorothiazide.

In our further laboratory testing, a fasting blood sample revealed a grossly lipemic serum, with a total cholesterol level of 536.34 mg/dL (normal range=146.94-201.08 mg/dL), total triglyceride level of 5927.4 mg/dL (normal=31.15-151.3 mg/dL), and high-density cholesterol (HDL-C) level of 23.4 mg/dL (normal=35.1-93.6 mg/dL). His thyroid-stimulating hormone (TSH) level was 0.94 mIU/L (normal=0.49-4.67 mIU/L).

Results were in the normal range for urea, creatinine, electrolytes, bilirubin, alkaline phosphatase, alanine aminotransferase, and albumin. Hemoglobin A1c (HbA1c) was 9.5%.

Following clues to an accurate diagnosis

When the lipid phenotype is a mixed hyperlipidemia—a common disorder that becomes more prevalent with increasing age—investigate potential underlying disorders such as diabetes mellitus, renal failure, hypothyroidism, and chronic liver disease (TABLE 1). Ask about alcohol intake and use of medications including glucocorticoids and oral contraceptives. And explore the family history, particularly for premature heart disease, pancreatitis, and known lipid disorders. Epidemiologic studies have shown that higher-than-normal triglyceride levels increase the risk of coronary artery disease (CAD), and triglyceride levels greater than 500.44 mg/dL are associated with pancreatitis.¹

What to look for in the physical examination. Measure body mass index (BMI), check blood pressure and carotid and peripheral pulses, and palpate the liver and thyroid. Inspect palms, soles, extensor surfaces of the arms, buttocks, and tendinous attachments for xanthomatous deposits.

Lab work. Order a fasting glucose test, renal panel, thyroid function tests, and a liver panel to detect or rule out diabetes, hypothyroidism, and renal and liver disease. Typically, in dyslipidemia due to excessive alcohol intake or estrogen use, HDL cholesterol is disproportionately elevated (TABLE 1). Patients with hypertriglyceridemia may also present with acute pancreatitis and relatively low amylase levels, due to interference by triglyceride-rich lipoproteins that can show falsely low amylase levels. Removal of chylomicrons from plasma by centrifugation before laboratory testing can eliminate such artifacts.² In addition, hypertriglyceridemia can interfere with biochemical measurement of glucose, leading to falsely normal levels in these patients.³

To further refine the diagnosis, order lipoprotein electrophoresis, which identifies mixed hyperlipidemias according to the Fredrickson classification (types I–V).⁴

TABLE 1
Secondary causes of hyperlipidemia

Making sense of findings

Although patients with type 2 diabetes and hyperlipidemia most often have the type IV variety, they can also have other types, including type V. In uncontrolled diabetes, increased lipid metabolism mobilizes fat stores and increases VLDL and chylomicrons in plasma. Lipoprotein lipase activity is insulin dependent and is transiently reduced in insulin-deficient states, further increasing triglyceride levels.⁵

Hypothyroidism is classically associated with elevated plasma LDL cholesterol, but is also sometimes linked with high plasma triglycerides. The elevated plasma LDL cholesterol in hypothyroidism is due to reduced expression of LDL receptors resulting in impaired clearance of LDL.⁶ Elevated triglycerides in hypothyroidism are due to decreased lipoprotein lipase activity.⁷

Suspect primary (familial) hyperlipidemia (TABLE 2) if blood test results exclude such disorders as diabetes or hypothyroidism, and excessive alcohol intake and medication use have been ruled out. Some genetic causes of hyperchylomicronemia are rare and include familial lipoprotein lipase deficiency and apoprotein C-II deficiency. The differential diagnosis of mixed hyperlipidemia also includes familial combined hyperlipidemia (FCHL), familial dysbetalipoproteinemia, and familial hypertriglyceridemia.

FCHL can be difficult to differentiate from dyslipidemia of metabolic syndrome. A dominant inheritance pattern favors a diagnosis of FCHL, while environmental factors are more important in dyslipidemia of metabolic syndrome.⁸

TABLE 2
Primary hyperlipidemia

How my patient’s case resolved

My patient’s case was consistent with secondary dyslipidemia due to diabetes and metabolic syndrome. But patients with triglyceride levels above 2001.77 mg/dL almost always have both a secondary and a genetic form of hyperlipidemia.⁹ My colleagues and I suspected Fredrickson’s type V hyperlipoproteinemia because of the high triglycerides. This was confirmed when the lipoprotein electrophoresis showed decreased alpha, increased prebeta, and normal beta fractions and chylomicronemia.

Treatment. Therapy choices differ depending on the type of mixed hyperlipidemia a patient has. However, fibrates are usually needed in addition to statins. (Of note: Statin-induced myopathy is more likely in patients who are also taking fibrates, so careful monitoring is important.)

I added fenofibrate, metformin, and rosuvastatin to the patient’s regimen, which included ramipril, glyburide, and hydrochlorothiazide. I also recommended lifestyle modifications and arranged a consultation with a dietician.

Four weeks later, his fasting lipid profile had improved: Total serum cholesterol level was 213.45 mg/dL, triglyceride level was 825.5 mg/dL, and HDL-C level was 37.05 mg/dL. Apolipoprotein B100 was 2.54 g/L (normal=0.59-1.46 g/L). At follow-up 3 months later, the patient’s total cholesterol level was 145.9 mg/dL, triglyceride level was 330.4 mg/dL, and HDL-C level was 27.84 mg/dL.

CORRESPONDENCE H.U. Rehman, MB, Clinical Associate Professor, Department of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440 14th Avenue, Regina, SK, S4P 0W5, Canada; [email protected]

A 42-year-old man with type 2 diabetes mellitus and hypertension was referred to our clinic for assessment of mixed hyperlipidemia found on routine investigation. Results of our physical examination were unremarkable. The patient had no xanthomatous deposits. His family history was strongly positive for type 2 diabetes. His medications included ramipril, glyburide, and hydrochlorothiazide.

In our further laboratory testing, a fasting blood sample revealed a grossly lipemic serum, with a total cholesterol level of 536.34 mg/dL (normal range=146.94-201.08 mg/dL), total triglyceride level of 5927.4 mg/dL (normal=31.15-151.3 mg/dL), and high-density cholesterol (HDL-C) level of 23.4 mg/dL (normal=35.1-93.6 mg/dL). His thyroid-stimulating hormone (TSH) level was 0.94 mIU/L (normal=0.49-4.67 mIU/L).

Results were in the normal range for urea, creatinine, electrolytes, bilirubin, alkaline phosphatase, alanine aminotransferase, and albumin. Hemoglobin A1c (HbA1c) was 9.5%.

Following clues to an accurate diagnosis

When the lipid phenotype is a mixed hyperlipidemia—a common disorder that becomes more prevalent with increasing age—investigate potential underlying disorders such as diabetes mellitus, renal failure, hypothyroidism, and chronic liver disease (TABLE 1). Ask about alcohol intake and use of medications including glucocorticoids and oral contraceptives. And explore the family history, particularly for premature heart disease, pancreatitis, and known lipid disorders. Epidemiologic studies have shown that higher-than-normal triglyceride levels increase the risk of coronary artery disease (CAD), and triglyceride levels greater than 500.44 mg/dL are associated with pancreatitis.¹

What to look for in the physical examination. Measure body mass index (BMI), check blood pressure and carotid and peripheral pulses, and palpate the liver and thyroid. Inspect palms, soles, extensor surfaces of the arms, buttocks, and tendinous attachments for xanthomatous deposits.

Lab work. Order a fasting glucose test, renal panel, thyroid function tests, and a liver panel to detect or rule out diabetes, hypothyroidism, and renal and liver disease. Typically, in dyslipidemia due to excessive alcohol intake or estrogen use, HDL cholesterol is disproportionately elevated (TABLE 1). Patients with hypertriglyceridemia may also present with acute pancreatitis and relatively low amylase levels, due to interference by triglyceride-rich lipoproteins that can show falsely low amylase levels. Removal of chylomicrons from plasma by centrifugation before laboratory testing can eliminate such artifacts.² In addition, hypertriglyceridemia can interfere with biochemical measurement of glucose, leading to falsely normal levels in these patients.³

To further refine the diagnosis, order lipoprotein electrophoresis, which identifies mixed hyperlipidemias according to the Fredrickson classification (types I–V).⁴

TABLE 1
Secondary causes of hyperlipidemia

Making sense of findings

Although patients with type 2 diabetes and hyperlipidemia most often have the type IV variety, they can also have other types, including type V. In uncontrolled diabetes, increased lipid metabolism mobilizes fat stores and increases VLDL and chylomicrons in plasma. Lipoprotein lipase activity is insulin dependent and is transiently reduced in insulin-deficient states, further increasing triglyceride levels.⁵

Hypothyroidism is classically associated with elevated plasma LDL cholesterol, but is also sometimes linked with high plasma triglycerides. The elevated plasma LDL cholesterol in hypothyroidism is due to reduced expression of LDL receptors resulting in impaired clearance of LDL.⁶ Elevated triglycerides in hypothyroidism are due to decreased lipoprotein lipase activity.⁷

Suspect primary (familial) hyperlipidemia (TABLE 2) if blood test results exclude such disorders as diabetes or hypothyroidism, and excessive alcohol intake and medication use have been ruled out. Some genetic causes of hyperchylomicronemia are rare and include familial lipoprotein lipase deficiency and apoprotein C-II deficiency. The differential diagnosis of mixed hyperlipidemia also includes familial combined hyperlipidemia (FCHL), familial dysbetalipoproteinemia, and familial hypertriglyceridemia.

FCHL can be difficult to differentiate from dyslipidemia of metabolic syndrome. A dominant inheritance pattern favors a diagnosis of FCHL, while environmental factors are more important in dyslipidemia of metabolic syndrome.⁸

TABLE 2
Primary hyperlipidemia

How my patient’s case resolved

My patient’s case was consistent with secondary dyslipidemia due to diabetes and metabolic syndrome. But patients with triglyceride levels above 2001.77 mg/dL almost always have both a secondary and a genetic form of hyperlipidemia.⁹ My colleagues and I suspected Fredrickson’s type V hyperlipoproteinemia because of the high triglycerides. This was confirmed when the lipoprotein electrophoresis showed decreased alpha, increased prebeta, and normal beta fractions and chylomicronemia.

Treatment. Therapy choices differ depending on the type of mixed hyperlipidemia a patient has. However, fibrates are usually needed in addition to statins. (Of note: Statin-induced myopathy is more likely in patients who are also taking fibrates, so careful monitoring is important.)

I added fenofibrate, metformin, and rosuvastatin to the patient’s regimen, which included ramipril, glyburide, and hydrochlorothiazide. I also recommended lifestyle modifications and arranged a consultation with a dietician.

Four weeks later, his fasting lipid profile had improved: Total serum cholesterol level was 213.45 mg/dL, triglyceride level was 825.5 mg/dL, and HDL-C level was 37.05 mg/dL. Apolipoprotein B100 was 2.54 g/L (normal=0.59-1.46 g/L). At follow-up 3 months later, the patient’s total cholesterol level was 145.9 mg/dL, triglyceride level was 330.4 mg/dL, and HDL-C level was 27.84 mg/dL.

CORRESPONDENCE H.U. Rehman, MB, Clinical Associate Professor, Department of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440 14th Avenue, Regina, SK, S4P 0W5, Canada; [email protected]

A 42-year-old man with type 2 diabetes mellitus and hypertension was referred to our clinic for assessment of mixed hyperlipidemia found on routine investigation. Results of our physical examination were unremarkable. The patient had no xanthomatous deposits. His family history was strongly positive for type 2 diabetes. His medications included ramipril, glyburide, and hydrochlorothiazide.

In our further laboratory testing, a fasting blood sample revealed a grossly lipemic serum, with a total cholesterol level of 536.34 mg/dL (normal range=146.94-201.08 mg/dL), total triglyceride level of 5927.4 mg/dL (normal=31.15-151.3 mg/dL), and high-density cholesterol (HDL-C) level of 23.4 mg/dL (normal=35.1-93.6 mg/dL). His thyroid-stimulating hormone (TSH) level was 0.94 mIU/L (normal=0.49-4.67 mIU/L).

Results were in the normal range for urea, creatinine, electrolytes, bilirubin, alkaline phosphatase, alanine aminotransferase, and albumin. Hemoglobin A1c (HbA1c) was 9.5%.

Following clues to an accurate diagnosis

When the lipid phenotype is a mixed hyperlipidemia—a common disorder that becomes more prevalent with increasing age—investigate potential underlying disorders such as diabetes mellitus, renal failure, hypothyroidism, and chronic liver disease (TABLE 1). Ask about alcohol intake and use of medications including glucocorticoids and oral contraceptives. And explore the family history, particularly for premature heart disease, pancreatitis, and known lipid disorders. Epidemiologic studies have shown that higher-than-normal triglyceride levels increase the risk of coronary artery disease (CAD), and triglyceride levels greater than 500.44 mg/dL are associated with pancreatitis.¹

What to look for in the physical examination. Measure body mass index (BMI), check blood pressure and carotid and peripheral pulses, and palpate the liver and thyroid. Inspect palms, soles, extensor surfaces of the arms, buttocks, and tendinous attachments for xanthomatous deposits.

Lab work. Order a fasting glucose test, renal panel, thyroid function tests, and a liver panel to detect or rule out diabetes, hypothyroidism, and renal and liver disease. Typically, in dyslipidemia due to excessive alcohol intake or estrogen use, HDL cholesterol is disproportionately elevated (TABLE 1). Patients with hypertriglyceridemia may also present with acute pancreatitis and relatively low amylase levels, due to interference by triglyceride-rich lipoproteins that can show falsely low amylase levels. Removal of chylomicrons from plasma by centrifugation before laboratory testing can eliminate such artifacts.² In addition, hypertriglyceridemia can interfere with biochemical measurement of glucose, leading to falsely normal levels in these patients.³

To further refine the diagnosis, order lipoprotein electrophoresis, which identifies mixed hyperlipidemias according to the Fredrickson classification (types I–V).⁴

TABLE 1
Secondary causes of hyperlipidemia

Making sense of findings

Although patients with type 2 diabetes and hyperlipidemia most often have the type IV variety, they can also have other types, including type V. In uncontrolled diabetes, increased lipid metabolism mobilizes fat stores and increases VLDL and chylomicrons in plasma. Lipoprotein lipase activity is insulin dependent and is transiently reduced in insulin-deficient states, further increasing triglyceride levels.⁵

Hypothyroidism is classically associated with elevated plasma LDL cholesterol, but is also sometimes linked with high plasma triglycerides. The elevated plasma LDL cholesterol in hypothyroidism is due to reduced expression of LDL receptors resulting in impaired clearance of LDL.⁶ Elevated triglycerides in hypothyroidism are due to decreased lipoprotein lipase activity.⁷

Suspect primary (familial) hyperlipidemia (TABLE 2) if blood test results exclude such disorders as diabetes or hypothyroidism, and excessive alcohol intake and medication use have been ruled out. Some genetic causes of hyperchylomicronemia are rare and include familial lipoprotein lipase deficiency and apoprotein C-II deficiency. The differential diagnosis of mixed hyperlipidemia also includes familial combined hyperlipidemia (FCHL), familial dysbetalipoproteinemia, and familial hypertriglyceridemia.

FCHL can be difficult to differentiate from dyslipidemia of metabolic syndrome. A dominant inheritance pattern favors a diagnosis of FCHL, while environmental factors are more important in dyslipidemia of metabolic syndrome.⁸

TABLE 2
Primary hyperlipidemia

How my patient’s case resolved

My patient’s case was consistent with secondary dyslipidemia due to diabetes and metabolic syndrome. But patients with triglyceride levels above 2001.77 mg/dL almost always have both a secondary and a genetic form of hyperlipidemia.⁹ My colleagues and I suspected Fredrickson’s type V hyperlipoproteinemia because of the high triglycerides. This was confirmed when the lipoprotein electrophoresis showed decreased alpha, increased prebeta, and normal beta fractions and chylomicronemia.

Treatment. Therapy choices differ depending on the type of mixed hyperlipidemia a patient has. However, fibrates are usually needed in addition to statins. (Of note: Statin-induced myopathy is more likely in patients who are also taking fibrates, so careful monitoring is important.)

I added fenofibrate, metformin, and rosuvastatin to the patient’s regimen, which included ramipril, glyburide, and hydrochlorothiazide. I also recommended lifestyle modifications and arranged a consultation with a dietician.

Four weeks later, his fasting lipid profile had improved: Total serum cholesterol level was 213.45 mg/dL, triglyceride level was 825.5 mg/dL, and HDL-C level was 37.05 mg/dL. Apolipoprotein B100 was 2.54 g/L (normal=0.59-1.46 g/L). At follow-up 3 months later, the patient’s total cholesterol level was 145.9 mg/dL, triglyceride level was 330.4 mg/dL, and HDL-C level was 27.84 mg/dL.

CORRESPONDENCE H.U. Rehman, MB, Clinical Associate Professor, Department of Medicine, Regina Qu’Appelle Health Region, Regina General Hospital, 1440 14th Avenue, Regina, SK, S4P 0W5, Canada; [email protected]

During an annual visit, a patient confides in you that she and her husband have been trying to get pregnant for a year, but haven’t had any success. She tells you that she’s starting to get worried.

How do you advise her? What are your next steps?

The approach to evaluating infertility complaints is usually straightforward and can lead to a positive outcome. Not surprisingly, the dialogue often begins with you, the family physician. Your attention to clues in each partner’s history can do much to get to the heart of the problem. And even if a couple requires a specialty referral, it’s best to be familiar with the more extensive evaluation and management options they’ll encounter to help them anticipate likely discussions in their consultations. In this article, we review the best evidence for the care of your patients who want to conceive.

Who’s affected?

Infertility difficulties may be attributable to one or both partners, may be multifactorial, or may be unexplained (TABLE).

In women, infertility is the inability to conceive after 1 year of unprotected regular intercourse in those younger than 35 years, and after 6 months in those 35 years and older.¹ Fecundability is the probability of achieving pregnancy in 1 menstrual cycle. Normal fecundability with a single menstrual cycle is ~20%, peaking between the ages of 20 and 24 years.² Fecundability decreases slightly at age 32 and declines progressively and more rapidly after age 40. Spontaneous miscarriage is a factor; its rate in younger women is ~10% and in women >40 years is ~40%.² Overall, approximately 13% of women between the ages of 15 and 44 have fecundity impairment, with more than 6 million women in the United States affected.²

About 24% of all cases of infertility are due to male factors—seminiferous dysfunction, including problems with motility, morphology, and volume of sperm; primary hypogonadism; posttesticular defects; and hypothalamic pituitary disease.³ Recent observational trends show declines in fertility among men older than 40, and among men from different areas in the country, thus raising the issue of the role that environmental pollutants or toxins may play. Supposed increases in urogenital abnormalities and testicular cancers may also contribute to declining fertility rates.^4,5

TABLE
Consider these factors in cases of suspected infertility^{3,6,21,23,40,41}

Zero in on these areas of the history
As with any diagnostic work-up, the most important aspect of an infertility evaluation is the history. Document menstrual cycle length and regularity and the timing of intercourse. (Ideally, this would be done when a couple first decides to conceive.) It’s important to know how long the couple has been trying to become pregnant. More time may be all they need to achieve pregnancy. Educate them on reproductive cycles and optimal timing to achieve pregnancy. Some women experience lower abdominal pain (mittelschmerz) signifying release of an egg from the ovary, which can help identify the time of ovulation.

Remember, too, the role that a couple’s psychological state can play; worries over suspected infertility may cause anxiety, anger, depression, and marital troubles.

Is it her?

Regular menstrual cycles—menses occurring every 21 to 35 days—carry an ovulation probability of 95% with each cycle.⁶ With normal menses, ovulatory dysfunction is an unlikely cause of infertility. If menstrual cycles are irregular, ovulatory function is not normal and cyclical. Explore the woman’s medical, surgical, and gynecologic histories, looking particularly for thyroid disease, galactorrhea, hirsutism, pelvic or abdominal pain, dysmenorrhea, dyspareunia, pelvic inflammatory disease (PID), and abdominal or pelvic surgery.

The fallopian tubes. When menstruation is normal, evaluate the fallopian tubes and their patency; 30% to 40% of infertility cases can be related to peritoneal pathology.^3,7 Inability to conceive in a previous relationship, history of PID, or prior tubal surgery all correlate to infertility. Ten percent of patients with a history of one PID episode and 54% to 75% of patients with 3 episodes will have patency issues.⁷

Consider arranging for a hysterosalpingogram (HSG) in all patients as part of an initial work-up for infertility.⁸ HSG is useful in evaluating tubal patency and the uterine cavity, and it can be therapeutic. HSG is not useful in detecting peritubal adhesions or endometriosis; patients in whom you suspect these conditions should undergo diagnostic laparoscopy. If abnormalities are found on HSG, refer patients to a reproductive endocrinologist to evaluate treatment options.

Chlamydia trachomatis IgG antibody testing can predict the presence of tubal disease. For women with low risk of tubal disease, it may be more cost effective to test for the Chlamydia antibody and proceed with HSG if the result is positive. Antibody testing is also useful for women with an allergy to contrast dye who cannot undergo an HSG. If the antibody test result is positive, consider arranging for a sonohysterogram to evaluate for the presence of fluid in the cul-de-sac, or an intrauterine infusion of saline to evaluate the patency of at least one tube.⁹

Ovulatory function. To assess ovulatory function, measure a midluteal-phase serum progesterone level, drawn 1 week before the expected day of menses (Day 21 of a 28-day cycle). A level >3 ng/mL is evidence of ovulation. Over-the-counter ovulation kits detect the luteinizing hormone (LH) surge but have false-positive and false-negative rates of 5% to 10%, respectively.¹⁰ Recording basal body temperature is a noninvasive and inexpensive means of evaluating ovulation. The patient must record temperatures at exactly the same time each day. Have her log the temperatures and watch for a spike that occurs 1 to 2 days after the LH surge. The average woman’s temperature rises above 98ºF in progressing from the follicular to the luteal phase. Since the spike occurs 1 to 2 days after ovulation, this method is best used for many months so the woman can predict her cycle.¹¹

Once timing of ovulation has been established, you can check lab results at Day 3 of the woman’s cycle for follicle-stimulating hormone (FSH), LH, estradiol, thyroid-stimulating hormone (TSH), prolactin, and 2-hour fasting glucose tolerance. In addition to polycystic ovarian syndrome (PCOS), patients may have ovulatory dysfunction secondary to glucose intolerance.

A clomiphene (Clomid) challenge can help in assessing ovarian reserve. Administer 100 mg clomiphene on Days 5 through 9 of the patient’s cycle, and check FSH and estradiol levels on Day 10. With diminished ovarian reserve, FSH will increase to >12 mIU/mL and estradiol to >300 pg/mL.¹² If this occurs, consider referring for an ultrasound measurement of antral follicle count. The presence of 4 to 10 follicles measuring 2 to 10 mm in diameter suggests adequate reserve.¹³

Although not widely available in the United States, the test for antimüllerian hormone (AMH) levels may be useful in reflecting the size of the primordial follicle pool. At menopause, the level is undetectable. A level above 0.5 ng/mL correlates with good ovarian reserve; levels <0.15 ng/mL suggest poor response to in vitro fertilization (IVF).¹⁴

Endocrine factors account for 45% to 55% of female infertility and include thyroid disease, PCOS, diabetes mellitus, prolactinemia, and luteal phase defects. Subclinical hypothyroidism, often evidenced only by high levels of TSH, decreases the chance of a successful pregnancy. This can occur even if the dysfunction is not severe enough to affect cycle regularity.¹⁵ Clinical hypo- or hyperthyroidism can affect ovulation by interfering with normal hormonal feedback loops, and correcting thyroid disease can improve fertility.

Galactorrhea discovered during the history and physical may be caused by elevated prolactin levels, which also inhibit normal ovulatory function. Chronically elevated prolactin levels in patients with PCOS can be attributed to elevated estrogen levels. Adiposity, acne, and hirsutism with menstrual irregularity can indicate PCOS as the primary cause, and your work-up should focus on a hyperandrogenic state.¹⁶ Low or normal FSH levels are common in patients with PCOS. Also test for 17a-hydroxyprogestrone and serum testosterone levels.¹⁷

Endometriosis. How endometriosis affects fertility is controversial. One hypothesis is that it is associated with overproduction of prostaglandins, metalloproteinases, cytokines, and chemokines. The inflammatory process impairs ovarian, peritoneal, tubal, and endometrial function.¹⁸

Discourage the use of the postcoital test. Patients may inquire about this test, in which the cervical mucus is obtained after intercourse to assess stretch ability and sperm motility. This test has been used for more than a century, but has poor predictive value and is not recommended.¹⁹

Or is it him?

Inquire about sexual development and medical history, including mumps orchitis or other infections, sinopulmonary symptoms suggesting cystic fibrosis, sexually transmitted infections (STIs) and genitourinary infections, and surgical procedures of the inguinal and scrotal areas. Also ask about prescription and illicit drug use, environmental exposures, and sexual history.

Physical exam. Look for signs of androgen deficiency, such as an arm span >2 cm longer than height (eunuchoidal proportions), or loss of pubic, axillary, or facial hair.²⁰ Examine the external genitalia to evaluate for complete sexual development (Tanner stage of 5). The scrotum can provide clues to disorders that can affect sperm maturation and transport. Examination may reveal absence of the vas deferens, epididymal thickening, varicocele, or hernia.²¹ Testicular volume, if <15 mL with testicular length <3.6 cm, can point to a decreased number of seminiferous tubules.²¹

Semen analysis. If the physical examination is normal, analyze semen for volume and pH; microscopic debris and agglutination; sperm concentration, motility, and morphology; leukocyte count; and immature germ cells. Have the man abstain from sex for 2 to 7 days before semen collection. If collection is not possible to do in the office, the patient can drop it off at a lab within an hour of collection. Analyze 2 samples at least 2 weeks apart.²²

More detailed semen analysis can be done, especially if evaluation of the female partner does not reveal a cause of infertility. Tests include sperm autoantibodies, sperm biochemistry, semen culture, sperm function tests, and sperm-cervical mucus interaction. Typically, these tests and further evaluation of the male partner after an abnormal semen analysis are best done by a urologist specializing in reproduction.

Oligospermia or azoospermia point toward hypogonadism. Elevated morning FSH and low total testosterone correlate with primary hypogonadism, whereas low levels of both hormones correlate with secondary hypogonadism. Hyperprolactinemia is a cause of secondary hypogonadism.³ Low volume of semen can be further evaluated by testing a postejaculatory urinalysis and transrectal ultrasonography to rule out retrograde ejaculation and ejaculatory duct obstruction.²³

Fixing the problem
Focus initial counseling for couples on lifestyle modifications. Advise patients to quit smoking, reduce excessive caffeine and alcohol consumption, and engage in intercourse every day or every other day around ovulation. Patients should also avoid lubricants and douching as they can interfere with sperm deposition.

Managing female infertility

Tubal, pelvic, and uterine infertility. Patients with bilateral tubal obstruction may wish to undergo tubal reconstruction, especially if IVF treatments are not readily available to them. Counsel them that surgery for proximal tubal occlusion is not effective and the risk of ectopic pregnancy in the future is high, at approximately 20%.²⁴ Because of the low efficacy of surgery and high ectopic rate, most patients with tubal disease favor IVF. Patients with endometriosis sometimes benefit from laser ablation or surgical resection, but often do well with intrauterine insemination (IUI) or IVF in conjunction with ovulation induction.²⁵ Uterine abnormalities including submucous fibroid, endometrial polyp, septate uterus, or uterine synechiae frequently benefit from surgical correction.²⁶ Patients with irreparable defects may want to consider a surrogate.

Ovulatory dysfunction. Anovulation can be hypogonadotropic hypogonadal (secondary to functional factors such as exercise and weight), normogonadotropic normoestrogenic with PCOS, or hypergonadotropic hypoestrogenic infertility (premature ovarian failure).

A body mass index >17 and <27 kg/m² is optimal to achieve fertility and to sustain a healthy pregnancy.²⁷ Individuals who are obese or very thin or who overexercise and do not respond to behavioral modification are known to benefit from pulsatile gonadotropin-releasing hormone therapy. This treatment, however, is not available in the United States.²⁸

Dopaminergic agents can restore normal ovulation in patients with hyperprolactinemia,²⁹ but they should receive ovulation induction first. Patients who have glucose intolerance may benefit from an insulin-sensitizing agent such as metformin. It is particularly useful if patients also have PCOS; however, it is not an FDA-approved indication for the medication. Clomiphene has recently been shown to result in a higher rate of ovulation, but not pregnancy, than metformin.³⁰

Most patients with ovulatory dysfunction are best treated with clomiphene.³¹ Give 50 mg of the drug on cycle Days 3 through 7; ovulation occurs between Days 10 through 15.¹² If, after the first cycle, pregnancy has not occurred, increase the dose by 50 mg with each cycle, to a maximum of 150 mg daily.³² Higher doses are not FDA approved, nor are they more effective. Clomiphene is most effective in the first 6 cycles, and the American Congress of Obstetricians and Gynecologists recommends limiting its use to fewer than 12 cycles due to the risk of ovarian neoplasm.³³ Clomiphene yields an ovulation rate of 73% and a pregnancy rate of 36% per cycle. Multiple births, primarily twinning, occur at a rate of 8% to 13%.³³ If clomiphene is unsuccessful, refer patients to a reproductive endocrinologist for evaluation for IVF and injectable ovulation-inducing agents.

Managing male infertility

Men who have hyperprolactinemic infertility can often be treated with dopaminergic agents such as bromocriptine. Inform them that normal spermatogenesis can take 3 to 6 months. Gonadotropin therapy may be effective for patients with hypothalamic or pituitary diseases. Surgery may correct obstruction, but may not actually increase pregnancy rates. Repairing a varicocele, for instance, increases sperm counts but not conception rates.³⁴ Other obstructive problems may need sperm extraction followed by IUI or IVF, with or without intracytoplasmic sperm injection, where the sperm is injected into the ovum in the lab before implantation.³⁴

Managing unexplained infertility

Fifteen percent of infertility is unexplained.³⁵ Assisting these patients is challenging. Performing IUI with or without clomiphene, or giving clomiphene alone is often attempted. Pregnancy rates are 2% for expectant management, 5% for IUI alone, 9.5% for clomiphene alone, and 19% for combined IUI with clomiphene.³⁶ Gonadotropins are no more effective in achieving conception than clomiphene, but gonadotropin injection and IUI together are more effective than no treatment.³⁷ IVF, if successful, leads to pregnancy in the shortest amount of time. But it is the most costly intervention and the most likely to result in multiple births. In randomized controlled trials, however, IVF has not proved beneficial for unexplained infertility.³⁸

Trends likely to affect fertility treatment
Currently in the United States, there is little regulation to guide reproductive technologies. But there is a trend, varying by state, toward legislation similar to child protection laws and adoption services, under which couples are evaluated for suitability as parents for the potential child’s safety.³⁹ Other countries have acts regulating reproductive technologies and infertility services. England focuses on the child’s welfare; Australia restricts access by eligibility requirements.³⁹ In the United States we may see similar policies, especially as controversy grows regarding multiple births. Cost is a factor in the treatment of infertility. Education and household income correlate with the amount of money spent on fertility care.

CORRESPONDENCE Heather Bell, MD, Center for Family Medicine, 1115 East 20th Street, Sioux Falls, SD 57105; [email protected]

During an annual visit, a patient confides in you that she and her husband have been trying to get pregnant for a year, but haven’t had any success. She tells you that she’s starting to get worried.

How do you advise her? What are your next steps?

The approach to evaluating infertility complaints is usually straightforward and can lead to a positive outcome. Not surprisingly, the dialogue often begins with you, the family physician. Your attention to clues in each partner’s history can do much to get to the heart of the problem. And even if a couple requires a specialty referral, it’s best to be familiar with the more extensive evaluation and management options they’ll encounter to help them anticipate likely discussions in their consultations. In this article, we review the best evidence for the care of your patients who want to conceive.

Who’s affected?

Infertility difficulties may be attributable to one or both partners, may be multifactorial, or may be unexplained (TABLE).

In women, infertility is the inability to conceive after 1 year of unprotected regular intercourse in those younger than 35 years, and after 6 months in those 35 years and older.¹ Fecundability is the probability of achieving pregnancy in 1 menstrual cycle. Normal fecundability with a single menstrual cycle is ~20%, peaking between the ages of 20 and 24 years.² Fecundability decreases slightly at age 32 and declines progressively and more rapidly after age 40. Spontaneous miscarriage is a factor; its rate in younger women is ~10% and in women >40 years is ~40%.² Overall, approximately 13% of women between the ages of 15 and 44 have fecundity impairment, with more than 6 million women in the United States affected.²

About 24% of all cases of infertility are due to male factors—seminiferous dysfunction, including problems with motility, morphology, and volume of sperm; primary hypogonadism; posttesticular defects; and hypothalamic pituitary disease.³ Recent observational trends show declines in fertility among men older than 40, and among men from different areas in the country, thus raising the issue of the role that environmental pollutants or toxins may play. Supposed increases in urogenital abnormalities and testicular cancers may also contribute to declining fertility rates.^4,5

TABLE
Consider these factors in cases of suspected infertility^{3,6,21,23,40,41}

Zero in on these areas of the history
As with any diagnostic work-up, the most important aspect of an infertility evaluation is the history. Document menstrual cycle length and regularity and the timing of intercourse. (Ideally, this would be done when a couple first decides to conceive.) It’s important to know how long the couple has been trying to become pregnant. More time may be all they need to achieve pregnancy. Educate them on reproductive cycles and optimal timing to achieve pregnancy. Some women experience lower abdominal pain (mittelschmerz) signifying release of an egg from the ovary, which can help identify the time of ovulation.

Remember, too, the role that a couple’s psychological state can play; worries over suspected infertility may cause anxiety, anger, depression, and marital troubles.

Is it her?

Regular menstrual cycles—menses occurring every 21 to 35 days—carry an ovulation probability of 95% with each cycle.⁶ With normal menses, ovulatory dysfunction is an unlikely cause of infertility. If menstrual cycles are irregular, ovulatory function is not normal and cyclical. Explore the woman’s medical, surgical, and gynecologic histories, looking particularly for thyroid disease, galactorrhea, hirsutism, pelvic or abdominal pain, dysmenorrhea, dyspareunia, pelvic inflammatory disease (PID), and abdominal or pelvic surgery.

The fallopian tubes. When menstruation is normal, evaluate the fallopian tubes and their patency; 30% to 40% of infertility cases can be related to peritoneal pathology.^3,7 Inability to conceive in a previous relationship, history of PID, or prior tubal surgery all correlate to infertility. Ten percent of patients with a history of one PID episode and 54% to 75% of patients with 3 episodes will have patency issues.⁷

Consider arranging for a hysterosalpingogram (HSG) in all patients as part of an initial work-up for infertility.⁸ HSG is useful in evaluating tubal patency and the uterine cavity, and it can be therapeutic. HSG is not useful in detecting peritubal adhesions or endometriosis; patients in whom you suspect these conditions should undergo diagnostic laparoscopy. If abnormalities are found on HSG, refer patients to a reproductive endocrinologist to evaluate treatment options.

Chlamydia trachomatis IgG antibody testing can predict the presence of tubal disease. For women with low risk of tubal disease, it may be more cost effective to test for the Chlamydia antibody and proceed with HSG if the result is positive. Antibody testing is also useful for women with an allergy to contrast dye who cannot undergo an HSG. If the antibody test result is positive, consider arranging for a sonohysterogram to evaluate for the presence of fluid in the cul-de-sac, or an intrauterine infusion of saline to evaluate the patency of at least one tube.⁹

Ovulatory function. To assess ovulatory function, measure a midluteal-phase serum progesterone level, drawn 1 week before the expected day of menses (Day 21 of a 28-day cycle). A level >3 ng/mL is evidence of ovulation. Over-the-counter ovulation kits detect the luteinizing hormone (LH) surge but have false-positive and false-negative rates of 5% to 10%, respectively.¹⁰ Recording basal body temperature is a noninvasive and inexpensive means of evaluating ovulation. The patient must record temperatures at exactly the same time each day. Have her log the temperatures and watch for a spike that occurs 1 to 2 days after the LH surge. The average woman’s temperature rises above 98ºF in progressing from the follicular to the luteal phase. Since the spike occurs 1 to 2 days after ovulation, this method is best used for many months so the woman can predict her cycle.¹¹

Once timing of ovulation has been established, you can check lab results at Day 3 of the woman’s cycle for follicle-stimulating hormone (FSH), LH, estradiol, thyroid-stimulating hormone (TSH), prolactin, and 2-hour fasting glucose tolerance. In addition to polycystic ovarian syndrome (PCOS), patients may have ovulatory dysfunction secondary to glucose intolerance.

A clomiphene (Clomid) challenge can help in assessing ovarian reserve. Administer 100 mg clomiphene on Days 5 through 9 of the patient’s cycle, and check FSH and estradiol levels on Day 10. With diminished ovarian reserve, FSH will increase to >12 mIU/mL and estradiol to >300 pg/mL.¹² If this occurs, consider referring for an ultrasound measurement of antral follicle count. The presence of 4 to 10 follicles measuring 2 to 10 mm in diameter suggests adequate reserve.¹³

Although not widely available in the United States, the test for antimüllerian hormone (AMH) levels may be useful in reflecting the size of the primordial follicle pool. At menopause, the level is undetectable. A level above 0.5 ng/mL correlates with good ovarian reserve; levels <0.15 ng/mL suggest poor response to in vitro fertilization (IVF).¹⁴

Endocrine factors account for 45% to 55% of female infertility and include thyroid disease, PCOS, diabetes mellitus, prolactinemia, and luteal phase defects. Subclinical hypothyroidism, often evidenced only by high levels of TSH, decreases the chance of a successful pregnancy. This can occur even if the dysfunction is not severe enough to affect cycle regularity.¹⁵ Clinical hypo- or hyperthyroidism can affect ovulation by interfering with normal hormonal feedback loops, and correcting thyroid disease can improve fertility.

Galactorrhea discovered during the history and physical may be caused by elevated prolactin levels, which also inhibit normal ovulatory function. Chronically elevated prolactin levels in patients with PCOS can be attributed to elevated estrogen levels. Adiposity, acne, and hirsutism with menstrual irregularity can indicate PCOS as the primary cause, and your work-up should focus on a hyperandrogenic state.¹⁶ Low or normal FSH levels are common in patients with PCOS. Also test for 17a-hydroxyprogestrone and serum testosterone levels.¹⁷

Endometriosis. How endometriosis affects fertility is controversial. One hypothesis is that it is associated with overproduction of prostaglandins, metalloproteinases, cytokines, and chemokines. The inflammatory process impairs ovarian, peritoneal, tubal, and endometrial function.¹⁸

Discourage the use of the postcoital test. Patients may inquire about this test, in which the cervical mucus is obtained after intercourse to assess stretch ability and sperm motility. This test has been used for more than a century, but has poor predictive value and is not recommended.¹⁹

Or is it him?

Inquire about sexual development and medical history, including mumps orchitis or other infections, sinopulmonary symptoms suggesting cystic fibrosis, sexually transmitted infections (STIs) and genitourinary infections, and surgical procedures of the inguinal and scrotal areas. Also ask about prescription and illicit drug use, environmental exposures, and sexual history.

Physical exam. Look for signs of androgen deficiency, such as an arm span >2 cm longer than height (eunuchoidal proportions), or loss of pubic, axillary, or facial hair.²⁰ Examine the external genitalia to evaluate for complete sexual development (Tanner stage of 5). The scrotum can provide clues to disorders that can affect sperm maturation and transport. Examination may reveal absence of the vas deferens, epididymal thickening, varicocele, or hernia.²¹ Testicular volume, if <15 mL with testicular length <3.6 cm, can point to a decreased number of seminiferous tubules.²¹

Semen analysis. If the physical examination is normal, analyze semen for volume and pH; microscopic debris and agglutination; sperm concentration, motility, and morphology; leukocyte count; and immature germ cells. Have the man abstain from sex for 2 to 7 days before semen collection. If collection is not possible to do in the office, the patient can drop it off at a lab within an hour of collection. Analyze 2 samples at least 2 weeks apart.²²

More detailed semen analysis can be done, especially if evaluation of the female partner does not reveal a cause of infertility. Tests include sperm autoantibodies, sperm biochemistry, semen culture, sperm function tests, and sperm-cervical mucus interaction. Typically, these tests and further evaluation of the male partner after an abnormal semen analysis are best done by a urologist specializing in reproduction.

Oligospermia or azoospermia point toward hypogonadism. Elevated morning FSH and low total testosterone correlate with primary hypogonadism, whereas low levels of both hormones correlate with secondary hypogonadism. Hyperprolactinemia is a cause of secondary hypogonadism.³ Low volume of semen can be further evaluated by testing a postejaculatory urinalysis and transrectal ultrasonography to rule out retrograde ejaculation and ejaculatory duct obstruction.²³

Fixing the problem
Focus initial counseling for couples on lifestyle modifications. Advise patients to quit smoking, reduce excessive caffeine and alcohol consumption, and engage in intercourse every day or every other day around ovulation. Patients should also avoid lubricants and douching as they can interfere with sperm deposition.

Managing female infertility

Tubal, pelvic, and uterine infertility. Patients with bilateral tubal obstruction may wish to undergo tubal reconstruction, especially if IVF treatments are not readily available to them. Counsel them that surgery for proximal tubal occlusion is not effective and the risk of ectopic pregnancy in the future is high, at approximately 20%.²⁴ Because of the low efficacy of surgery and high ectopic rate, most patients with tubal disease favor IVF. Patients with endometriosis sometimes benefit from laser ablation or surgical resection, but often do well with intrauterine insemination (IUI) or IVF in conjunction with ovulation induction.²⁵ Uterine abnormalities including submucous fibroid, endometrial polyp, septate uterus, or uterine synechiae frequently benefit from surgical correction.²⁶ Patients with irreparable defects may want to consider a surrogate.

Ovulatory dysfunction. Anovulation can be hypogonadotropic hypogonadal (secondary to functional factors such as exercise and weight), normogonadotropic normoestrogenic with PCOS, or hypergonadotropic hypoestrogenic infertility (premature ovarian failure).

A body mass index >17 and <27 kg/m² is optimal to achieve fertility and to sustain a healthy pregnancy.²⁷ Individuals who are obese or very thin or who overexercise and do not respond to behavioral modification are known to benefit from pulsatile gonadotropin-releasing hormone therapy. This treatment, however, is not available in the United States.²⁸

Dopaminergic agents can restore normal ovulation in patients with hyperprolactinemia,²⁹ but they should receive ovulation induction first. Patients who have glucose intolerance may benefit from an insulin-sensitizing agent such as metformin. It is particularly useful if patients also have PCOS; however, it is not an FDA-approved indication for the medication. Clomiphene has recently been shown to result in a higher rate of ovulation, but not pregnancy, than metformin.³⁰

Most patients with ovulatory dysfunction are best treated with clomiphene.³¹ Give 50 mg of the drug on cycle Days 3 through 7; ovulation occurs between Days 10 through 15.¹² If, after the first cycle, pregnancy has not occurred, increase the dose by 50 mg with each cycle, to a maximum of 150 mg daily.³² Higher doses are not FDA approved, nor are they more effective. Clomiphene is most effective in the first 6 cycles, and the American Congress of Obstetricians and Gynecologists recommends limiting its use to fewer than 12 cycles due to the risk of ovarian neoplasm.³³ Clomiphene yields an ovulation rate of 73% and a pregnancy rate of 36% per cycle. Multiple births, primarily twinning, occur at a rate of 8% to 13%.³³ If clomiphene is unsuccessful, refer patients to a reproductive endocrinologist for evaluation for IVF and injectable ovulation-inducing agents.

Managing male infertility

Men who have hyperprolactinemic infertility can often be treated with dopaminergic agents such as bromocriptine. Inform them that normal spermatogenesis can take 3 to 6 months. Gonadotropin therapy may be effective for patients with hypothalamic or pituitary diseases. Surgery may correct obstruction, but may not actually increase pregnancy rates. Repairing a varicocele, for instance, increases sperm counts but not conception rates.³⁴ Other obstructive problems may need sperm extraction followed by IUI or IVF, with or without intracytoplasmic sperm injection, where the sperm is injected into the ovum in the lab before implantation.³⁴

Managing unexplained infertility

Fifteen percent of infertility is unexplained.³⁵ Assisting these patients is challenging. Performing IUI with or without clomiphene, or giving clomiphene alone is often attempted. Pregnancy rates are 2% for expectant management, 5% for IUI alone, 9.5% for clomiphene alone, and 19% for combined IUI with clomiphene.³⁶ Gonadotropins are no more effective in achieving conception than clomiphene, but gonadotropin injection and IUI together are more effective than no treatment.³⁷ IVF, if successful, leads to pregnancy in the shortest amount of time. But it is the most costly intervention and the most likely to result in multiple births. In randomized controlled trials, however, IVF has not proved beneficial for unexplained infertility.³⁸

Trends likely to affect fertility treatment
Currently in the United States, there is little regulation to guide reproductive technologies. But there is a trend, varying by state, toward legislation similar to child protection laws and adoption services, under which couples are evaluated for suitability as parents for the potential child’s safety.³⁹ Other countries have acts regulating reproductive technologies and infertility services. England focuses on the child’s welfare; Australia restricts access by eligibility requirements.³⁹ In the United States we may see similar policies, especially as controversy grows regarding multiple births. Cost is a factor in the treatment of infertility. Education and household income correlate with the amount of money spent on fertility care.

CORRESPONDENCE Heather Bell, MD, Center for Family Medicine, 1115 East 20th Street, Sioux Falls, SD 57105; [email protected]

During an annual visit, a patient confides in you that she and her husband have been trying to get pregnant for a year, but haven’t had any success. She tells you that she’s starting to get worried.

How do you advise her? What are your next steps?

The approach to evaluating infertility complaints is usually straightforward and can lead to a positive outcome. Not surprisingly, the dialogue often begins with you, the family physician. Your attention to clues in each partner’s history can do much to get to the heart of the problem. And even if a couple requires a specialty referral, it’s best to be familiar with the more extensive evaluation and management options they’ll encounter to help them anticipate likely discussions in their consultations. In this article, we review the best evidence for the care of your patients who want to conceive.

Who’s affected?

Infertility difficulties may be attributable to one or both partners, may be multifactorial, or may be unexplained (TABLE).

In women, infertility is the inability to conceive after 1 year of unprotected regular intercourse in those younger than 35 years, and after 6 months in those 35 years and older.¹ Fecundability is the probability of achieving pregnancy in 1 menstrual cycle. Normal fecundability with a single menstrual cycle is ~20%, peaking between the ages of 20 and 24 years.² Fecundability decreases slightly at age 32 and declines progressively and more rapidly after age 40. Spontaneous miscarriage is a factor; its rate in younger women is ~10% and in women >40 years is ~40%.² Overall, approximately 13% of women between the ages of 15 and 44 have fecundity impairment, with more than 6 million women in the United States affected.²

About 24% of all cases of infertility are due to male factors—seminiferous dysfunction, including problems with motility, morphology, and volume of sperm; primary hypogonadism; posttesticular defects; and hypothalamic pituitary disease.³ Recent observational trends show declines in fertility among men older than 40, and among men from different areas in the country, thus raising the issue of the role that environmental pollutants or toxins may play. Supposed increases in urogenital abnormalities and testicular cancers may also contribute to declining fertility rates.^4,5

TABLE
Consider these factors in cases of suspected infertility^{3,6,21,23,40,41}

Zero in on these areas of the history
As with any diagnostic work-up, the most important aspect of an infertility evaluation is the history. Document menstrual cycle length and regularity and the timing of intercourse. (Ideally, this would be done when a couple first decides to conceive.) It’s important to know how long the couple has been trying to become pregnant. More time may be all they need to achieve pregnancy. Educate them on reproductive cycles and optimal timing to achieve pregnancy. Some women experience lower abdominal pain (mittelschmerz) signifying release of an egg from the ovary, which can help identify the time of ovulation.

Remember, too, the role that a couple’s psychological state can play; worries over suspected infertility may cause anxiety, anger, depression, and marital troubles.

Is it her?

Regular menstrual cycles—menses occurring every 21 to 35 days—carry an ovulation probability of 95% with each cycle.⁶ With normal menses, ovulatory dysfunction is an unlikely cause of infertility. If menstrual cycles are irregular, ovulatory function is not normal and cyclical. Explore the woman’s medical, surgical, and gynecologic histories, looking particularly for thyroid disease, galactorrhea, hirsutism, pelvic or abdominal pain, dysmenorrhea, dyspareunia, pelvic inflammatory disease (PID), and abdominal or pelvic surgery.

The fallopian tubes. When menstruation is normal, evaluate the fallopian tubes and their patency; 30% to 40% of infertility cases can be related to peritoneal pathology.^3,7 Inability to conceive in a previous relationship, history of PID, or prior tubal surgery all correlate to infertility. Ten percent of patients with a history of one PID episode and 54% to 75% of patients with 3 episodes will have patency issues.⁷

Consider arranging for a hysterosalpingogram (HSG) in all patients as part of an initial work-up for infertility.⁸ HSG is useful in evaluating tubal patency and the uterine cavity, and it can be therapeutic. HSG is not useful in detecting peritubal adhesions or endometriosis; patients in whom you suspect these conditions should undergo diagnostic laparoscopy. If abnormalities are found on HSG, refer patients to a reproductive endocrinologist to evaluate treatment options.

Chlamydia trachomatis IgG antibody testing can predict the presence of tubal disease. For women with low risk of tubal disease, it may be more cost effective to test for the Chlamydia antibody and proceed with HSG if the result is positive. Antibody testing is also useful for women with an allergy to contrast dye who cannot undergo an HSG. If the antibody test result is positive, consider arranging for a sonohysterogram to evaluate for the presence of fluid in the cul-de-sac, or an intrauterine infusion of saline to evaluate the patency of at least one tube.⁹

Ovulatory function. To assess ovulatory function, measure a midluteal-phase serum progesterone level, drawn 1 week before the expected day of menses (Day 21 of a 28-day cycle). A level >3 ng/mL is evidence of ovulation. Over-the-counter ovulation kits detect the luteinizing hormone (LH) surge but have false-positive and false-negative rates of 5% to 10%, respectively.¹⁰ Recording basal body temperature is a noninvasive and inexpensive means of evaluating ovulation. The patient must record temperatures at exactly the same time each day. Have her log the temperatures and watch for a spike that occurs 1 to 2 days after the LH surge. The average woman’s temperature rises above 98ºF in progressing from the follicular to the luteal phase. Since the spike occurs 1 to 2 days after ovulation, this method is best used for many months so the woman can predict her cycle.¹¹

Once timing of ovulation has been established, you can check lab results at Day 3 of the woman’s cycle for follicle-stimulating hormone (FSH), LH, estradiol, thyroid-stimulating hormone (TSH), prolactin, and 2-hour fasting glucose tolerance. In addition to polycystic ovarian syndrome (PCOS), patients may have ovulatory dysfunction secondary to glucose intolerance.

A clomiphene (Clomid) challenge can help in assessing ovarian reserve. Administer 100 mg clomiphene on Days 5 through 9 of the patient’s cycle, and check FSH and estradiol levels on Day 10. With diminished ovarian reserve, FSH will increase to >12 mIU/mL and estradiol to >300 pg/mL.¹² If this occurs, consider referring for an ultrasound measurement of antral follicle count. The presence of 4 to 10 follicles measuring 2 to 10 mm in diameter suggests adequate reserve.¹³

Although not widely available in the United States, the test for antimüllerian hormone (AMH) levels may be useful in reflecting the size of the primordial follicle pool. At menopause, the level is undetectable. A level above 0.5 ng/mL correlates with good ovarian reserve; levels <0.15 ng/mL suggest poor response to in vitro fertilization (IVF).¹⁴

Endocrine factors account for 45% to 55% of female infertility and include thyroid disease, PCOS, diabetes mellitus, prolactinemia, and luteal phase defects. Subclinical hypothyroidism, often evidenced only by high levels of TSH, decreases the chance of a successful pregnancy. This can occur even if the dysfunction is not severe enough to affect cycle regularity.¹⁵ Clinical hypo- or hyperthyroidism can affect ovulation by interfering with normal hormonal feedback loops, and correcting thyroid disease can improve fertility.

Galactorrhea discovered during the history and physical may be caused by elevated prolactin levels, which also inhibit normal ovulatory function. Chronically elevated prolactin levels in patients with PCOS can be attributed to elevated estrogen levels. Adiposity, acne, and hirsutism with menstrual irregularity can indicate PCOS as the primary cause, and your work-up should focus on a hyperandrogenic state.¹⁶ Low or normal FSH levels are common in patients with PCOS. Also test for 17a-hydroxyprogestrone and serum testosterone levels.¹⁷

Endometriosis. How endometriosis affects fertility is controversial. One hypothesis is that it is associated with overproduction of prostaglandins, metalloproteinases, cytokines, and chemokines. The inflammatory process impairs ovarian, peritoneal, tubal, and endometrial function.¹⁸

Discourage the use of the postcoital test. Patients may inquire about this test, in which the cervical mucus is obtained after intercourse to assess stretch ability and sperm motility. This test has been used for more than a century, but has poor predictive value and is not recommended.¹⁹

Or is it him?

Inquire about sexual development and medical history, including mumps orchitis or other infections, sinopulmonary symptoms suggesting cystic fibrosis, sexually transmitted infections (STIs) and genitourinary infections, and surgical procedures of the inguinal and scrotal areas. Also ask about prescription and illicit drug use, environmental exposures, and sexual history.

Physical exam. Look for signs of androgen deficiency, such as an arm span >2 cm longer than height (eunuchoidal proportions), or loss of pubic, axillary, or facial hair.²⁰ Examine the external genitalia to evaluate for complete sexual development (Tanner stage of 5). The scrotum can provide clues to disorders that can affect sperm maturation and transport. Examination may reveal absence of the vas deferens, epididymal thickening, varicocele, or hernia.²¹ Testicular volume, if <15 mL with testicular length <3.6 cm, can point to a decreased number of seminiferous tubules.²¹

Semen analysis. If the physical examination is normal, analyze semen for volume and pH; microscopic debris and agglutination; sperm concentration, motility, and morphology; leukocyte count; and immature germ cells. Have the man abstain from sex for 2 to 7 days before semen collection. If collection is not possible to do in the office, the patient can drop it off at a lab within an hour of collection. Analyze 2 samples at least 2 weeks apart.²²

More detailed semen analysis can be done, especially if evaluation of the female partner does not reveal a cause of infertility. Tests include sperm autoantibodies, sperm biochemistry, semen culture, sperm function tests, and sperm-cervical mucus interaction. Typically, these tests and further evaluation of the male partner after an abnormal semen analysis are best done by a urologist specializing in reproduction.

Oligospermia or azoospermia point toward hypogonadism. Elevated morning FSH and low total testosterone correlate with primary hypogonadism, whereas low levels of both hormones correlate with secondary hypogonadism. Hyperprolactinemia is a cause of secondary hypogonadism.³ Low volume of semen can be further evaluated by testing a postejaculatory urinalysis and transrectal ultrasonography to rule out retrograde ejaculation and ejaculatory duct obstruction.²³

Fixing the problem
Focus initial counseling for couples on lifestyle modifications. Advise patients to quit smoking, reduce excessive caffeine and alcohol consumption, and engage in intercourse every day or every other day around ovulation. Patients should also avoid lubricants and douching as they can interfere with sperm deposition.

Managing female infertility

Tubal, pelvic, and uterine infertility. Patients with bilateral tubal obstruction may wish to undergo tubal reconstruction, especially if IVF treatments are not readily available to them. Counsel them that surgery for proximal tubal occlusion is not effective and the risk of ectopic pregnancy in the future is high, at approximately 20%.²⁴ Because of the low efficacy of surgery and high ectopic rate, most patients with tubal disease favor IVF. Patients with endometriosis sometimes benefit from laser ablation or surgical resection, but often do well with intrauterine insemination (IUI) or IVF in conjunction with ovulation induction.²⁵ Uterine abnormalities including submucous fibroid, endometrial polyp, septate uterus, or uterine synechiae frequently benefit from surgical correction.²⁶ Patients with irreparable defects may want to consider a surrogate.

Ovulatory dysfunction. Anovulation can be hypogonadotropic hypogonadal (secondary to functional factors such as exercise and weight), normogonadotropic normoestrogenic with PCOS, or hypergonadotropic hypoestrogenic infertility (premature ovarian failure).

A body mass index >17 and <27 kg/m² is optimal to achieve fertility and to sustain a healthy pregnancy.²⁷ Individuals who are obese or very thin or who overexercise and do not respond to behavioral modification are known to benefit from pulsatile gonadotropin-releasing hormone therapy. This treatment, however, is not available in the United States.²⁸

Dopaminergic agents can restore normal ovulation in patients with hyperprolactinemia,²⁹ but they should receive ovulation induction first. Patients who have glucose intolerance may benefit from an insulin-sensitizing agent such as metformin. It is particularly useful if patients also have PCOS; however, it is not an FDA-approved indication for the medication. Clomiphene has recently been shown to result in a higher rate of ovulation, but not pregnancy, than metformin.³⁰

Most patients with ovulatory dysfunction are best treated with clomiphene.³¹ Give 50 mg of the drug on cycle Days 3 through 7; ovulation occurs between Days 10 through 15.¹² If, after the first cycle, pregnancy has not occurred, increase the dose by 50 mg with each cycle, to a maximum of 150 mg daily.³² Higher doses are not FDA approved, nor are they more effective. Clomiphene is most effective in the first 6 cycles, and the American Congress of Obstetricians and Gynecologists recommends limiting its use to fewer than 12 cycles due to the risk of ovarian neoplasm.³³ Clomiphene yields an ovulation rate of 73% and a pregnancy rate of 36% per cycle. Multiple births, primarily twinning, occur at a rate of 8% to 13%.³³ If clomiphene is unsuccessful, refer patients to a reproductive endocrinologist for evaluation for IVF and injectable ovulation-inducing agents.

Managing male infertility

Men who have hyperprolactinemic infertility can often be treated with dopaminergic agents such as bromocriptine. Inform them that normal spermatogenesis can take 3 to 6 months. Gonadotropin therapy may be effective for patients with hypothalamic or pituitary diseases. Surgery may correct obstruction, but may not actually increase pregnancy rates. Repairing a varicocele, for instance, increases sperm counts but not conception rates.³⁴ Other obstructive problems may need sperm extraction followed by IUI or IVF, with or without intracytoplasmic sperm injection, where the sperm is injected into the ovum in the lab before implantation.³⁴

Managing unexplained infertility

Fifteen percent of infertility is unexplained.³⁵ Assisting these patients is challenging. Performing IUI with or without clomiphene, or giving clomiphene alone is often attempted. Pregnancy rates are 2% for expectant management, 5% for IUI alone, 9.5% for clomiphene alone, and 19% for combined IUI with clomiphene.³⁶ Gonadotropins are no more effective in achieving conception than clomiphene, but gonadotropin injection and IUI together are more effective than no treatment.³⁷ IVF, if successful, leads to pregnancy in the shortest amount of time. But it is the most costly intervention and the most likely to result in multiple births. In randomized controlled trials, however, IVF has not proved beneficial for unexplained infertility.³⁸

Trends likely to affect fertility treatment
Currently in the United States, there is little regulation to guide reproductive technologies. But there is a trend, varying by state, toward legislation similar to child protection laws and adoption services, under which couples are evaluated for suitability as parents for the potential child’s safety.³⁹ Other countries have acts regulating reproductive technologies and infertility services. England focuses on the child’s welfare; Australia restricts access by eligibility requirements.³⁹ In the United States we may see similar policies, especially as controversy grows regarding multiple births. Cost is a factor in the treatment of infertility. Education and household income correlate with the amount of money spent on fertility care.

CORRESPONDENCE Heather Bell, MD, Center for Family Medicine, 1115 East 20th Street, Sioux Falls, SD 57105; [email protected]

The usual approach to dermatologic conditions—honed pattern recognition, a deliberate differential diagnosis, and empiric treatment with longer follow-up—runs counter to the response that dermatologic red flags require. Because patients with signs and symptoms associated with dermatologic emergencies have the potential for rapid clinical deterioration, urgent action is paramount.

With this in mind, we’ve focused on 4 red flags—erythroderma, desquamation, skin pain, and petechiae/purpura—as a starting point, rather than presenting a list of dermatologic emergencies and discussing each diagnosis in turn. The text, tables, and images on the pages that follow will increase your awareness of dermatologic presentations that require an immediate response and help you differentiate between signs and symptoms of serious skin disorders and benign findings that might be described as red flag mimics (TABLE 1).

TABLE 1
Conditions that mimic dermatologic emergencies

Erythroderma: Red skin that’s life-threatening

From an etymological perspective, “erythroderma” simply means red skin. Clinically, however, it is defined as extensive erythema, typically covering ≥90% of the skin surface (FIGURE 1). True erythroderma can be life-threatening and must always be considered a dermatologic emergency.^1,2

Diligent monitoring of the speed of progression and the presence of fever, systemic symptoms, and multiorgan dysfunction is essential. In a case review of 56 children who presented to an emergency department with fever and erythroderma, 45% progressed to shock.³ Some common causes of erythroderma are psoriasis; contact, atopic, and seborrheic dermatitis; pityriasis rubra pilaris; cutaneous T-cell lymphoma; drug reaction; and toxic shock syndrome (TSS).⁴

Is it a drug reaction? Erythroderma, fever, and evidence of multiorgan involvement in a patient taking any medication—not just a new one—prompts consideration of a drug reaction. Antiepileptics, dapsone, and sulfonamides are the most frequent offenders.⁵

DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) is characterized by fever, lymphadenopathy, elevated liver enzymes, and leukocytosis with eosinophilia, as well as erythroderma. The rash may be urticarial or morbilliform in appearance; petechiae, purpura, and blisters may be present, as well.

Because fever, leukocytosis, and transaminitis are also suggestive of an infectious etiology, DRESS syndrome is frequently overlooked. As a result, its true incidence is unknown. Estimates range from about one in 1000 to one in 10,000 drug exposures.⁶

In addition to discontinuing the medication, treatment for DRESS calls for systemic corticosteroids—which may actually be harmful when infection, rather than a drug reaction, is the cause. Thus, it is necessary to maintain a high index of suspicion and to thoroughly review the medication history of
any patient who presents with erythroderma and systemic symptoms.

When to suspect toxic shock syndrome. Consider TSS in any patient with erythroderma and hypotension, as well as laboratory evidence of end-organ involvement (including transaminitis, elevated creatinine, anemia, thrombocytopenia, and elevated creatinine kinase). Diagnostic criteria are detailed in FIGURE 2.⁷ Group A Streptococcus and Staphylococcus aureus are the classic infectious causes, but other bacteria have been implicated, as well. In most cases, the responsible bacterium is not known initially.

Because the toxins produced by these streptococcal and staphylococcal strains act as superantigens that fuel the immune response and worsen the shock, patients with a presumptive diagnosis of TSS should begin empiric treatment with an antimicrobial agent that inhibits toxin synthesis, such as clindamycin, immediately.^8,9

FIGURE 1
Erythema covering the chest and arms

FIGURE 2
Diagnostic criteria for toxic shock syndrome

Desquamation/blistering: Act quickly when it’s widespread

Although desquamation can be seen in benign skin conditions, widespread desquamation with or without bullae requires careful evaluation and a rapid response. Separation, either at the dermal-epidermal junction or intraepidermally, raises the specter of 2 emergent conditions: the Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) spectrum and staphylococcal scalded skin syndrome (SSSS). Mucosal involvement is another red flag, if the patient appears ill and the desquamation is progressing rapidly. Conjunctival involvement, in particular, is associated with greater morbidity, and a consult with an ophthalmologist is prude

Rapid progression is a hallmark of SJS/TEN. Desquamation that’s widespread and rapidly progressive in a patient with fever, hypotension, and end-organ involvement is suggestive of SJS/TEN (FIGURE 3). Medications, including allopurinol, antimicrobials, and antiepileptics, are frequent culprits.^10,11

Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been linked to SJS/TEN.¹⁰ Given their widespread use (1-2 per million users per week), however, the likelihood of NSAIDs leading to SJS/TEN is exceedingly low.¹²

Signs and symptoms of SJS/TEN may include target lesions with dusky centers, erythroderma, or significant pain without any visible skin abnormality, typically accompanied by fever and malaise. Widespread sloughing of the skin may be seen within several hours.¹¹

Admission to an intensive care unit—preferably a burn unit—is suggested for aggressive fluid resuscitation and management of shock and end-organ dysfunction. Intravenous immunoglobulin G (IVIG) and steroids are often used, although there is little consensus as to the most effective treatment.¹³ Mortality from TEN approaches 50%.¹³

SSSS can present at any age. Newborns often present with SSSS during their first week of life: Widespread erythema is quickly followed by fragile blisters, which may have already ruptured by the time the infant receives medical attention. Mucosal surfaces are not typically involved. Nikolsky’s sign (separation of the upper epidermis with gentle pressure) is a classic finding.

Infants with SSSS are frequently irritable, suggesting that the skin may be painful. Cultures from unruptured bullae will be negative as the blisters represent a cutaneous reaction to an infection, rather than a skin infection, but blood, urine, and nasopharynx cultures may be positive. Systemic treatment with nafcillin or oxacillin should be initiated, and supportive skin care provided.^14,15 Clindamycin or vancomycin should be used in parts of the country in which methicillin-resistant Staphylococcus aureus is prevalent. In very young infants, the outcome of SSSS is generally favorable. Not so with adults.

Because mature kidneys have a greater ability to excrete exfoliative toxins, SSSS primarily affects adults with significant comorbidities—and has a much poorer prognosis.¹⁶ You may also see chronic autoimmune bullous diseases, such as bullous pemphigoid and pemphigus vulgaris, with widespread desquamation and blistering, in the adult population. Untreated, the secondary infection and electrolyte disturbances from fluid loss associated with pemphigus vulgaris can be fatal.

Desquamation is a late finding in Kawasaki disease. Desquamation is often cited as a potential skin finding in children with Kawasaki disease (KD) (FIGURE 4), but usually not until the convalescent stage.¹⁷ (Desquamation may also appear during the recovery period of several other infections, including scarlet fever and TSS.) IVIG can prevent coronary aneurysm, the major complication of KD, but only if it is administered during the acute phase of the illness. Therefore, early diagnosis of KD (TABLE 2)¹⁸—before desquamation occurs—is critical.¹⁹

FIGURE 3
Desquamation, full-thickness epidermal necrosis on the upper back

FIGURE 4
Desquamation on a young patient

TABLE 2
Diagnostic criteria for Kawasaki disease

Skin pain is always a red flag

Widespread skin pain should always be taken seriously, as it is rarely associated with minor dermatoses.²⁰ Infectious cellulitis is the most likely diagnosis of a painful erythematous skin lesion. Patients with cellulitis do not usually have erythroderma, as the affected area tends to be very localized.

Cellulitis may be over- or undertreated. Once cellulitis has been diagnosed, the next thing to consider is severity. A recent retrospective study found that misclassification of skin and soft-tissue infections may result in both significant overtreatment of mild soft-tissue infections and dangerous undertreatment of severe infections, with consequent morbidity.²¹

Location is a key consideration, as cellulitis in certain locations—including the eye, perineum, and hand—carries an increased risk of morbidity. Orbital cellulitis—which may be characterized by proptosis, ophthalmoplegia, and pain with extraocular movements—most often results from initial sinusitis, and can lead to vision loss, intracranial infection, and significant invasive disease. Prompt antimicrobial therapy and urgent ophthalmologic consultation are essential, as operative drainage may be required.^22,23

When the perineum is involved, a careful exam must be performed to determine the limits of the affected area. Although Fournier’s gangrene is uncommon, it is a life-threatening infection. In one small retrospective study, more than half of the patients presented with a perianal abscess.²⁴

Similarly, the hand is vulnerable to significant infection, particularly if it is inoculated with bacteria from human mouth flora (the well-described “fight bite”). In a review of 100 cases of human fight bites, 18 patients ultimately required amputation.²⁵

Early necrotizing fasciitis is often missed. Clinicians generally expect painful lesions to also have erythema, swelling, and increased warmth—the cardinal signs of inflammation. As a result, early necrotizing fasciitis, which initially presents with pain out of proportion to other dermatologic findings, may be overlooked. In fact, pain can precede significant skin findings by 24 to 48 hours; prior to that, only mild erythema or swelling (with minimal pain, in some cases) may be evident.^26,27

The general pattern, however, is for a site with exquisite tenderness to evolve into a smooth, swollen area, then to develop dusky plaques and late-stage full thickness necrosis with hemorrhagic bullae.²⁶ At that point, necrosis can render the skin insensate. Case reviews have found necrotizing fasciitis to be protean, with only 3 findings—erythema, edema, and tenderness beyond the expected lesion borders—present in most patients.²⁷ Assiduous attention to skin pain in the presence of any other skin manifestation is the key to early diagnosis and rapid treatment.

Petechiae/purpura may be severe or benign

Petechiae are flat, pinpoint, nonblanching spots caused by intradermal hemorrhage associated with a wide variety of conditions, ranging from benign (local trauma) to severe (eg, disseminated intravascular coagulation [DIC] and sepsis). Similarly, purpura—larger lesions that may be palpable—can accompany less severe diseases, such as Henoch-Schönlein purpura (HSP), or life-threatening conditions like sepsis and DIC (FIGURE 5). Here, as in many other dermatologic conditions, the key differentiating features are location (local vs diffuse), speed of progression, and signs and symptoms of systemic illness.

FIGURE 5
Signs of a life-threatening condition

Localized petechiae are common with direct trauma, as well as barotrauma associated with coughing, vomiting, or even asphyxiation. Location is an important clue. Periorbital petechiae and petechiae on the chest above the nipple line suggest that the lesions were caused by the force of the barotrauma, rather than systemic disease.²⁸ A careful history and physical exam are needed to rule out serious underlying conditions, such as pneumonia, dehydration, and abdominal obstruction.

Petechiae out of proportion to the force applied may be an indication of an underlying bleeding diathesis, including thrombocytopenia, coagulation defects, and some fulminant infections. Idiopathic thrombocytopenic purpura (ITP) and HSP may present with more widespread petechiae/purpura, but without fever or systemic symptoms. ITP can develop spontaneously, after a viral infection or after a child’s inoculation with the measles-mumps-rubella vaccine.²⁹ ITP typically presents as easy bruising and petechiae out of proportion to the condition that caused it. These patients, as a rule, will have a healthy appearance.

Treatment (with steroids, IVIG, or anti-D immunoglobulin) is generally not required for children with ITP unless they have bleeding that is mucosal or substantial, as spontaneous remission is expected. Adults, who are more likely to develop chronic ITP, may benefit from treatment.³⁰

HSP occurs most commonly in children, who may have palpable purpura, typically in the lower extremities, as well as arthritis or arthralgia, abdominal pain, and renal involvement that can progress from microscopic hematuria or proteinuria to renal insufficiency.³¹ Typically, children whose disease is in the acute phase do not appear to be sick, with an important exception: Those who develop hemorrhage and edema in the bowel wall, resulting in intussusception, have significant abdominal pain and are more likely to need surgical reduction.³²

Diffuse petechiae in the absence of any trauma, accompanied by significant signs of systemic illness, may be an indication of fulminant infection, including meningococcemia, DIC, and Rocky Mountain spotted fever (RMSF). (Fever and diffuse petechiae can also be seen in viral exanthema, but patients usually look well and the rash often has both blanching and petechial components.³³)

When a returning traveler presents with a rash and systemic symptoms, it is important to take a thorough history and to consider infections endemic to the area visited. RMSF may initially be localized to the wrists and progress to widespread petechiae over hours to days. Because the cutaneous findings may not be as fulminant—and up to 10% of patients with RMSF have no rash at all³⁴—attention to the noncutaneous features is important. Fever, headache, neurologic symptoms, joint complaints, and abdominal pain (or only a few of these manifestations) in the context of potential tick bite exposure should prompt consideration of RMSF.³⁵

Keep in mind, too, that in cases of fulminant infections such as meningococcemia and DIC, the hallmark purpura fulminans may not be present initially.³⁶ Although the initial cutaneous findings may be subtle, however, such patients will appear quite ill, and their condition will deteriorate rapidly. Because prompt antibiotic therapy can save life and limb, a high index of suspicion should be maintained for any patient who presents with a rash in the setting of fever and hypotension or other evidence of shock.

The usual approach to dermatologic conditions—honed pattern recognition, a deliberate differential diagnosis, and empiric treatment with longer follow-up—runs counter to the response that dermatologic red flags require. Because patients with signs and symptoms associated with dermatologic emergencies have the potential for rapid clinical deterioration, urgent action is paramount.

With this in mind, we’ve focused on 4 red flags—erythroderma, desquamation, skin pain, and petechiae/purpura—as a starting point, rather than presenting a list of dermatologic emergencies and discussing each diagnosis in turn. The text, tables, and images on the pages that follow will increase your awareness of dermatologic presentations that require an immediate response and help you differentiate between signs and symptoms of serious skin disorders and benign findings that might be described as red flag mimics (TABLE 1).

TABLE 1
Conditions that mimic dermatologic emergencies

Erythroderma: Red skin that’s life-threatening

From an etymological perspective, “erythroderma” simply means red skin. Clinically, however, it is defined as extensive erythema, typically covering ≥90% of the skin surface (FIGURE 1). True erythroderma can be life-threatening and must always be considered a dermatologic emergency.^1,2

Diligent monitoring of the speed of progression and the presence of fever, systemic symptoms, and multiorgan dysfunction is essential. In a case review of 56 children who presented to an emergency department with fever and erythroderma, 45% progressed to shock.³ Some common causes of erythroderma are psoriasis; contact, atopic, and seborrheic dermatitis; pityriasis rubra pilaris; cutaneous T-cell lymphoma; drug reaction; and toxic shock syndrome (TSS).⁴

Is it a drug reaction? Erythroderma, fever, and evidence of multiorgan involvement in a patient taking any medication—not just a new one—prompts consideration of a drug reaction. Antiepileptics, dapsone, and sulfonamides are the most frequent offenders.⁵

DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) is characterized by fever, lymphadenopathy, elevated liver enzymes, and leukocytosis with eosinophilia, as well as erythroderma. The rash may be urticarial or morbilliform in appearance; petechiae, purpura, and blisters may be present, as well.

Because fever, leukocytosis, and transaminitis are also suggestive of an infectious etiology, DRESS syndrome is frequently overlooked. As a result, its true incidence is unknown. Estimates range from about one in 1000 to one in 10,000 drug exposures.⁶

In addition to discontinuing the medication, treatment for DRESS calls for systemic corticosteroids—which may actually be harmful when infection, rather than a drug reaction, is the cause. Thus, it is necessary to maintain a high index of suspicion and to thoroughly review the medication history of
any patient who presents with erythroderma and systemic symptoms.

When to suspect toxic shock syndrome. Consider TSS in any patient with erythroderma and hypotension, as well as laboratory evidence of end-organ involvement (including transaminitis, elevated creatinine, anemia, thrombocytopenia, and elevated creatinine kinase). Diagnostic criteria are detailed in FIGURE 2.⁷ Group A Streptococcus and Staphylococcus aureus are the classic infectious causes, but other bacteria have been implicated, as well. In most cases, the responsible bacterium is not known initially.

Because the toxins produced by these streptococcal and staphylococcal strains act as superantigens that fuel the immune response and worsen the shock, patients with a presumptive diagnosis of TSS should begin empiric treatment with an antimicrobial agent that inhibits toxin synthesis, such as clindamycin, immediately.^8,9

FIGURE 1
Erythema covering the chest and arms

FIGURE 2
Diagnostic criteria for toxic shock syndrome

Desquamation/blistering: Act quickly when it’s widespread

Although desquamation can be seen in benign skin conditions, widespread desquamation with or without bullae requires careful evaluation and a rapid response. Separation, either at the dermal-epidermal junction or intraepidermally, raises the specter of 2 emergent conditions: the Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) spectrum and staphylococcal scalded skin syndrome (SSSS). Mucosal involvement is another red flag, if the patient appears ill and the desquamation is progressing rapidly. Conjunctival involvement, in particular, is associated with greater morbidity, and a consult with an ophthalmologist is prude

Rapid progression is a hallmark of SJS/TEN. Desquamation that’s widespread and rapidly progressive in a patient with fever, hypotension, and end-organ involvement is suggestive of SJS/TEN (FIGURE 3). Medications, including allopurinol, antimicrobials, and antiepileptics, are frequent culprits.^10,11

Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been linked to SJS/TEN.¹⁰ Given their widespread use (1-2 per million users per week), however, the likelihood of NSAIDs leading to SJS/TEN is exceedingly low.¹²

Signs and symptoms of SJS/TEN may include target lesions with dusky centers, erythroderma, or significant pain without any visible skin abnormality, typically accompanied by fever and malaise. Widespread sloughing of the skin may be seen within several hours.¹¹

Admission to an intensive care unit—preferably a burn unit—is suggested for aggressive fluid resuscitation and management of shock and end-organ dysfunction. Intravenous immunoglobulin G (IVIG) and steroids are often used, although there is little consensus as to the most effective treatment.¹³ Mortality from TEN approaches 50%.¹³

SSSS can present at any age. Newborns often present with SSSS during their first week of life: Widespread erythema is quickly followed by fragile blisters, which may have already ruptured by the time the infant receives medical attention. Mucosal surfaces are not typically involved. Nikolsky’s sign (separation of the upper epidermis with gentle pressure) is a classic finding.

Infants with SSSS are frequently irritable, suggesting that the skin may be painful. Cultures from unruptured bullae will be negative as the blisters represent a cutaneous reaction to an infection, rather than a skin infection, but blood, urine, and nasopharynx cultures may be positive. Systemic treatment with nafcillin or oxacillin should be initiated, and supportive skin care provided.^14,15 Clindamycin or vancomycin should be used in parts of the country in which methicillin-resistant Staphylococcus aureus is prevalent. In very young infants, the outcome of SSSS is generally favorable. Not so with adults.

Because mature kidneys have a greater ability to excrete exfoliative toxins, SSSS primarily affects adults with significant comorbidities—and has a much poorer prognosis.¹⁶ You may also see chronic autoimmune bullous diseases, such as bullous pemphigoid and pemphigus vulgaris, with widespread desquamation and blistering, in the adult population. Untreated, the secondary infection and electrolyte disturbances from fluid loss associated with pemphigus vulgaris can be fatal.

Desquamation is a late finding in Kawasaki disease. Desquamation is often cited as a potential skin finding in children with Kawasaki disease (KD) (FIGURE 4), but usually not until the convalescent stage.¹⁷ (Desquamation may also appear during the recovery period of several other infections, including scarlet fever and TSS.) IVIG can prevent coronary aneurysm, the major complication of KD, but only if it is administered during the acute phase of the illness. Therefore, early diagnosis of KD (TABLE 2)¹⁸—before desquamation occurs—is critical.¹⁹

FIGURE 3
Desquamation, full-thickness epidermal necrosis on the upper back

FIGURE 4
Desquamation on a young patient

TABLE 2
Diagnostic criteria for Kawasaki disease

Skin pain is always a red flag

Widespread skin pain should always be taken seriously, as it is rarely associated with minor dermatoses.²⁰ Infectious cellulitis is the most likely diagnosis of a painful erythematous skin lesion. Patients with cellulitis do not usually have erythroderma, as the affected area tends to be very localized.

Cellulitis may be over- or undertreated. Once cellulitis has been diagnosed, the next thing to consider is severity. A recent retrospective study found that misclassification of skin and soft-tissue infections may result in both significant overtreatment of mild soft-tissue infections and dangerous undertreatment of severe infections, with consequent morbidity.²¹

Location is a key consideration, as cellulitis in certain locations—including the eye, perineum, and hand—carries an increased risk of morbidity. Orbital cellulitis—which may be characterized by proptosis, ophthalmoplegia, and pain with extraocular movements—most often results from initial sinusitis, and can lead to vision loss, intracranial infection, and significant invasive disease. Prompt antimicrobial therapy and urgent ophthalmologic consultation are essential, as operative drainage may be required.^22,23

When the perineum is involved, a careful exam must be performed to determine the limits of the affected area. Although Fournier’s gangrene is uncommon, it is a life-threatening infection. In one small retrospective study, more than half of the patients presented with a perianal abscess.²⁴

Similarly, the hand is vulnerable to significant infection, particularly if it is inoculated with bacteria from human mouth flora (the well-described “fight bite”). In a review of 100 cases of human fight bites, 18 patients ultimately required amputation.²⁵

Early necrotizing fasciitis is often missed. Clinicians generally expect painful lesions to also have erythema, swelling, and increased warmth—the cardinal signs of inflammation. As a result, early necrotizing fasciitis, which initially presents with pain out of proportion to other dermatologic findings, may be overlooked. In fact, pain can precede significant skin findings by 24 to 48 hours; prior to that, only mild erythema or swelling (with minimal pain, in some cases) may be evident.^26,27

The general pattern, however, is for a site with exquisite tenderness to evolve into a smooth, swollen area, then to develop dusky plaques and late-stage full thickness necrosis with hemorrhagic bullae.²⁶ At that point, necrosis can render the skin insensate. Case reviews have found necrotizing fasciitis to be protean, with only 3 findings—erythema, edema, and tenderness beyond the expected lesion borders—present in most patients.²⁷ Assiduous attention to skin pain in the presence of any other skin manifestation is the key to early diagnosis and rapid treatment.

Petechiae/purpura may be severe or benign

Petechiae are flat, pinpoint, nonblanching spots caused by intradermal hemorrhage associated with a wide variety of conditions, ranging from benign (local trauma) to severe (eg, disseminated intravascular coagulation [DIC] and sepsis). Similarly, purpura—larger lesions that may be palpable—can accompany less severe diseases, such as Henoch-Schönlein purpura (HSP), or life-threatening conditions like sepsis and DIC (FIGURE 5). Here, as in many other dermatologic conditions, the key differentiating features are location (local vs diffuse), speed of progression, and signs and symptoms of systemic illness.

FIGURE 5
Signs of a life-threatening condition

Localized petechiae are common with direct trauma, as well as barotrauma associated with coughing, vomiting, or even asphyxiation. Location is an important clue. Periorbital petechiae and petechiae on the chest above the nipple line suggest that the lesions were caused by the force of the barotrauma, rather than systemic disease.²⁸ A careful history and physical exam are needed to rule out serious underlying conditions, such as pneumonia, dehydration, and abdominal obstruction.

Petechiae out of proportion to the force applied may be an indication of an underlying bleeding diathesis, including thrombocytopenia, coagulation defects, and some fulminant infections. Idiopathic thrombocytopenic purpura (ITP) and HSP may present with more widespread petechiae/purpura, but without fever or systemic symptoms. ITP can develop spontaneously, after a viral infection or after a child’s inoculation with the measles-mumps-rubella vaccine.²⁹ ITP typically presents as easy bruising and petechiae out of proportion to the condition that caused it. These patients, as a rule, will have a healthy appearance.

Treatment (with steroids, IVIG, or anti-D immunoglobulin) is generally not required for children with ITP unless they have bleeding that is mucosal or substantial, as spontaneous remission is expected. Adults, who are more likely to develop chronic ITP, may benefit from treatment.³⁰

HSP occurs most commonly in children, who may have palpable purpura, typically in the lower extremities, as well as arthritis or arthralgia, abdominal pain, and renal involvement that can progress from microscopic hematuria or proteinuria to renal insufficiency.³¹ Typically, children whose disease is in the acute phase do not appear to be sick, with an important exception: Those who develop hemorrhage and edema in the bowel wall, resulting in intussusception, have significant abdominal pain and are more likely to need surgical reduction.³²

Diffuse petechiae in the absence of any trauma, accompanied by significant signs of systemic illness, may be an indication of fulminant infection, including meningococcemia, DIC, and Rocky Mountain spotted fever (RMSF). (Fever and diffuse petechiae can also be seen in viral exanthema, but patients usually look well and the rash often has both blanching and petechial components.³³)

When a returning traveler presents with a rash and systemic symptoms, it is important to take a thorough history and to consider infections endemic to the area visited. RMSF may initially be localized to the wrists and progress to widespread petechiae over hours to days. Because the cutaneous findings may not be as fulminant—and up to 10% of patients with RMSF have no rash at all³⁴—attention to the noncutaneous features is important. Fever, headache, neurologic symptoms, joint complaints, and abdominal pain (or only a few of these manifestations) in the context of potential tick bite exposure should prompt consideration of RMSF.³⁵

Keep in mind, too, that in cases of fulminant infections such as meningococcemia and DIC, the hallmark purpura fulminans may not be present initially.³⁶ Although the initial cutaneous findings may be subtle, however, such patients will appear quite ill, and their condition will deteriorate rapidly. Because prompt antibiotic therapy can save life and limb, a high index of suspicion should be maintained for any patient who presents with a rash in the setting of fever and hypotension or other evidence of shock.

The usual approach to dermatologic conditions—honed pattern recognition, a deliberate differential diagnosis, and empiric treatment with longer follow-up—runs counter to the response that dermatologic red flags require. Because patients with signs and symptoms associated with dermatologic emergencies have the potential for rapid clinical deterioration, urgent action is paramount.

With this in mind, we’ve focused on 4 red flags—erythroderma, desquamation, skin pain, and petechiae/purpura—as a starting point, rather than presenting a list of dermatologic emergencies and discussing each diagnosis in turn. The text, tables, and images on the pages that follow will increase your awareness of dermatologic presentations that require an immediate response and help you differentiate between signs and symptoms of serious skin disorders and benign findings that might be described as red flag mimics (TABLE 1).

TABLE 1
Conditions that mimic dermatologic emergencies

Erythroderma: Red skin that’s life-threatening

From an etymological perspective, “erythroderma” simply means red skin. Clinically, however, it is defined as extensive erythema, typically covering ≥90% of the skin surface (FIGURE 1). True erythroderma can be life-threatening and must always be considered a dermatologic emergency.^1,2

Diligent monitoring of the speed of progression and the presence of fever, systemic symptoms, and multiorgan dysfunction is essential. In a case review of 56 children who presented to an emergency department with fever and erythroderma, 45% progressed to shock.³ Some common causes of erythroderma are psoriasis; contact, atopic, and seborrheic dermatitis; pityriasis rubra pilaris; cutaneous T-cell lymphoma; drug reaction; and toxic shock syndrome (TSS).⁴

Is it a drug reaction? Erythroderma, fever, and evidence of multiorgan involvement in a patient taking any medication—not just a new one—prompts consideration of a drug reaction. Antiepileptics, dapsone, and sulfonamides are the most frequent offenders.⁵

DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) is characterized by fever, lymphadenopathy, elevated liver enzymes, and leukocytosis with eosinophilia, as well as erythroderma. The rash may be urticarial or morbilliform in appearance; petechiae, purpura, and blisters may be present, as well.

Because fever, leukocytosis, and transaminitis are also suggestive of an infectious etiology, DRESS syndrome is frequently overlooked. As a result, its true incidence is unknown. Estimates range from about one in 1000 to one in 10,000 drug exposures.⁶

In addition to discontinuing the medication, treatment for DRESS calls for systemic corticosteroids—which may actually be harmful when infection, rather than a drug reaction, is the cause. Thus, it is necessary to maintain a high index of suspicion and to thoroughly review the medication history of
any patient who presents with erythroderma and systemic symptoms.

When to suspect toxic shock syndrome. Consider TSS in any patient with erythroderma and hypotension, as well as laboratory evidence of end-organ involvement (including transaminitis, elevated creatinine, anemia, thrombocytopenia, and elevated creatinine kinase). Diagnostic criteria are detailed in FIGURE 2.⁷ Group A Streptococcus and Staphylococcus aureus are the classic infectious causes, but other bacteria have been implicated, as well. In most cases, the responsible bacterium is not known initially.

Because the toxins produced by these streptococcal and staphylococcal strains act as superantigens that fuel the immune response and worsen the shock, patients with a presumptive diagnosis of TSS should begin empiric treatment with an antimicrobial agent that inhibits toxin synthesis, such as clindamycin, immediately.^8,9

FIGURE 1
Erythema covering the chest and arms

FIGURE 2
Diagnostic criteria for toxic shock syndrome

Desquamation/blistering: Act quickly when it’s widespread

Although desquamation can be seen in benign skin conditions, widespread desquamation with or without bullae requires careful evaluation and a rapid response. Separation, either at the dermal-epidermal junction or intraepidermally, raises the specter of 2 emergent conditions: the Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) spectrum and staphylococcal scalded skin syndrome (SSSS). Mucosal involvement is another red flag, if the patient appears ill and the desquamation is progressing rapidly. Conjunctival involvement, in particular, is associated with greater morbidity, and a consult with an ophthalmologist is prude

Rapid progression is a hallmark of SJS/TEN. Desquamation that’s widespread and rapidly progressive in a patient with fever, hypotension, and end-organ involvement is suggestive of SJS/TEN (FIGURE 3). Medications, including allopurinol, antimicrobials, and antiepileptics, are frequent culprits.^10,11

Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been linked to SJS/TEN.¹⁰ Given their widespread use (1-2 per million users per week), however, the likelihood of NSAIDs leading to SJS/TEN is exceedingly low.¹²

Signs and symptoms of SJS/TEN may include target lesions with dusky centers, erythroderma, or significant pain without any visible skin abnormality, typically accompanied by fever and malaise. Widespread sloughing of the skin may be seen within several hours.¹¹

Admission to an intensive care unit—preferably a burn unit—is suggested for aggressive fluid resuscitation and management of shock and end-organ dysfunction. Intravenous immunoglobulin G (IVIG) and steroids are often used, although there is little consensus as to the most effective treatment.¹³ Mortality from TEN approaches 50%.¹³

SSSS can present at any age. Newborns often present with SSSS during their first week of life: Widespread erythema is quickly followed by fragile blisters, which may have already ruptured by the time the infant receives medical attention. Mucosal surfaces are not typically involved. Nikolsky’s sign (separation of the upper epidermis with gentle pressure) is a classic finding.

Infants with SSSS are frequently irritable, suggesting that the skin may be painful. Cultures from unruptured bullae will be negative as the blisters represent a cutaneous reaction to an infection, rather than a skin infection, but blood, urine, and nasopharynx cultures may be positive. Systemic treatment with nafcillin or oxacillin should be initiated, and supportive skin care provided.^14,15 Clindamycin or vancomycin should be used in parts of the country in which methicillin-resistant Staphylococcus aureus is prevalent. In very young infants, the outcome of SSSS is generally favorable. Not so with adults.

Because mature kidneys have a greater ability to excrete exfoliative toxins, SSSS primarily affects adults with significant comorbidities—and has a much poorer prognosis.¹⁶ You may also see chronic autoimmune bullous diseases, such as bullous pemphigoid and pemphigus vulgaris, with widespread desquamation and blistering, in the adult population. Untreated, the secondary infection and electrolyte disturbances from fluid loss associated with pemphigus vulgaris can be fatal.

Desquamation is a late finding in Kawasaki disease. Desquamation is often cited as a potential skin finding in children with Kawasaki disease (KD) (FIGURE 4), but usually not until the convalescent stage.¹⁷ (Desquamation may also appear during the recovery period of several other infections, including scarlet fever and TSS.) IVIG can prevent coronary aneurysm, the major complication of KD, but only if it is administered during the acute phase of the illness. Therefore, early diagnosis of KD (TABLE 2)¹⁸—before desquamation occurs—is critical.¹⁹

FIGURE 3
Desquamation, full-thickness epidermal necrosis on the upper back

FIGURE 4
Desquamation on a young patient

TABLE 2
Diagnostic criteria for Kawasaki disease

Skin pain is always a red flag

Widespread skin pain should always be taken seriously, as it is rarely associated with minor dermatoses.²⁰ Infectious cellulitis is the most likely diagnosis of a painful erythematous skin lesion. Patients with cellulitis do not usually have erythroderma, as the affected area tends to be very localized.

Cellulitis may be over- or undertreated. Once cellulitis has been diagnosed, the next thing to consider is severity. A recent retrospective study found that misclassification of skin and soft-tissue infections may result in both significant overtreatment of mild soft-tissue infections and dangerous undertreatment of severe infections, with consequent morbidity.²¹

Location is a key consideration, as cellulitis in certain locations—including the eye, perineum, and hand—carries an increased risk of morbidity. Orbital cellulitis—which may be characterized by proptosis, ophthalmoplegia, and pain with extraocular movements—most often results from initial sinusitis, and can lead to vision loss, intracranial infection, and significant invasive disease. Prompt antimicrobial therapy and urgent ophthalmologic consultation are essential, as operative drainage may be required.^22,23

When the perineum is involved, a careful exam must be performed to determine the limits of the affected area. Although Fournier’s gangrene is uncommon, it is a life-threatening infection. In one small retrospective study, more than half of the patients presented with a perianal abscess.²⁴

Similarly, the hand is vulnerable to significant infection, particularly if it is inoculated with bacteria from human mouth flora (the well-described “fight bite”). In a review of 100 cases of human fight bites, 18 patients ultimately required amputation.²⁵

Early necrotizing fasciitis is often missed. Clinicians generally expect painful lesions to also have erythema, swelling, and increased warmth—the cardinal signs of inflammation. As a result, early necrotizing fasciitis, which initially presents with pain out of proportion to other dermatologic findings, may be overlooked. In fact, pain can precede significant skin findings by 24 to 48 hours; prior to that, only mild erythema or swelling (with minimal pain, in some cases) may be evident.^26,27

The general pattern, however, is for a site with exquisite tenderness to evolve into a smooth, swollen area, then to develop dusky plaques and late-stage full thickness necrosis with hemorrhagic bullae.²⁶ At that point, necrosis can render the skin insensate. Case reviews have found necrotizing fasciitis to be protean, with only 3 findings—erythema, edema, and tenderness beyond the expected lesion borders—present in most patients.²⁷ Assiduous attention to skin pain in the presence of any other skin manifestation is the key to early diagnosis and rapid treatment.

Petechiae/purpura may be severe or benign

Petechiae are flat, pinpoint, nonblanching spots caused by intradermal hemorrhage associated with a wide variety of conditions, ranging from benign (local trauma) to severe (eg, disseminated intravascular coagulation [DIC] and sepsis). Similarly, purpura—larger lesions that may be palpable—can accompany less severe diseases, such as Henoch-Schönlein purpura (HSP), or life-threatening conditions like sepsis and DIC (FIGURE 5). Here, as in many other dermatologic conditions, the key differentiating features are location (local vs diffuse), speed of progression, and signs and symptoms of systemic illness.

FIGURE 5
Signs of a life-threatening condition

Localized petechiae are common with direct trauma, as well as barotrauma associated with coughing, vomiting, or even asphyxiation. Location is an important clue. Periorbital petechiae and petechiae on the chest above the nipple line suggest that the lesions were caused by the force of the barotrauma, rather than systemic disease.²⁸ A careful history and physical exam are needed to rule out serious underlying conditions, such as pneumonia, dehydration, and abdominal obstruction.

Petechiae out of proportion to the force applied may be an indication of an underlying bleeding diathesis, including thrombocytopenia, coagulation defects, and some fulminant infections. Idiopathic thrombocytopenic purpura (ITP) and HSP may present with more widespread petechiae/purpura, but without fever or systemic symptoms. ITP can develop spontaneously, after a viral infection or after a child’s inoculation with the measles-mumps-rubella vaccine.²⁹ ITP typically presents as easy bruising and petechiae out of proportion to the condition that caused it. These patients, as a rule, will have a healthy appearance.

Treatment (with steroids, IVIG, or anti-D immunoglobulin) is generally not required for children with ITP unless they have bleeding that is mucosal or substantial, as spontaneous remission is expected. Adults, who are more likely to develop chronic ITP, may benefit from treatment.³⁰

HSP occurs most commonly in children, who may have palpable purpura, typically in the lower extremities, as well as arthritis or arthralgia, abdominal pain, and renal involvement that can progress from microscopic hematuria or proteinuria to renal insufficiency.³¹ Typically, children whose disease is in the acute phase do not appear to be sick, with an important exception: Those who develop hemorrhage and edema in the bowel wall, resulting in intussusception, have significant abdominal pain and are more likely to need surgical reduction.³²

Diffuse petechiae in the absence of any trauma, accompanied by significant signs of systemic illness, may be an indication of fulminant infection, including meningococcemia, DIC, and Rocky Mountain spotted fever (RMSF). (Fever and diffuse petechiae can also be seen in viral exanthema, but patients usually look well and the rash often has both blanching and petechial components.³³)

When a returning traveler presents with a rash and systemic symptoms, it is important to take a thorough history and to consider infections endemic to the area visited. RMSF may initially be localized to the wrists and progress to widespread petechiae over hours to days. Because the cutaneous findings may not be as fulminant—and up to 10% of patients with RMSF have no rash at all³⁴—attention to the noncutaneous features is important. Fever, headache, neurologic symptoms, joint complaints, and abdominal pain (or only a few of these manifestations) in the context of potential tick bite exposure should prompt consideration of RMSF.³⁵

Keep in mind, too, that in cases of fulminant infections such as meningococcemia and DIC, the hallmark purpura fulminans may not be present initially.³⁶ Although the initial cutaneous findings may be subtle, however, such patients will appear quite ill, and their condition will deteriorate rapidly. Because prompt antibiotic therapy can save life and limb, a high index of suspicion should be maintained for any patient who presents with a rash in the setting of fever and hypotension or other evidence of shock.

Some inherited diseases are found as a result of routine neonatal screening. Others remain hidden for years—until a pregnant woman is tested, an older patient receives a particular laboratory test, or signs and symptoms of a previously undetected disorder emerge.

To recognize the signs and respond appropriately, you need to know which patient populations are at heightened risk for which inherited diseases. It is crucial, too, to routinely obtain a comprehensive medical history.

General questions about the health status of family members may be sufficient when there is no reason to suspect a genetic disease. When you have evidence or a reasonable suspicion of a particular disorder, however, a targeted family history (TABLE) is essential. It is crucial, too, to thoroughly document any evidence of an inherited condition found at birth, as well as to advise patients of reproductive age who may be carriers to seek genetic testing or counseling when they begin thinking about starting a family. This review focuses on inherited blood disorders, but these principles apply to other genetic diseases, as well.

TABLE
Family history as a guide to genetic disease

Sickle cell disease

About one in 500 African Americans are born with sickle cell disease (SCD)—perhaps the best-known inherited blood disorder. Far more (approximately one in 12) are carriers. SCD also affects people of Hispanic origin, although the incidence (about one in 36,000) is much lower than that of blacks. Overall, an estimated 70,000 to 100,000 US residents have SCD.^1,2

Inheritance
The genetics of SCD are fairly straightforward: A mutation in the hemoglobin beta chain results in a single amino acid substitution of the normal glutamic acid.³ The mode of inheritance is autosomal recessive. Simply put, patients with SCD have 2 abnormal genes (one from each parent) that cause their red blood cells to change shape. People with sickle cell trait have only one abnormal gene. They cannot develop SCD themselves, but they are carriers of the disease.

Testing
SCD is typically diagnosed as a result of routine neonatal screening (screening newborns for SCD is mandatory in every state).⁴ The gold standard test is hemoglobin electrophoresis. Although gene sequencing can be used to distinguish SCD from other hemoglobinopathies in equivocal cases, this is rarely necessary.⁵

Clinical presentation
Infants with SCD are typically asymptomatic for the first few months of life. This is because of the persistence of fetal hemoglobin, which is not predisposed to sickling.⁶

In many cases, hand/mouth syndrome—a painful swelling of the hands and feet—is the first physical manifestation of SCD and is treated with pain medication and an increase in fluids. The clinical course of SCD, although somewhat variable, is characterized by sickle cell and pain crises.

Sickle cell crisis occurs when a precipitating factor, such as a temperature change, dehydration, or infection, induces the abnormal genes to polymerize and deform the red blood cells, which then hemolyze. Microinfarctions can occur throughout the body, causing intense pain. The hematocrit may fall precipitously. If the bone marrow is unable to replace the hemolyzed red blood cells, an aplastic crisis may result.

A pain crisis is similar, with one key difference: Hematocrit levels do not drop precipitously. It is not always possible to distinguish between a sickle cell crisis and a pain crisis within the first few hours of presentation. However, prompt recognition and rapid treatment of an acute flare-up (with analgesia, oxygen, hydration, and a search for the precipitating cause) can sometimes prevent the drop in hematocrit associated with a sickle cell crisis.⁷

Treatment and follow-up
A rapid response to flare-ups is a key reason for primary care physicians and patients with SCD (or their parents) to develop a close relationship. Physicians caring for such patients must ensure that they receive adequate pain management, control of sickling events, and, when necessary, access to emergency services without delay. Blood transfusions are needed to treat severe anemia, which may develop as a result of an infection or enlargement of the spleen.

Beyond the crisis. Management of SCD involves more than responding to crises. Magnesium, taken regularly, can stabilize red cell membranes, and hydroxyurea, which increases fetal hemoglobin, may reduce the frequency of attacks.⁸ Screening for folate and B12 deficiency should be considered prior to supplementation.⁹ Bone marrow transplantation and gene therapy are being explored, as well.¹⁰

Growing awareness of SCD and improvements in disease management have extended the life expectancy of patients with the disease in recent years to the mid-40s, on average.¹¹ Advances in our understanding of SCD, however, have done little to reduce the incidence of the disease.⁶

Part of the problem is that sickle cell trait—like carrier status of other genetic diseases identified at birth—is often forgotten or overlooked by the time the patient reaches reproductive age. Family physicians can help by educating parents of a newborn with an SCD diagnosis—or with sickle cell trait—about the risks of passing on the disorder. It is equally important to advise teens and young adults to find out whether they or their partners are carriers, stressing the need for both parties to be tested before they marry or start a family.

Thalassemia

Originally described by Thomas Cooley in 1925,¹² thalassemia is named for the Greek word for sea (thalassa)—reflecting the fact that for many years, those most affected lived in the vicinity of the Mediterranean Sea.¹³ Unlike SCD, which is caused by a qualitative problem involving the beta chain of hemoglobin, thalassemia is characterized by quantitative defects in the synthesis of either the alpha or beta hemoglobin chain.

Thus, thalassemia is a spectrum disorder designated in part by the chain of hemoglobin (alpha or beta) that is affected. The HbVar Database of Human Hemoglobin Variants and Thalassemia Mutations (http://globin.bx.psu.edu/hbvar/) lists hundreds of mutations associated with various subtypes, with particular forms of the disease found in certain ethnic groups.

The number of Americans affected by thalassemia is not known. It is estimated, however, that 15% of African Americans (the US population with the highest incidence of any form of thalassemia) are affected by alpha thalassemia.¹⁴ The incidence of beta thalassemia among Mediterranean, African, and Middle Eastern populations ranges from about 5% to 25%.¹⁵

Inheritance
Most people have 4 genes for the alpha chain of hemoglobin (2 from each parent) and 2 genes for the beta chain of hemoglobin (one maternal and one paternal). The severity of the disorder typically depends on the number of genes affected.

Individuals in which one alpha gene is missing or damaged are silent carriers, while those with 2 affected genes may have a subclinical anemia, often mistaken for iron deficiency anemia. Those in which 3 alpha genes are missing or defective have hemoglobin H disease, a serious condition that causes an enlarged liver and spleen and hemolytic anemia. When all 4 alpha genes are affected, the result is hydrops fetalis, a condition that leads to the death of the fetus or newborn.¹⁶

Beta thalassemia—the group of disorders caused by reduced or absent synthesis of the beta chains of hemoglobin—is further classified as minor, intermediate, or major (also known as Cooley’s anemia). People with minor beta thalassemia are typically asymptomatic; those with major thalassemia are severely affected, and often die by the age of 20 years.¹⁷

Testing
Routine neonatal screening can detect both alpha and beta thalassemia and identify asymptomatic carriers. Confirmation testing is widely available by hemoglobin electrophoresis. Antenatal testing can be performed via amniocentesis or chorionic villus sampling, and is indicated in countries in which thalassemia is relatively prevalent. In the United States, we typically take a family history and may screen the parents for carrier status.¹⁸

Clinical presentation
Mild forms of thalassemia are often mistaken for iron deficiency anemia, and it is likely that the prevalence of this inherited disease is underestimated.¹⁹ Patients at the intermediate level often need transfusions under circumstances in which they’re not typically required, such as childbirth. Those with thalassemia major develop splenomegaly and bone malformations. Although patients with thalassemia major have not been expected to live much beyond adulthood, the disorder has been treated successfully with bone marrow transplantation in recent years.²⁰

Treatment and follow-up
Patients who are severely affected by thalassemia need frequent transfusions; ensuring that they receive emergency services, as needed, is key. When caring for such patients—or for individuals who have symptoms suggestive of thalassemia or whose children are found to be carriers—targeted questions about family medical history are necessary, as well. Asking whether anyone in the family has required blood transfusions or had “problems with their blood” may help you detect patterns suggestive of a family history of thalassemia.

As is the case with sickle cell trait, however, the significance (or evidence) of carrier status may be lost by the time a child reaches reproductive age. Thus, the medical records of patients found to be carriers of any genetic disorder should be flagged, and individuals from affected racial/ethnic groups should be routinely advised to review their own and their partner’s genetic status as part of the family planning process. Parents who fail to consider carrier status may have children who inherit SCD, thalassemia, or a combination of these diseases.^21,22

Porphyria

Porphyria may encompass an even wider spectrum of disorders than thalassemia. The various clinical entities have little in common other than their pathophysiology—disordered heme synthesis. As heme is synthesized, it transitions through several highly reactive states, and deficiencies in different areas result in different syndromes. When there is a deficiency in one of the enzymes in the heme degradation pathway, reactive metabolites upstream of the defect may occur.

However, all porphyrias have one common feature: the accumulation of porphyrins or their precursors, which sometimes gives the urine a reddish color. A number of porphyrias are extremely rare—only 5 cases of dehydrogenase deficiency porphyria have been reported, for example, and the incidence of congenital erythropoietic porphyria is <1 in a million.^23,24

Others occur a bit more frequently in particular ethnic groups. Variegate porphyria, a hepatic form of the disorder associated with acute attacks and photosensitivity, is particularly common among the white South African population, for example.²⁵ Among Eastern Europeans, the incidence of porphyria cutanea tarda (PCT)—the most common porphyria—may be as high as 1 in 5000.²⁵ The “tarda” in the name reflects the fact that, unlike other porphyrias, onset of PCT occurs later in life.²⁶

Inheritance
Inheritance varies by condition. PCT is autosomal dominant, as are most porphyrias; acute intermittent porphyria, however, is autosomal recessive. Some cases of PCT are acquired, occurring as a result of exposure to environmental or infectious agents.²⁷

Testing
A random urine porphobilinogen (PBG) is a useful screening test for porphyria, although checking urine for fluorescence may be the most readily available clinical examination. Further delineation using urine and fecal porphyrins is usually not readily available, and may require sending specimens to a specialized laboratory. “GeneReviews” (http://www.ncbi.nlm.nih.gov/sites/GeneTests/review?db=GeneTests) is a useful resource for locating such labs; the site also provides educational material about genetic diseases as well as information about specimen collection and billing.

Clinical presentation

Characterized by irritable and erratic behavior provoked by sunlight (with varying degrees of hirsutism) and ameliorated by ingesting fresh blood, porphyria could have been the inspiration for the vampire legends.²⁸ Although symptoms vary from one type of porphyria to another, most affect either the nervous system or the skin. Some porphyrias, including PCT, are associated with a blistering, photosensitive rash.²⁹

The acute porphyrias—a grouping of several variants, including acute intermittent porphyria and variegate porphyria—typically cause severe abdominal pain and neurologic symptoms, while erythropoietic porphyria patients may present with anemia, hypo- and hyperpigmentation of the skin, red urine, and reddish coloration of the teeth (FIGURE).²⁹ Porphyrias are an often-overlooked cause of neuropathy, as well.³⁰

FIGURE
Erythropoietic porphyria: Distinguishing characteristics

Treatment and follow-up
The abdominal pain associated with porphyria can be treated with dextrose infusions, analgesics, and hematin. Long-term management includes monitoring for cirrhosis, iron overload, and possibly, hepatocellular carcinoma.²⁷

The treatment for anemia resulting from ineffective erythropoiesis—which ironically, results in iron overload—is phlebotomy, with 400 mL of blood removed every 2 weeks until the iron overload is relieved.³¹ Erythropoietin may be used to treat anemia resulting from phlebotomy, and is thought to mobilize iron stores.³²

For patients with PCT (and any other porphyria associated with photosensitivity), avoidance of sunlight—and any known precipitating factors—is essential. Hydroxychloroquine 200 mg can be given by mouth twice a week.³³ Fresh blisters should be kept clean and free from infection.

In addition to symptom management, it is important to learn as much as possible about the family history of patients who have, or whom you suspect of having, any variant of this little-known genetic disease. Start with these 2 questions:

1. Do you have family members who are unusually sensitive to the sun?
2. Do you have any family members who always seem to be in the hospital but no one knows what’s wrong with them?

Hemochromatosis

Hereditary hemochromatosis (HH), also referred to as iron overload disease, is a little-known genetic disease that primarily affects Caucasians of Northern European descent, although other ethnic groups may also be affected.^34,35

Iron is such a precious commodity that no mechanism has evolved for excreting it. During times of systemic infection, there is a tendency for the body to “hide” iron from invading bacteria, resulting in an increased serum and tissue ferritin—and causing chronic anemia if this continues for long periods of time. The balance of iron homeostasis depends on the regulation of iron absorption, which HH interferes with. In patients with HH, the excess iron builds up in the body, particularly in the liver, heart, pancreas, joints, and pituitary gland, and can cause tissue and organ damage.

Inheritance
Although our understanding of the mechanism by which HH occurs may not be complete, it appears that most cases involve a dysregulation of hepcidin, the major regulator of iron transfer. About 10% of white Americans are carriers of the disorder, which is autosomal recessive, and approximately 0.3% to 0.5% have the double mutation and are therefore at high risk for developing HH.^34,35 In many cases, the disease does not develop until middle age.

Testing
HH often goes undetected for years. In some cases, routine lab tests that reveal a polycythemia with a high serum iron and a high ferritin and elevated liver enzymes are the first indication of a problem.

While iron studies can raise the suspicion of HH, however, pinning down the genetic mutation can be a little more complicated. The most common allele in Caucasians results from a C282Y mutation thought to be traced to a Celtic or Viking who lived several centuries ago. For this reason, patients with signs of iron overload who are of northern European ancestry are sometimes tested immediately for the gene associated with HH. Patients who present with cirrhosis may have had a liver biopsy before HH was suspected, and may be offered genetic testing, as well.³⁶

Clinical presentation
Iron overload results in iron deposits in many tissues, with varying results: Infiltration of the liver can cause cirrhosis, infiltration of the pancreas can lead to diabetes, and infiltration of the skin results in a bronzed appearance. Diabetes is a primary complication when HH—sometimes referred to as “bronze diabetes”—goes untreated.³⁷

Treatment
With the exception of a small amount of iron that is sloughed off in dead skin cells each day, bleeding is the only way to rid the body of excess iron. Most patients with HH can be treated with phlebotomy (See “A case for phlebotomized blood)”. One unit of whole blood is removed at approximately 2-week intervals until the serum ferritin is <20 ng/mL. This process takes about 13 months.³⁸

Unlike other genetic disorders, HH can be completely controlled—provided it is detected before major organ damage occurs. Thus, it is particularly important that all family members of an individual diagnosed with HH—or found to be a carrier of the disorder—undergo genetic testing. They should also be asked whether they have (or have had) any relatives who frequently donate blood or have been told to give blood frequently.

A referral for genetic counseling may be indicated, not only for families affected by HH, but for those suspected of having (or carrying) other genetic disorders, as well.

CORRESPONDENCE S. Paul Starr, MD, LSU Family Medicine, 200 West Esplanade #412, Kenner, LA 70065; [email protected]

Some inherited diseases are found as a result of routine neonatal screening. Others remain hidden for years—until a pregnant woman is tested, an older patient receives a particular laboratory test, or signs and symptoms of a previously undetected disorder emerge.

To recognize the signs and respond appropriately, you need to know which patient populations are at heightened risk for which inherited diseases. It is crucial, too, to routinely obtain a comprehensive medical history.

General questions about the health status of family members may be sufficient when there is no reason to suspect a genetic disease. When you have evidence or a reasonable suspicion of a particular disorder, however, a targeted family history (TABLE) is essential. It is crucial, too, to thoroughly document any evidence of an inherited condition found at birth, as well as to advise patients of reproductive age who may be carriers to seek genetic testing or counseling when they begin thinking about starting a family. This review focuses on inherited blood disorders, but these principles apply to other genetic diseases, as well.

TABLE
Family history as a guide to genetic disease

Sickle cell disease

About one in 500 African Americans are born with sickle cell disease (SCD)—perhaps the best-known inherited blood disorder. Far more (approximately one in 12) are carriers. SCD also affects people of Hispanic origin, although the incidence (about one in 36,000) is much lower than that of blacks. Overall, an estimated 70,000 to 100,000 US residents have SCD.^1,2

Inheritance
The genetics of SCD are fairly straightforward: A mutation in the hemoglobin beta chain results in a single amino acid substitution of the normal glutamic acid.³ The mode of inheritance is autosomal recessive. Simply put, patients with SCD have 2 abnormal genes (one from each parent) that cause their red blood cells to change shape. People with sickle cell trait have only one abnormal gene. They cannot develop SCD themselves, but they are carriers of the disease.

Testing
SCD is typically diagnosed as a result of routine neonatal screening (screening newborns for SCD is mandatory in every state).⁴ The gold standard test is hemoglobin electrophoresis. Although gene sequencing can be used to distinguish SCD from other hemoglobinopathies in equivocal cases, this is rarely necessary.⁵

Clinical presentation
Infants with SCD are typically asymptomatic for the first few months of life. This is because of the persistence of fetal hemoglobin, which is not predisposed to sickling.⁶

In many cases, hand/mouth syndrome—a painful swelling of the hands and feet—is the first physical manifestation of SCD and is treated with pain medication and an increase in fluids. The clinical course of SCD, although somewhat variable, is characterized by sickle cell and pain crises.

Sickle cell crisis occurs when a precipitating factor, such as a temperature change, dehydration, or infection, induces the abnormal genes to polymerize and deform the red blood cells, which then hemolyze. Microinfarctions can occur throughout the body, causing intense pain. The hematocrit may fall precipitously. If the bone marrow is unable to replace the hemolyzed red blood cells, an aplastic crisis may result.

A pain crisis is similar, with one key difference: Hematocrit levels do not drop precipitously. It is not always possible to distinguish between a sickle cell crisis and a pain crisis within the first few hours of presentation. However, prompt recognition and rapid treatment of an acute flare-up (with analgesia, oxygen, hydration, and a search for the precipitating cause) can sometimes prevent the drop in hematocrit associated with a sickle cell crisis.⁷

Treatment and follow-up
A rapid response to flare-ups is a key reason for primary care physicians and patients with SCD (or their parents) to develop a close relationship. Physicians caring for such patients must ensure that they receive adequate pain management, control of sickling events, and, when necessary, access to emergency services without delay. Blood transfusions are needed to treat severe anemia, which may develop as a result of an infection or enlargement of the spleen.

Beyond the crisis. Management of SCD involves more than responding to crises. Magnesium, taken regularly, can stabilize red cell membranes, and hydroxyurea, which increases fetal hemoglobin, may reduce the frequency of attacks.⁸ Screening for folate and B12 deficiency should be considered prior to supplementation.⁹ Bone marrow transplantation and gene therapy are being explored, as well.¹⁰

Growing awareness of SCD and improvements in disease management have extended the life expectancy of patients with the disease in recent years to the mid-40s, on average.¹¹ Advances in our understanding of SCD, however, have done little to reduce the incidence of the disease.⁶

Part of the problem is that sickle cell trait—like carrier status of other genetic diseases identified at birth—is often forgotten or overlooked by the time the patient reaches reproductive age. Family physicians can help by educating parents of a newborn with an SCD diagnosis—or with sickle cell trait—about the risks of passing on the disorder. It is equally important to advise teens and young adults to find out whether they or their partners are carriers, stressing the need for both parties to be tested before they marry or start a family.

Thalassemia

Originally described by Thomas Cooley in 1925,¹² thalassemia is named for the Greek word for sea (thalassa)—reflecting the fact that for many years, those most affected lived in the vicinity of the Mediterranean Sea.¹³ Unlike SCD, which is caused by a qualitative problem involving the beta chain of hemoglobin, thalassemia is characterized by quantitative defects in the synthesis of either the alpha or beta hemoglobin chain.

Thus, thalassemia is a spectrum disorder designated in part by the chain of hemoglobin (alpha or beta) that is affected. The HbVar Database of Human Hemoglobin Variants and Thalassemia Mutations (http://globin.bx.psu.edu/hbvar/) lists hundreds of mutations associated with various subtypes, with particular forms of the disease found in certain ethnic groups.

The number of Americans affected by thalassemia is not known. It is estimated, however, that 15% of African Americans (the US population with the highest incidence of any form of thalassemia) are affected by alpha thalassemia.¹⁴ The incidence of beta thalassemia among Mediterranean, African, and Middle Eastern populations ranges from about 5% to 25%.¹⁵

Inheritance
Most people have 4 genes for the alpha chain of hemoglobin (2 from each parent) and 2 genes for the beta chain of hemoglobin (one maternal and one paternal). The severity of the disorder typically depends on the number of genes affected.

Individuals in which one alpha gene is missing or damaged are silent carriers, while those with 2 affected genes may have a subclinical anemia, often mistaken for iron deficiency anemia. Those in which 3 alpha genes are missing or defective have hemoglobin H disease, a serious condition that causes an enlarged liver and spleen and hemolytic anemia. When all 4 alpha genes are affected, the result is hydrops fetalis, a condition that leads to the death of the fetus or newborn.¹⁶

Beta thalassemia—the group of disorders caused by reduced or absent synthesis of the beta chains of hemoglobin—is further classified as minor, intermediate, or major (also known as Cooley’s anemia). People with minor beta thalassemia are typically asymptomatic; those with major thalassemia are severely affected, and often die by the age of 20 years.¹⁷

Testing
Routine neonatal screening can detect both alpha and beta thalassemia and identify asymptomatic carriers. Confirmation testing is widely available by hemoglobin electrophoresis. Antenatal testing can be performed via amniocentesis or chorionic villus sampling, and is indicated in countries in which thalassemia is relatively prevalent. In the United States, we typically take a family history and may screen the parents for carrier status.¹⁸

Clinical presentation
Mild forms of thalassemia are often mistaken for iron deficiency anemia, and it is likely that the prevalence of this inherited disease is underestimated.¹⁹ Patients at the intermediate level often need transfusions under circumstances in which they’re not typically required, such as childbirth. Those with thalassemia major develop splenomegaly and bone malformations. Although patients with thalassemia major have not been expected to live much beyond adulthood, the disorder has been treated successfully with bone marrow transplantation in recent years.²⁰

Treatment and follow-up
Patients who are severely affected by thalassemia need frequent transfusions; ensuring that they receive emergency services, as needed, is key. When caring for such patients—or for individuals who have symptoms suggestive of thalassemia or whose children are found to be carriers—targeted questions about family medical history are necessary, as well. Asking whether anyone in the family has required blood transfusions or had “problems with their blood” may help you detect patterns suggestive of a family history of thalassemia.

As is the case with sickle cell trait, however, the significance (or evidence) of carrier status may be lost by the time a child reaches reproductive age. Thus, the medical records of patients found to be carriers of any genetic disorder should be flagged, and individuals from affected racial/ethnic groups should be routinely advised to review their own and their partner’s genetic status as part of the family planning process. Parents who fail to consider carrier status may have children who inherit SCD, thalassemia, or a combination of these diseases.^21,22

Porphyria

Porphyria may encompass an even wider spectrum of disorders than thalassemia. The various clinical entities have little in common other than their pathophysiology—disordered heme synthesis. As heme is synthesized, it transitions through several highly reactive states, and deficiencies in different areas result in different syndromes. When there is a deficiency in one of the enzymes in the heme degradation pathway, reactive metabolites upstream of the defect may occur.

However, all porphyrias have one common feature: the accumulation of porphyrins or their precursors, which sometimes gives the urine a reddish color. A number of porphyrias are extremely rare—only 5 cases of dehydrogenase deficiency porphyria have been reported, for example, and the incidence of congenital erythropoietic porphyria is <1 in a million.^23,24

Others occur a bit more frequently in particular ethnic groups. Variegate porphyria, a hepatic form of the disorder associated with acute attacks and photosensitivity, is particularly common among the white South African population, for example.²⁵ Among Eastern Europeans, the incidence of porphyria cutanea tarda (PCT)—the most common porphyria—may be as high as 1 in 5000.²⁵ The “tarda” in the name reflects the fact that, unlike other porphyrias, onset of PCT occurs later in life.²⁶

Inheritance
Inheritance varies by condition. PCT is autosomal dominant, as are most porphyrias; acute intermittent porphyria, however, is autosomal recessive. Some cases of PCT are acquired, occurring as a result of exposure to environmental or infectious agents.²⁷

Testing
A random urine porphobilinogen (PBG) is a useful screening test for porphyria, although checking urine for fluorescence may be the most readily available clinical examination. Further delineation using urine and fecal porphyrins is usually not readily available, and may require sending specimens to a specialized laboratory. “GeneReviews” (http://www.ncbi.nlm.nih.gov/sites/GeneTests/review?db=GeneTests) is a useful resource for locating such labs; the site also provides educational material about genetic diseases as well as information about specimen collection and billing.

Clinical presentation

Characterized by irritable and erratic behavior provoked by sunlight (with varying degrees of hirsutism) and ameliorated by ingesting fresh blood, porphyria could have been the inspiration for the vampire legends.²⁸ Although symptoms vary from one type of porphyria to another, most affect either the nervous system or the skin. Some porphyrias, including PCT, are associated with a blistering, photosensitive rash.²⁹

The acute porphyrias—a grouping of several variants, including acute intermittent porphyria and variegate porphyria—typically cause severe abdominal pain and neurologic symptoms, while erythropoietic porphyria patients may present with anemia, hypo- and hyperpigmentation of the skin, red urine, and reddish coloration of the teeth (FIGURE).²⁹ Porphyrias are an often-overlooked cause of neuropathy, as well.³⁰

FIGURE
Erythropoietic porphyria: Distinguishing characteristics

Treatment and follow-up
The abdominal pain associated with porphyria can be treated with dextrose infusions, analgesics, and hematin. Long-term management includes monitoring for cirrhosis, iron overload, and possibly, hepatocellular carcinoma.²⁷

The treatment for anemia resulting from ineffective erythropoiesis—which ironically, results in iron overload—is phlebotomy, with 400 mL of blood removed every 2 weeks until the iron overload is relieved.³¹ Erythropoietin may be used to treat anemia resulting from phlebotomy, and is thought to mobilize iron stores.³²

For patients with PCT (and any other porphyria associated with photosensitivity), avoidance of sunlight—and any known precipitating factors—is essential. Hydroxychloroquine 200 mg can be given by mouth twice a week.³³ Fresh blisters should be kept clean and free from infection.

In addition to symptom management, it is important to learn as much as possible about the family history of patients who have, or whom you suspect of having, any variant of this little-known genetic disease. Start with these 2 questions:

1. Do you have family members who are unusually sensitive to the sun?
2. Do you have any family members who always seem to be in the hospital but no one knows what’s wrong with them?

Hemochromatosis

Hereditary hemochromatosis (HH), also referred to as iron overload disease, is a little-known genetic disease that primarily affects Caucasians of Northern European descent, although other ethnic groups may also be affected.^34,35

Iron is such a precious commodity that no mechanism has evolved for excreting it. During times of systemic infection, there is a tendency for the body to “hide” iron from invading bacteria, resulting in an increased serum and tissue ferritin—and causing chronic anemia if this continues for long periods of time. The balance of iron homeostasis depends on the regulation of iron absorption, which HH interferes with. In patients with HH, the excess iron builds up in the body, particularly in the liver, heart, pancreas, joints, and pituitary gland, and can cause tissue and organ damage.

Inheritance
Although our understanding of the mechanism by which HH occurs may not be complete, it appears that most cases involve a dysregulation of hepcidin, the major regulator of iron transfer. About 10% of white Americans are carriers of the disorder, which is autosomal recessive, and approximately 0.3% to 0.5% have the double mutation and are therefore at high risk for developing HH.^34,35 In many cases, the disease does not develop until middle age.

Testing
HH often goes undetected for years. In some cases, routine lab tests that reveal a polycythemia with a high serum iron and a high ferritin and elevated liver enzymes are the first indication of a problem.

While iron studies can raise the suspicion of HH, however, pinning down the genetic mutation can be a little more complicated. The most common allele in Caucasians results from a C282Y mutation thought to be traced to a Celtic or Viking who lived several centuries ago. For this reason, patients with signs of iron overload who are of northern European ancestry are sometimes tested immediately for the gene associated with HH. Patients who present with cirrhosis may have had a liver biopsy before HH was suspected, and may be offered genetic testing, as well.³⁶

Clinical presentation
Iron overload results in iron deposits in many tissues, with varying results: Infiltration of the liver can cause cirrhosis, infiltration of the pancreas can lead to diabetes, and infiltration of the skin results in a bronzed appearance. Diabetes is a primary complication when HH—sometimes referred to as “bronze diabetes”—goes untreated.³⁷

Treatment
With the exception of a small amount of iron that is sloughed off in dead skin cells each day, bleeding is the only way to rid the body of excess iron. Most patients with HH can be treated with phlebotomy (See “A case for phlebotomized blood)”. One unit of whole blood is removed at approximately 2-week intervals until the serum ferritin is <20 ng/mL. This process takes about 13 months.³⁸

Unlike other genetic disorders, HH can be completely controlled—provided it is detected before major organ damage occurs. Thus, it is particularly important that all family members of an individual diagnosed with HH—or found to be a carrier of the disorder—undergo genetic testing. They should also be asked whether they have (or have had) any relatives who frequently donate blood or have been told to give blood frequently.

A referral for genetic counseling may be indicated, not only for families affected by HH, but for those suspected of having (or carrying) other genetic disorders, as well.

CORRESPONDENCE S. Paul Starr, MD, LSU Family Medicine, 200 West Esplanade #412, Kenner, LA 70065; [email protected]

Some inherited diseases are found as a result of routine neonatal screening. Others remain hidden for years—until a pregnant woman is tested, an older patient receives a particular laboratory test, or signs and symptoms of a previously undetected disorder emerge.

To recognize the signs and respond appropriately, you need to know which patient populations are at heightened risk for which inherited diseases. It is crucial, too, to routinely obtain a comprehensive medical history.

General questions about the health status of family members may be sufficient when there is no reason to suspect a genetic disease. When you have evidence or a reasonable suspicion of a particular disorder, however, a targeted family history (TABLE) is essential. It is crucial, too, to thoroughly document any evidence of an inherited condition found at birth, as well as to advise patients of reproductive age who may be carriers to seek genetic testing or counseling when they begin thinking about starting a family. This review focuses on inherited blood disorders, but these principles apply to other genetic diseases, as well.

TABLE
Family history as a guide to genetic disease

Sickle cell disease

About one in 500 African Americans are born with sickle cell disease (SCD)—perhaps the best-known inherited blood disorder. Far more (approximately one in 12) are carriers. SCD also affects people of Hispanic origin, although the incidence (about one in 36,000) is much lower than that of blacks. Overall, an estimated 70,000 to 100,000 US residents have SCD.^1,2

Inheritance
The genetics of SCD are fairly straightforward: A mutation in the hemoglobin beta chain results in a single amino acid substitution of the normal glutamic acid.³ The mode of inheritance is autosomal recessive. Simply put, patients with SCD have 2 abnormal genes (one from each parent) that cause their red blood cells to change shape. People with sickle cell trait have only one abnormal gene. They cannot develop SCD themselves, but they are carriers of the disease.

Testing
SCD is typically diagnosed as a result of routine neonatal screening (screening newborns for SCD is mandatory in every state).⁴ The gold standard test is hemoglobin electrophoresis. Although gene sequencing can be used to distinguish SCD from other hemoglobinopathies in equivocal cases, this is rarely necessary.⁵

Clinical presentation
Infants with SCD are typically asymptomatic for the first few months of life. This is because of the persistence of fetal hemoglobin, which is not predisposed to sickling.⁶

In many cases, hand/mouth syndrome—a painful swelling of the hands and feet—is the first physical manifestation of SCD and is treated with pain medication and an increase in fluids. The clinical course of SCD, although somewhat variable, is characterized by sickle cell and pain crises.

Sickle cell crisis occurs when a precipitating factor, such as a temperature change, dehydration, or infection, induces the abnormal genes to polymerize and deform the red blood cells, which then hemolyze. Microinfarctions can occur throughout the body, causing intense pain. The hematocrit may fall precipitously. If the bone marrow is unable to replace the hemolyzed red blood cells, an aplastic crisis may result.

A pain crisis is similar, with one key difference: Hematocrit levels do not drop precipitously. It is not always possible to distinguish between a sickle cell crisis and a pain crisis within the first few hours of presentation. However, prompt recognition and rapid treatment of an acute flare-up (with analgesia, oxygen, hydration, and a search for the precipitating cause) can sometimes prevent the drop in hematocrit associated with a sickle cell crisis.⁷

Treatment and follow-up
A rapid response to flare-ups is a key reason for primary care physicians and patients with SCD (or their parents) to develop a close relationship. Physicians caring for such patients must ensure that they receive adequate pain management, control of sickling events, and, when necessary, access to emergency services without delay. Blood transfusions are needed to treat severe anemia, which may develop as a result of an infection or enlargement of the spleen.

Beyond the crisis. Management of SCD involves more than responding to crises. Magnesium, taken regularly, can stabilize red cell membranes, and hydroxyurea, which increases fetal hemoglobin, may reduce the frequency of attacks.⁸ Screening for folate and B12 deficiency should be considered prior to supplementation.⁹ Bone marrow transplantation and gene therapy are being explored, as well.¹⁰

Growing awareness of SCD and improvements in disease management have extended the life expectancy of patients with the disease in recent years to the mid-40s, on average.¹¹ Advances in our understanding of SCD, however, have done little to reduce the incidence of the disease.⁶

Part of the problem is that sickle cell trait—like carrier status of other genetic diseases identified at birth—is often forgotten or overlooked by the time the patient reaches reproductive age. Family physicians can help by educating parents of a newborn with an SCD diagnosis—or with sickle cell trait—about the risks of passing on the disorder. It is equally important to advise teens and young adults to find out whether they or their partners are carriers, stressing the need for both parties to be tested before they marry or start a family.

Thalassemia

Originally described by Thomas Cooley in 1925,¹² thalassemia is named for the Greek word for sea (thalassa)—reflecting the fact that for many years, those most affected lived in the vicinity of the Mediterranean Sea.¹³ Unlike SCD, which is caused by a qualitative problem involving the beta chain of hemoglobin, thalassemia is characterized by quantitative defects in the synthesis of either the alpha or beta hemoglobin chain.

Thus, thalassemia is a spectrum disorder designated in part by the chain of hemoglobin (alpha or beta) that is affected. The HbVar Database of Human Hemoglobin Variants and Thalassemia Mutations (http://globin.bx.psu.edu/hbvar/) lists hundreds of mutations associated with various subtypes, with particular forms of the disease found in certain ethnic groups.

The number of Americans affected by thalassemia is not known. It is estimated, however, that 15% of African Americans (the US population with the highest incidence of any form of thalassemia) are affected by alpha thalassemia.¹⁴ The incidence of beta thalassemia among Mediterranean, African, and Middle Eastern populations ranges from about 5% to 25%.¹⁵

Inheritance
Most people have 4 genes for the alpha chain of hemoglobin (2 from each parent) and 2 genes for the beta chain of hemoglobin (one maternal and one paternal). The severity of the disorder typically depends on the number of genes affected.

Individuals in which one alpha gene is missing or damaged are silent carriers, while those with 2 affected genes may have a subclinical anemia, often mistaken for iron deficiency anemia. Those in which 3 alpha genes are missing or defective have hemoglobin H disease, a serious condition that causes an enlarged liver and spleen and hemolytic anemia. When all 4 alpha genes are affected, the result is hydrops fetalis, a condition that leads to the death of the fetus or newborn.¹⁶

Beta thalassemia—the group of disorders caused by reduced or absent synthesis of the beta chains of hemoglobin—is further classified as minor, intermediate, or major (also known as Cooley’s anemia). People with minor beta thalassemia are typically asymptomatic; those with major thalassemia are severely affected, and often die by the age of 20 years.¹⁷

Testing
Routine neonatal screening can detect both alpha and beta thalassemia and identify asymptomatic carriers. Confirmation testing is widely available by hemoglobin electrophoresis. Antenatal testing can be performed via amniocentesis or chorionic villus sampling, and is indicated in countries in which thalassemia is relatively prevalent. In the United States, we typically take a family history and may screen the parents for carrier status.¹⁸

Clinical presentation
Mild forms of thalassemia are often mistaken for iron deficiency anemia, and it is likely that the prevalence of this inherited disease is underestimated.¹⁹ Patients at the intermediate level often need transfusions under circumstances in which they’re not typically required, such as childbirth. Those with thalassemia major develop splenomegaly and bone malformations. Although patients with thalassemia major have not been expected to live much beyond adulthood, the disorder has been treated successfully with bone marrow transplantation in recent years.²⁰

Treatment and follow-up
Patients who are severely affected by thalassemia need frequent transfusions; ensuring that they receive emergency services, as needed, is key. When caring for such patients—or for individuals who have symptoms suggestive of thalassemia or whose children are found to be carriers—targeted questions about family medical history are necessary, as well. Asking whether anyone in the family has required blood transfusions or had “problems with their blood” may help you detect patterns suggestive of a family history of thalassemia.

As is the case with sickle cell trait, however, the significance (or evidence) of carrier status may be lost by the time a child reaches reproductive age. Thus, the medical records of patients found to be carriers of any genetic disorder should be flagged, and individuals from affected racial/ethnic groups should be routinely advised to review their own and their partner’s genetic status as part of the family planning process. Parents who fail to consider carrier status may have children who inherit SCD, thalassemia, or a combination of these diseases.^21,22

Porphyria

Porphyria may encompass an even wider spectrum of disorders than thalassemia. The various clinical entities have little in common other than their pathophysiology—disordered heme synthesis. As heme is synthesized, it transitions through several highly reactive states, and deficiencies in different areas result in different syndromes. When there is a deficiency in one of the enzymes in the heme degradation pathway, reactive metabolites upstream of the defect may occur.

However, all porphyrias have one common feature: the accumulation of porphyrins or their precursors, which sometimes gives the urine a reddish color. A number of porphyrias are extremely rare—only 5 cases of dehydrogenase deficiency porphyria have been reported, for example, and the incidence of congenital erythropoietic porphyria is <1 in a million.^23,24

Others occur a bit more frequently in particular ethnic groups. Variegate porphyria, a hepatic form of the disorder associated with acute attacks and photosensitivity, is particularly common among the white South African population, for example.²⁵ Among Eastern Europeans, the incidence of porphyria cutanea tarda (PCT)—the most common porphyria—may be as high as 1 in 5000.²⁵ The “tarda” in the name reflects the fact that, unlike other porphyrias, onset of PCT occurs later in life.²⁶

Inheritance
Inheritance varies by condition. PCT is autosomal dominant, as are most porphyrias; acute intermittent porphyria, however, is autosomal recessive. Some cases of PCT are acquired, occurring as a result of exposure to environmental or infectious agents.²⁷

Testing
A random urine porphobilinogen (PBG) is a useful screening test for porphyria, although checking urine for fluorescence may be the most readily available clinical examination. Further delineation using urine and fecal porphyrins is usually not readily available, and may require sending specimens to a specialized laboratory. “GeneReviews” (http://www.ncbi.nlm.nih.gov/sites/GeneTests/review?db=GeneTests) is a useful resource for locating such labs; the site also provides educational material about genetic diseases as well as information about specimen collection and billing.

Clinical presentation

Characterized by irritable and erratic behavior provoked by sunlight (with varying degrees of hirsutism) and ameliorated by ingesting fresh blood, porphyria could have been the inspiration for the vampire legends.²⁸ Although symptoms vary from one type of porphyria to another, most affect either the nervous system or the skin. Some porphyrias, including PCT, are associated with a blistering, photosensitive rash.²⁹

The acute porphyrias—a grouping of several variants, including acute intermittent porphyria and variegate porphyria—typically cause severe abdominal pain and neurologic symptoms, while erythropoietic porphyria patients may present with anemia, hypo- and hyperpigmentation of the skin, red urine, and reddish coloration of the teeth (FIGURE).²⁹ Porphyrias are an often-overlooked cause of neuropathy, as well.³⁰

FIGURE
Erythropoietic porphyria: Distinguishing characteristics

Treatment and follow-up
The abdominal pain associated with porphyria can be treated with dextrose infusions, analgesics, and hematin. Long-term management includes monitoring for cirrhosis, iron overload, and possibly, hepatocellular carcinoma.²⁷

The treatment for anemia resulting from ineffective erythropoiesis—which ironically, results in iron overload—is phlebotomy, with 400 mL of blood removed every 2 weeks until the iron overload is relieved.³¹ Erythropoietin may be used to treat anemia resulting from phlebotomy, and is thought to mobilize iron stores.³²

For patients with PCT (and any other porphyria associated with photosensitivity), avoidance of sunlight—and any known precipitating factors—is essential. Hydroxychloroquine 200 mg can be given by mouth twice a week.³³ Fresh blisters should be kept clean and free from infection.

In addition to symptom management, it is important to learn as much as possible about the family history of patients who have, or whom you suspect of having, any variant of this little-known genetic disease. Start with these 2 questions:

1. Do you have family members who are unusually sensitive to the sun?
2. Do you have any family members who always seem to be in the hospital but no one knows what’s wrong with them?

Hemochromatosis

Hereditary hemochromatosis (HH), also referred to as iron overload disease, is a little-known genetic disease that primarily affects Caucasians of Northern European descent, although other ethnic groups may also be affected.^34,35

Iron is such a precious commodity that no mechanism has evolved for excreting it. During times of systemic infection, there is a tendency for the body to “hide” iron from invading bacteria, resulting in an increased serum and tissue ferritin—and causing chronic anemia if this continues for long periods of time. The balance of iron homeostasis depends on the regulation of iron absorption, which HH interferes with. In patients with HH, the excess iron builds up in the body, particularly in the liver, heart, pancreas, joints, and pituitary gland, and can cause tissue and organ damage.

Inheritance
Although our understanding of the mechanism by which HH occurs may not be complete, it appears that most cases involve a dysregulation of hepcidin, the major regulator of iron transfer. About 10% of white Americans are carriers of the disorder, which is autosomal recessive, and approximately 0.3% to 0.5% have the double mutation and are therefore at high risk for developing HH.^34,35 In many cases, the disease does not develop until middle age.

Testing
HH often goes undetected for years. In some cases, routine lab tests that reveal a polycythemia with a high serum iron and a high ferritin and elevated liver enzymes are the first indication of a problem.

While iron studies can raise the suspicion of HH, however, pinning down the genetic mutation can be a little more complicated. The most common allele in Caucasians results from a C282Y mutation thought to be traced to a Celtic or Viking who lived several centuries ago. For this reason, patients with signs of iron overload who are of northern European ancestry are sometimes tested immediately for the gene associated with HH. Patients who present with cirrhosis may have had a liver biopsy before HH was suspected, and may be offered genetic testing, as well.³⁶

Clinical presentation
Iron overload results in iron deposits in many tissues, with varying results: Infiltration of the liver can cause cirrhosis, infiltration of the pancreas can lead to diabetes, and infiltration of the skin results in a bronzed appearance. Diabetes is a primary complication when HH—sometimes referred to as “bronze diabetes”—goes untreated.³⁷

Treatment
With the exception of a small amount of iron that is sloughed off in dead skin cells each day, bleeding is the only way to rid the body of excess iron. Most patients with HH can be treated with phlebotomy (See “A case for phlebotomized blood)”. One unit of whole blood is removed at approximately 2-week intervals until the serum ferritin is <20 ng/mL. This process takes about 13 months.³⁸

Unlike other genetic disorders, HH can be completely controlled—provided it is detected before major organ damage occurs. Thus, it is particularly important that all family members of an individual diagnosed with HH—or found to be a carrier of the disorder—undergo genetic testing. They should also be asked whether they have (or have had) any relatives who frequently donate blood or have been told to give blood frequently.

A referral for genetic counseling may be indicated, not only for families affected by HH, but for those suspected of having (or carrying) other genetic disorders, as well.

CORRESPONDENCE S. Paul Starr, MD, LSU Family Medicine, 200 West Esplanade #412, Kenner, LA 70065; [email protected]