Clinical Review

The American College of Obstetricians and Gynecologists (ACOG) has recommended dividing a woman's life cycle into four intervals—ages 13–18, 19–39, 40–64, and older than 65—in order to best organize the approach to primary and preventive health care.¹ This paradigm provides a structure for organizing the clinical approach to physical examination, laboratory testing, counseling, and immunizations. In addition, it helps to highlight the diseases and health problems most prevalent among women at each life-stage.

Different professional organizations—US Preventive Services Task Force (USPSTF), American Medical Association, American College of Physicians, ACOG, American Academy of Family Physicians, American Academy of Pediatrics, and Advisory Committee on Immunization Practices—have used varying analytical methods to determine recommended health services by age group; consequently, these organizations have somewhat divergent recommendations. However, the recommendations of most organizations share many similarities. In this comprehensive guide, I point out those similarities. Keep in mind that recommendations change over time, and it is important to use your professional judgment when approaching each patient.

TABLE

Physical examination and laboratory testing services according to a patient's age, based on ACOG recommendations¹

The adolescent: 13–18 years

Screen. Guide. Immunize. ACOG recommends that the first visit take place between 13 and 15 years of age, with annual visits thereafter. The purpose of the first, and subsequent, visits is to assess health status, including menstrual history and body mass index (BMI), and to provide health guidance, screening, and preventive health services. This initial visit generally does not include a pelvic examination. A physical examination is not required at every visit but is recommended to occur at least once during early, middle, and late adolescence.

Target your screening practices. Screen adolescents for the following conditions during clinical preventive services: hypertension; hyperlipidemia; obesity and eating disorders; physical, sexual, or emotional abuse; learning or school problems; substance use; depression and risk of suicide; sexual assault; sexual behavior that may lead to pregnancy or sexually transmitted disease (STD); and tuberculosis and HIV, unless the patient opts out (TABLE).

Anticipate. Then guide. Using anticipatory guidance, you can help adolescents understand their physical, psychosocial, and sexual development and motivate them to be involved in their health and health-care decisions. Issues relevant to adolescents include dietary habits; injury prevention, through the use of helmets and seatbelts; regular exercise; responsible sexual behaviors; avoidance of substances that can be abused; strategies for dealing with bullying; and avoidance of behaviors that might have negative consequences, such as vandalism, stealing, and sharing personal information with strangers.

Recommended immunizations. For this age group, immunizations, unless previously given, include:

• 1 or 2 doses of measles, mumps, and rubella
• 2 doses of varicella if not previously infected
• a booster dose of tetanus if ≥10 years have elapsed since the last dose
• human papillomavirus (HPV)
• annual influenza.

Other immunizations that may be warranted on the basis of medical condition, occupation, lifestyle, or other indications include: 3 doses of hepatitis B, 2 doses of hepatitis A, 1 or more doses of meningococcal, and 1 or 2 doses of pneumococcal.

Menses, an important "vital sign." Once menstruation begins, evaluating menstrual cycle characteristics is important. Patterns that may require evaluation include²:

• no menses within 3 years of thelarche
• no menses by age 13 with no sign of pubertal development
• no menses by age 14 with signs of hirsutism
• no menses by age 14 with indications of an eating disorder
• no menses by age 15
• history of regular menses that are now markedly irregular
• menses occur more frequently than 21 days or less frequently than every 45 days
• menses occur 90 days apart for one cycle
• menstrual bleeding that lasts more than 7 days
• frequent tampon/pad changes (more than 1 tampon/pad every 1 to 2 hours).

BMI predicts future disease. Overweight and obesity are important risk factors for diabetes mellitus, hyperlipidemia, hypertension, and various cancers. Eating disorders are common among adolescents and often occur in association with other mental health problems.

Non–sexually active teens and children

Gynecologic examination typically involves inspection of the genitalia and not instrumentation of the vagina. A careful explanation of the proposed examination is important. Ask young adolescents who they would like to have in the examination room with them. A hand mirror can be used to involve the patient in the genitalia inspection. If it's necessary to obtain magnification, use a hand lens, an otoscope without the speculum, or a colposcope. Record the configuration of the hymen, if present. If indicated, examination of the genitalia while the patient is in the knee-chest position often provides a good view of the vagina and sometimes the cervix, without instrumentation.

Sexually active teens

Effective contraception, including the use of emergency contraceptives, is an important health focus for sexually active teens. Vaginal speculum examination and bimanual gyn exam are not required prior to prescribing hormonal contraceptives to teens. Based on a review of the evidence and expert opinion,³ the current recommendation is that prior to prescribing a hormonal contraceptive, a medical history and blood pressure measurement are the only requirements; breast examination and a gyn exam (vaginal speculum and bimanual gyn exam) are not necessary. Testing for chlamydia and gonorrhea can be performed using a urine sample. A cervical cytology examination is not necessary until age 21 unless the patient is in a high-risk group, such as immunosuppressed or HIV-infected teens.

The young woman: 19–39 years

Focus on reproductive issues. Contraception, pregnancy, and cervical cancer screening are common reasons for visits among women in this age group. Gynecologic problems can include polycystic ovary syndrome (PCOS), endometriosis, fibroids, infertility, pelvic pain, vulvovaginal pain syndromes, vaginitis, adnexal masses, and STDs, including pelvic inflammatory diseases.

Offer effective contraception

Long-acting reversible contraceptives (LARCs) are the most clinically and cost-effective forms of reversible contraception. There are three LARC methods available in the United States: 1) the copper T380A intrauterine device (IUD; Paragard), 2) the levonorgestrel-releasing intrauterine system (Mirena), and 3) the single-rod etonogestrel implant (Implanon, Explanon).

The use of IUDs among American women has increased from about 2.4% of contracepting women of reproductive age in 2002 to 8.5% in 2009.⁴ In Norway and France, contracepting women of reproductive age use IUDs at a rate of 27% and 23%, respectively.⁵ Typical-use pregnancy rates for LARCs are lower and continuation rates are higher than observed with oral contraceptives (OCs).

In an economic analysis, the cost of LARCs was lower than almost all other forms of reversible contraception over a 5-year interval.⁶ When financial and access barriers are removed, most women starting a contraceptive will use a LARC, if offered.⁷

Be aware of STDs

STDs are common in this age group. In the United States, chlamydial genital infections reach a peak in women 18 to 25 years old, with a prevalence of about 4%.⁸

Counsel her about exercise and weight loss

Approximately 60% of women older than age 20 are overweight or obese.⁹ The rise in obesity is a key contributing factor to an increase in many diseases, including gestational diabetes, type 2 diabetes mellitus, and hypertension. Successful efforts to reduce the prevalence of obesity through diet and exercise could markedly improve population health.

Don't overlook autoimmune conditions

Many autoimmune diseases reach a peak incidence between ages 19 and 39, and, except for ankylosing spondylitis, are more of a concern for women than men. Systemic lupus erythematosus, lymphocytic thyroiditis, and rheumatoid arthritis occur much more frequently in women than in men, with ratios in the range of 7:1 observed during this age interval.

Keep her immunity up to date

Immunizations recommended in this age group include:

• one Tdap (tetanus toxoid, diphtheria, and pertussis)
• tetanus every 10 years
• influenza annually
• varicella if no evidence of immunity
• HPV for those aged 26 years or younger.

The mature woman: 40–64 years

Transition to postmenopause. The menstrual changes through perimenopause to postmenopause are often accompanied by changes in sleep patterns, vasomotor symptoms, and increasing vaginal dryness.

Open your eyes to a patient's insomnia

Perimenopausal and postmenopausal women report a much higher rate of insomnia than age-matched men.¹⁰ Women with moderate to severe vasomotor symptoms are more likely to report greater nighttime wakefulness and a greater number of nighttime long-awake episodes than women with mild vasomotor symptoms.¹¹ Insomnia can be associated with poor work performance and mood changes.

Hormone therapy: Be conservative

In the past, hormone therapy, with various estrogen and progestin combinations, was recommended to help prevent a number of diseases, including cardiovascular disease (CD) and osteoporosis. Based on clinical trial results, the current recommendation is to limit the use of hormone therapy in postmenopausal women to the treatment of vasomotor symptoms and vaginal symptoms caused by hypoestrogenism. To treat these problems, the lowest doses of hormones that are effective should be used for the shortest periods of time that achieve symptom resolution.

The older woman: 65+ years

Successful aging. Based on observational studies, behavioral and health factors associated with successful aging include more than 12 years of education; high socioeconomic status; absence of diabetes, asthma, stroke, and lower respiratory tract disease; absence of depression; presence of at least five close personal contacts; frequent walking; moderate use of alcohol; and nonsmoking status.¹²

Know her risks, and watch for them

Cardiovascular disease. Among women, CDs cause more deaths than malignant neoplasms, chronic lower respiratory disease, Alzheimer's disease, and accidents combined. Black women have rates of CD approximately 40% greater than white women. Hypertension, hypertriglyceridemia, obesity, and sedentary lifestyle among black women account for a part of this increased risk.

Effective lifestyle interventions for primary CD prevention in women include smoking cessation, a diet such as DASH (Dietary Approaches to Stop Hypertension) rich in fruits and vegetables, regular physical activity, and weight management.¹³

There are important gender differences in aspirin efficacy for primary prevention of stroke and myocardial infarction (MI) in men and women. Among women, aspirin used for primary prevention appears to reduce the risk of stroke but not MI.¹⁴ Among men, aspirin used for primary prevention appears to reduce the risk of MI but not stroke.^15,16 Based on these and other data, the USPSTF has recommended that aspirin not be used to prevent stroke in men but recommends aspirin to prevent stroke among women 55 to 79 years of age when benefits outweigh risks of gastrointestinal bleeding.¹⁷

Atrial fibrillation (AF), a risk factor for stroke, is more common in women than in men. In addition, women with AF who are not anticoagulated are at greater risk for stroke than men with AF who are not anticoagulated.¹⁸ The mechanisms that influence these gender differences are not well characterized.

Respiratory illness. Among women, the prevalence of chronic bronchitis and emphysema increased more than 2.8-fold from 1980 to 2000.¹⁹ These diseases are major contributors to physician office visits, hospitalizations, disability, and death. Tobacco use is the major risk factor that accounts for the marked increase in COPD among women during recent decades, although ambient pollutants in the environment, home, and workplace are also important contributors to COPD development.

Cognitive decline. Alzheimer's disease afflicts approximately twice as many women as men. Part of this difference is due to the greater longevity of women, but additional variables, such as gender differences in neurobiology, are also contributory. The role of estradiol in the development of Alzheimer's disease remains controversial.

Osteoporosis. This disease occurs about five times more frequently in women than in men. Among Medicare patients, the cost of caring for a hip fracture is more than $40,000 in the first year postfracture. Hip fracture is associated with a high risk of rapid health decline. Interventions that successfully prevent hip fracture are associated with a reduced mortality rate.^20,21

A concern at any age

Domestic violence

Domestic violence is common; approximately 5% of women report one episode during the past year and 25% report at least one lifetime episode.²² Domestic violence involves two people: a perpetrator and a victim. In some relationships, a recurrent cycle of violence and reconciliation is observed. Routine, confidential, and private screening is required to detect most cases of domestic violence.

Ask the right question(s). The single question, "At any time, has a partner hit, kicked, or otherwise hurt or threatened you?" can increase the rate of detection. Alternatively, a set of three questions can be used to screen for domestic violence:

1. "Within the past year, have you been hit, slapped, kicked or otherwise physically hurt by someone?"
2. "Within the past year, has anyone forced you to have sexual activity?"
3. In pregnancy: "Since you have been pregnant, have you been hit, slapped, kicked, or otherwise physically hurt by someone?"

Follow-up and refer. If a woman reports that she has suffered or is at risk for domestic violence, document the finding in her medical record. Then try to assess her safety by asking: "Are there guns in the home?", "Have there been threats of suicide or homicide?", "Has there been violence toward children?" Choking, specifically, could be a sign of future escalated violence—as many perpetrators choke their victims prior to further, escalated violence occurring—and should be taken as a threat of homicide. Refer women who report domestic violence to a specialist; often, the best trained and most available experts are experienced social workers.

Sexual assault

About 25% of women report at least one lifetime sexual assault. Most women who report being raped initially receive care in a hospital-based emergency department from nurses who are credentialed in Sexual Assault Nurse Evaluation (SANE) skills.

The initial evaluation includes rapid access to treatment by a specialized clinical team, assessment and treatment of bodily injuries with a focus on genital trauma, psychological assessment and support, pregnancy assessment and prevention, preventive treatment of STDs, and collection of forensic data, including toxicology testing for the presence of date-rape drugs.

When sexual assault is reported, treat for an STD. The Centers for Disease Control and Prevention (CDC) recommends the following approach to prevent and treat STDs in victims of sexual assault²³:

• ceftriaxone 125 mg IM to prevent gonorrhea
• azithromycin 1 g orally as a single dose or doxycycline 100 mg twice daily for 7 days to prevent chlamydia
• metronidazole 2 g orally as a single dose to prevent trichomoniasis
• hepatitis B vaccination, for women not previously vaccinated. (The CDC recommends against the use of hepatitis B immune globulin as the costs are believed to outweigh the benefits.)
• HIV postexposure prophylaxis for 3 to 7 days, with a follow-up visit to consider pros and cons of continued prophylaxis. (The risk of HIV infection following a sexual assault is low.)
• postcoital contraception (for example, levonorgestrel 1.5 mg orally as a single dose).

An antiemetic also should be offered to reduce the risk that the multiple prescribed medications will cause vomiting and nullify prophylaxis efforts. Approximately 2 weeks after the sexual assault the patient should have a pregnancy test and be assessed for ongoing mental health needs. If she did not adhere to the medications or if she shows relevant symptoms, perform follow-up STD testing. Follow-up HIV and syphilis testing can be performed at 12 and 24 weeks following the assault.

Sexual dysfunction

Sexuality is an important part of the human experience. Sexual dysfunction is the inability to participate as desired in a sexual relationship. Problems of sexual dysfunction are best approached from a biopsychosocial framework that recognizes the important contributions of biological, psychological, and social-cultural factors in sexual health. Masters and Johnson posited four stages of sexual response: excitement, plateau, orgasm, and resolution. Building on this linear model, investigators later divided the excitement phase into desire and arousal.

Recent models of sexual response have emphasized a circular model, in which sequential responses overlap and build on previous stimuli. These models also emphasize the importance of emotional intimacy and the quality of the relationship in achieving optimal sexual health.

Approximately 40% of women and 30% of men report sexual dysfunction.²⁴ Common sexual problems reported by heterosexual women include:

• lack of interest in sex
• inability to achieve orgasm
• pain caused by sexual intercourse
• lack of pleasure with sex
• trouble lubricating.

The majority of men and women will not voluntarily report sexual dysfunction to their clinician. To elicit the presence of sexual concerns, you must initiate the conversation.²⁵ You can begin the sexual history by asking, "Do you have any concerns about your sex life?" Additional helpful, open-ended questions include: "Are you having sexual relations currently? With men or women or both?", "If you are not having sex, when did you last have intercourse?", "Are you satisfied with the frequency and quality of your sexual experiences?", "What is the emotional quality and intimacy of your relationship with your sex partner?"

The common sexual disorders in women are categorized as desire, arousal, orgasm, and pain disorders. There are two desire disorders: hypoactive sexual desire disorder and sexual aversion disorder. There are two arousal disorders: female sexual arousal disorder and persistent genital arousal disorder. There are four pain disorders: dyspareunia, vulvodynia, vaginismus, and noncoital nonsexual pain.

Most experts recommend that treatment of female sexual dysfunction include multiple modalities that reflect the complex biopsychosocial factors that cause the problem. For example, a treatment plan might include cognitive behavioral therapy, sex therapy, and appropriate medications.

Mental health issues

Depression, anxiety, bulimia, and anorexia nervosa are more common in women than men. For instance, the lifetime risk of depression in women is approximately 20%, compared with about 10% in men. The gender difference is first observed in adolescence and becomes minimal after age 60. The gender differences are observed across racial and ethnic groups.²⁶

It's on us

As leaders in women's health care, we are uniquely trained to guide, counsel, diagnose, and treat women across their entire lifetime, from adolescence to postmenopause. We are at the vanguard in the effort to continually improve the health of all women.

We want to hear from you! Tell us what you think.

The American College of Obstetricians and Gynecologists (ACOG) has recommended dividing a woman's life cycle into four intervals—ages 13–18, 19–39, 40–64, and older than 65—in order to best organize the approach to primary and preventive health care.¹ This paradigm provides a structure for organizing the clinical approach to physical examination, laboratory testing, counseling, and immunizations. In addition, it helps to highlight the diseases and health problems most prevalent among women at each life-stage.

Different professional organizations—US Preventive Services Task Force (USPSTF), American Medical Association, American College of Physicians, ACOG, American Academy of Family Physicians, American Academy of Pediatrics, and Advisory Committee on Immunization Practices—have used varying analytical methods to determine recommended health services by age group; consequently, these organizations have somewhat divergent recommendations. However, the recommendations of most organizations share many similarities. In this comprehensive guide, I point out those similarities. Keep in mind that recommendations change over time, and it is important to use your professional judgment when approaching each patient.

TABLE

Physical examination and laboratory testing services according to a patient's age, based on ACOG recommendations¹

The adolescent: 13–18 years

Screen. Guide. Immunize. ACOG recommends that the first visit take place between 13 and 15 years of age, with annual visits thereafter. The purpose of the first, and subsequent, visits is to assess health status, including menstrual history and body mass index (BMI), and to provide health guidance, screening, and preventive health services. This initial visit generally does not include a pelvic examination. A physical examination is not required at every visit but is recommended to occur at least once during early, middle, and late adolescence.

Target your screening practices. Screen adolescents for the following conditions during clinical preventive services: hypertension; hyperlipidemia; obesity and eating disorders; physical, sexual, or emotional abuse; learning or school problems; substance use; depression and risk of suicide; sexual assault; sexual behavior that may lead to pregnancy or sexually transmitted disease (STD); and tuberculosis and HIV, unless the patient opts out (TABLE).

Anticipate. Then guide. Using anticipatory guidance, you can help adolescents understand their physical, psychosocial, and sexual development and motivate them to be involved in their health and health-care decisions. Issues relevant to adolescents include dietary habits; injury prevention, through the use of helmets and seatbelts; regular exercise; responsible sexual behaviors; avoidance of substances that can be abused; strategies for dealing with bullying; and avoidance of behaviors that might have negative consequences, such as vandalism, stealing, and sharing personal information with strangers.

Recommended immunizations. For this age group, immunizations, unless previously given, include:

• 1 or 2 doses of measles, mumps, and rubella
• 2 doses of varicella if not previously infected
• a booster dose of tetanus if ≥10 years have elapsed since the last dose
• human papillomavirus (HPV)
• annual influenza.

Other immunizations that may be warranted on the basis of medical condition, occupation, lifestyle, or other indications include: 3 doses of hepatitis B, 2 doses of hepatitis A, 1 or more doses of meningococcal, and 1 or 2 doses of pneumococcal.

Menses, an important "vital sign." Once menstruation begins, evaluating menstrual cycle characteristics is important. Patterns that may require evaluation include²:

• no menses within 3 years of thelarche
• no menses by age 13 with no sign of pubertal development
• no menses by age 14 with signs of hirsutism
• no menses by age 14 with indications of an eating disorder
• no menses by age 15
• history of regular menses that are now markedly irregular
• menses occur more frequently than 21 days or less frequently than every 45 days
• menses occur 90 days apart for one cycle
• menstrual bleeding that lasts more than 7 days
• frequent tampon/pad changes (more than 1 tampon/pad every 1 to 2 hours).

BMI predicts future disease. Overweight and obesity are important risk factors for diabetes mellitus, hyperlipidemia, hypertension, and various cancers. Eating disorders are common among adolescents and often occur in association with other mental health problems.

Non–sexually active teens and children

Gynecologic examination typically involves inspection of the genitalia and not instrumentation of the vagina. A careful explanation of the proposed examination is important. Ask young adolescents who they would like to have in the examination room with them. A hand mirror can be used to involve the patient in the genitalia inspection. If it's necessary to obtain magnification, use a hand lens, an otoscope without the speculum, or a colposcope. Record the configuration of the hymen, if present. If indicated, examination of the genitalia while the patient is in the knee-chest position often provides a good view of the vagina and sometimes the cervix, without instrumentation.

Sexually active teens

Effective contraception, including the use of emergency contraceptives, is an important health focus for sexually active teens. Vaginal speculum examination and bimanual gyn exam are not required prior to prescribing hormonal contraceptives to teens. Based on a review of the evidence and expert opinion,³ the current recommendation is that prior to prescribing a hormonal contraceptive, a medical history and blood pressure measurement are the only requirements; breast examination and a gyn exam (vaginal speculum and bimanual gyn exam) are not necessary. Testing for chlamydia and gonorrhea can be performed using a urine sample. A cervical cytology examination is not necessary until age 21 unless the patient is in a high-risk group, such as immunosuppressed or HIV-infected teens.

The young woman: 19–39 years

Focus on reproductive issues. Contraception, pregnancy, and cervical cancer screening are common reasons for visits among women in this age group. Gynecologic problems can include polycystic ovary syndrome (PCOS), endometriosis, fibroids, infertility, pelvic pain, vulvovaginal pain syndromes, vaginitis, adnexal masses, and STDs, including pelvic inflammatory diseases.

Offer effective contraception

Long-acting reversible contraceptives (LARCs) are the most clinically and cost-effective forms of reversible contraception. There are three LARC methods available in the United States: 1) the copper T380A intrauterine device (IUD; Paragard), 2) the levonorgestrel-releasing intrauterine system (Mirena), and 3) the single-rod etonogestrel implant (Implanon, Explanon).

The use of IUDs among American women has increased from about 2.4% of contracepting women of reproductive age in 2002 to 8.5% in 2009.⁴ In Norway and France, contracepting women of reproductive age use IUDs at a rate of 27% and 23%, respectively.⁵ Typical-use pregnancy rates for LARCs are lower and continuation rates are higher than observed with oral contraceptives (OCs).

In an economic analysis, the cost of LARCs was lower than almost all other forms of reversible contraception over a 5-year interval.⁶ When financial and access barriers are removed, most women starting a contraceptive will use a LARC, if offered.⁷

Be aware of STDs

STDs are common in this age group. In the United States, chlamydial genital infections reach a peak in women 18 to 25 years old, with a prevalence of about 4%.⁸

Counsel her about exercise and weight loss

Approximately 60% of women older than age 20 are overweight or obese.⁹ The rise in obesity is a key contributing factor to an increase in many diseases, including gestational diabetes, type 2 diabetes mellitus, and hypertension. Successful efforts to reduce the prevalence of obesity through diet and exercise could markedly improve population health.

Don't overlook autoimmune conditions

Many autoimmune diseases reach a peak incidence between ages 19 and 39, and, except for ankylosing spondylitis, are more of a concern for women than men. Systemic lupus erythematosus, lymphocytic thyroiditis, and rheumatoid arthritis occur much more frequently in women than in men, with ratios in the range of 7:1 observed during this age interval.

Keep her immunity up to date

Immunizations recommended in this age group include:

• one Tdap (tetanus toxoid, diphtheria, and pertussis)
• tetanus every 10 years
• influenza annually
• varicella if no evidence of immunity
• HPV for those aged 26 years or younger.

The mature woman: 40–64 years

Transition to postmenopause. The menstrual changes through perimenopause to postmenopause are often accompanied by changes in sleep patterns, vasomotor symptoms, and increasing vaginal dryness.

Open your eyes to a patient's insomnia

Perimenopausal and postmenopausal women report a much higher rate of insomnia than age-matched men.¹⁰ Women with moderate to severe vasomotor symptoms are more likely to report greater nighttime wakefulness and a greater number of nighttime long-awake episodes than women with mild vasomotor symptoms.¹¹ Insomnia can be associated with poor work performance and mood changes.

Hormone therapy: Be conservative

In the past, hormone therapy, with various estrogen and progestin combinations, was recommended to help prevent a number of diseases, including cardiovascular disease (CD) and osteoporosis. Based on clinical trial results, the current recommendation is to limit the use of hormone therapy in postmenopausal women to the treatment of vasomotor symptoms and vaginal symptoms caused by hypoestrogenism. To treat these problems, the lowest doses of hormones that are effective should be used for the shortest periods of time that achieve symptom resolution.

The older woman: 65+ years

Successful aging. Based on observational studies, behavioral and health factors associated with successful aging include more than 12 years of education; high socioeconomic status; absence of diabetes, asthma, stroke, and lower respiratory tract disease; absence of depression; presence of at least five close personal contacts; frequent walking; moderate use of alcohol; and nonsmoking status.¹²

Know her risks, and watch for them

Cardiovascular disease. Among women, CDs cause more deaths than malignant neoplasms, chronic lower respiratory disease, Alzheimer's disease, and accidents combined. Black women have rates of CD approximately 40% greater than white women. Hypertension, hypertriglyceridemia, obesity, and sedentary lifestyle among black women account for a part of this increased risk.

Effective lifestyle interventions for primary CD prevention in women include smoking cessation, a diet such as DASH (Dietary Approaches to Stop Hypertension) rich in fruits and vegetables, regular physical activity, and weight management.¹³

There are important gender differences in aspirin efficacy for primary prevention of stroke and myocardial infarction (MI) in men and women. Among women, aspirin used for primary prevention appears to reduce the risk of stroke but not MI.¹⁴ Among men, aspirin used for primary prevention appears to reduce the risk of MI but not stroke.^15,16 Based on these and other data, the USPSTF has recommended that aspirin not be used to prevent stroke in men but recommends aspirin to prevent stroke among women 55 to 79 years of age when benefits outweigh risks of gastrointestinal bleeding.¹⁷

Atrial fibrillation (AF), a risk factor for stroke, is more common in women than in men. In addition, women with AF who are not anticoagulated are at greater risk for stroke than men with AF who are not anticoagulated.¹⁸ The mechanisms that influence these gender differences are not well characterized.

Respiratory illness. Among women, the prevalence of chronic bronchitis and emphysema increased more than 2.8-fold from 1980 to 2000.¹⁹ These diseases are major contributors to physician office visits, hospitalizations, disability, and death. Tobacco use is the major risk factor that accounts for the marked increase in COPD among women during recent decades, although ambient pollutants in the environment, home, and workplace are also important contributors to COPD development.

Cognitive decline. Alzheimer's disease afflicts approximately twice as many women as men. Part of this difference is due to the greater longevity of women, but additional variables, such as gender differences in neurobiology, are also contributory. The role of estradiol in the development of Alzheimer's disease remains controversial.

Osteoporosis. This disease occurs about five times more frequently in women than in men. Among Medicare patients, the cost of caring for a hip fracture is more than $40,000 in the first year postfracture. Hip fracture is associated with a high risk of rapid health decline. Interventions that successfully prevent hip fracture are associated with a reduced mortality rate.^20,21

A concern at any age

Domestic violence

Domestic violence is common; approximately 5% of women report one episode during the past year and 25% report at least one lifetime episode.²² Domestic violence involves two people: a perpetrator and a victim. In some relationships, a recurrent cycle of violence and reconciliation is observed. Routine, confidential, and private screening is required to detect most cases of domestic violence.

Ask the right question(s). The single question, "At any time, has a partner hit, kicked, or otherwise hurt or threatened you?" can increase the rate of detection. Alternatively, a set of three questions can be used to screen for domestic violence:

1. "Within the past year, have you been hit, slapped, kicked or otherwise physically hurt by someone?"
2. "Within the past year, has anyone forced you to have sexual activity?"
3. In pregnancy: "Since you have been pregnant, have you been hit, slapped, kicked, or otherwise physically hurt by someone?"

Follow-up and refer. If a woman reports that she has suffered or is at risk for domestic violence, document the finding in her medical record. Then try to assess her safety by asking: "Are there guns in the home?", "Have there been threats of suicide or homicide?", "Has there been violence toward children?" Choking, specifically, could be a sign of future escalated violence—as many perpetrators choke their victims prior to further, escalated violence occurring—and should be taken as a threat of homicide. Refer women who report domestic violence to a specialist; often, the best trained and most available experts are experienced social workers.

Sexual assault

About 25% of women report at least one lifetime sexual assault. Most women who report being raped initially receive care in a hospital-based emergency department from nurses who are credentialed in Sexual Assault Nurse Evaluation (SANE) skills.

The initial evaluation includes rapid access to treatment by a specialized clinical team, assessment and treatment of bodily injuries with a focus on genital trauma, psychological assessment and support, pregnancy assessment and prevention, preventive treatment of STDs, and collection of forensic data, including toxicology testing for the presence of date-rape drugs.

When sexual assault is reported, treat for an STD. The Centers for Disease Control and Prevention (CDC) recommends the following approach to prevent and treat STDs in victims of sexual assault²³:

• ceftriaxone 125 mg IM to prevent gonorrhea
• azithromycin 1 g orally as a single dose or doxycycline 100 mg twice daily for 7 days to prevent chlamydia
• metronidazole 2 g orally as a single dose to prevent trichomoniasis
• hepatitis B vaccination, for women not previously vaccinated. (The CDC recommends against the use of hepatitis B immune globulin as the costs are believed to outweigh the benefits.)
• HIV postexposure prophylaxis for 3 to 7 days, with a follow-up visit to consider pros and cons of continued prophylaxis. (The risk of HIV infection following a sexual assault is low.)
• postcoital contraception (for example, levonorgestrel 1.5 mg orally as a single dose).

An antiemetic also should be offered to reduce the risk that the multiple prescribed medications will cause vomiting and nullify prophylaxis efforts. Approximately 2 weeks after the sexual assault the patient should have a pregnancy test and be assessed for ongoing mental health needs. If she did not adhere to the medications or if she shows relevant symptoms, perform follow-up STD testing. Follow-up HIV and syphilis testing can be performed at 12 and 24 weeks following the assault.

Sexual dysfunction

Sexuality is an important part of the human experience. Sexual dysfunction is the inability to participate as desired in a sexual relationship. Problems of sexual dysfunction are best approached from a biopsychosocial framework that recognizes the important contributions of biological, psychological, and social-cultural factors in sexual health. Masters and Johnson posited four stages of sexual response: excitement, plateau, orgasm, and resolution. Building on this linear model, investigators later divided the excitement phase into desire and arousal.

Recent models of sexual response have emphasized a circular model, in which sequential responses overlap and build on previous stimuli. These models also emphasize the importance of emotional intimacy and the quality of the relationship in achieving optimal sexual health.

Approximately 40% of women and 30% of men report sexual dysfunction.²⁴ Common sexual problems reported by heterosexual women include:

• lack of interest in sex
• inability to achieve orgasm
• pain caused by sexual intercourse
• lack of pleasure with sex
• trouble lubricating.

The majority of men and women will not voluntarily report sexual dysfunction to their clinician. To elicit the presence of sexual concerns, you must initiate the conversation.²⁵ You can begin the sexual history by asking, "Do you have any concerns about your sex life?" Additional helpful, open-ended questions include: "Are you having sexual relations currently? With men or women or both?", "If you are not having sex, when did you last have intercourse?", "Are you satisfied with the frequency and quality of your sexual experiences?", "What is the emotional quality and intimacy of your relationship with your sex partner?"

The common sexual disorders in women are categorized as desire, arousal, orgasm, and pain disorders. There are two desire disorders: hypoactive sexual desire disorder and sexual aversion disorder. There are two arousal disorders: female sexual arousal disorder and persistent genital arousal disorder. There are four pain disorders: dyspareunia, vulvodynia, vaginismus, and noncoital nonsexual pain.

Most experts recommend that treatment of female sexual dysfunction include multiple modalities that reflect the complex biopsychosocial factors that cause the problem. For example, a treatment plan might include cognitive behavioral therapy, sex therapy, and appropriate medications.

Mental health issues

Depression, anxiety, bulimia, and anorexia nervosa are more common in women than men. For instance, the lifetime risk of depression in women is approximately 20%, compared with about 10% in men. The gender difference is first observed in adolescence and becomes minimal after age 60. The gender differences are observed across racial and ethnic groups.²⁶

It's on us

As leaders in women's health care, we are uniquely trained to guide, counsel, diagnose, and treat women across their entire lifetime, from adolescence to postmenopause. We are at the vanguard in the effort to continually improve the health of all women.

We want to hear from you! Tell us what you think.

The American College of Obstetricians and Gynecologists (ACOG) has recommended dividing a woman's life cycle into four intervals—ages 13–18, 19–39, 40–64, and older than 65—in order to best organize the approach to primary and preventive health care.¹ This paradigm provides a structure for organizing the clinical approach to physical examination, laboratory testing, counseling, and immunizations. In addition, it helps to highlight the diseases and health problems most prevalent among women at each life-stage.

Different professional organizations—US Preventive Services Task Force (USPSTF), American Medical Association, American College of Physicians, ACOG, American Academy of Family Physicians, American Academy of Pediatrics, and Advisory Committee on Immunization Practices—have used varying analytical methods to determine recommended health services by age group; consequently, these organizations have somewhat divergent recommendations. However, the recommendations of most organizations share many similarities. In this comprehensive guide, I point out those similarities. Keep in mind that recommendations change over time, and it is important to use your professional judgment when approaching each patient.

TABLE

Physical examination and laboratory testing services according to a patient's age, based on ACOG recommendations¹

The adolescent: 13–18 years

Screen. Guide. Immunize. ACOG recommends that the first visit take place between 13 and 15 years of age, with annual visits thereafter. The purpose of the first, and subsequent, visits is to assess health status, including menstrual history and body mass index (BMI), and to provide health guidance, screening, and preventive health services. This initial visit generally does not include a pelvic examination. A physical examination is not required at every visit but is recommended to occur at least once during early, middle, and late adolescence.

Target your screening practices. Screen adolescents for the following conditions during clinical preventive services: hypertension; hyperlipidemia; obesity and eating disorders; physical, sexual, or emotional abuse; learning or school problems; substance use; depression and risk of suicide; sexual assault; sexual behavior that may lead to pregnancy or sexually transmitted disease (STD); and tuberculosis and HIV, unless the patient opts out (TABLE).

Anticipate. Then guide. Using anticipatory guidance, you can help adolescents understand their physical, psychosocial, and sexual development and motivate them to be involved in their health and health-care decisions. Issues relevant to adolescents include dietary habits; injury prevention, through the use of helmets and seatbelts; regular exercise; responsible sexual behaviors; avoidance of substances that can be abused; strategies for dealing with bullying; and avoidance of behaviors that might have negative consequences, such as vandalism, stealing, and sharing personal information with strangers.

Recommended immunizations. For this age group, immunizations, unless previously given, include:

• 1 or 2 doses of measles, mumps, and rubella
• 2 doses of varicella if not previously infected
• a booster dose of tetanus if ≥10 years have elapsed since the last dose
• human papillomavirus (HPV)
• annual influenza.

Other immunizations that may be warranted on the basis of medical condition, occupation, lifestyle, or other indications include: 3 doses of hepatitis B, 2 doses of hepatitis A, 1 or more doses of meningococcal, and 1 or 2 doses of pneumococcal.

Menses, an important "vital sign." Once menstruation begins, evaluating menstrual cycle characteristics is important. Patterns that may require evaluation include²:

• no menses within 3 years of thelarche
• no menses by age 13 with no sign of pubertal development
• no menses by age 14 with signs of hirsutism
• no menses by age 14 with indications of an eating disorder
• no menses by age 15
• history of regular menses that are now markedly irregular
• menses occur more frequently than 21 days or less frequently than every 45 days
• menses occur 90 days apart for one cycle
• menstrual bleeding that lasts more than 7 days
• frequent tampon/pad changes (more than 1 tampon/pad every 1 to 2 hours).

BMI predicts future disease. Overweight and obesity are important risk factors for diabetes mellitus, hyperlipidemia, hypertension, and various cancers. Eating disorders are common among adolescents and often occur in association with other mental health problems.

Non–sexually active teens and children

Gynecologic examination typically involves inspection of the genitalia and not instrumentation of the vagina. A careful explanation of the proposed examination is important. Ask young adolescents who they would like to have in the examination room with them. A hand mirror can be used to involve the patient in the genitalia inspection. If it's necessary to obtain magnification, use a hand lens, an otoscope without the speculum, or a colposcope. Record the configuration of the hymen, if present. If indicated, examination of the genitalia while the patient is in the knee-chest position often provides a good view of the vagina and sometimes the cervix, without instrumentation.

Sexually active teens

Effective contraception, including the use of emergency contraceptives, is an important health focus for sexually active teens. Vaginal speculum examination and bimanual gyn exam are not required prior to prescribing hormonal contraceptives to teens. Based on a review of the evidence and expert opinion,³ the current recommendation is that prior to prescribing a hormonal contraceptive, a medical history and blood pressure measurement are the only requirements; breast examination and a gyn exam (vaginal speculum and bimanual gyn exam) are not necessary. Testing for chlamydia and gonorrhea can be performed using a urine sample. A cervical cytology examination is not necessary until age 21 unless the patient is in a high-risk group, such as immunosuppressed or HIV-infected teens.

The young woman: 19–39 years

Focus on reproductive issues. Contraception, pregnancy, and cervical cancer screening are common reasons for visits among women in this age group. Gynecologic problems can include polycystic ovary syndrome (PCOS), endometriosis, fibroids, infertility, pelvic pain, vulvovaginal pain syndromes, vaginitis, adnexal masses, and STDs, including pelvic inflammatory diseases.

Offer effective contraception

Long-acting reversible contraceptives (LARCs) are the most clinically and cost-effective forms of reversible contraception. There are three LARC methods available in the United States: 1) the copper T380A intrauterine device (IUD; Paragard), 2) the levonorgestrel-releasing intrauterine system (Mirena), and 3) the single-rod etonogestrel implant (Implanon, Explanon).

The use of IUDs among American women has increased from about 2.4% of contracepting women of reproductive age in 2002 to 8.5% in 2009.⁴ In Norway and France, contracepting women of reproductive age use IUDs at a rate of 27% and 23%, respectively.⁵ Typical-use pregnancy rates for LARCs are lower and continuation rates are higher than observed with oral contraceptives (OCs).

In an economic analysis, the cost of LARCs was lower than almost all other forms of reversible contraception over a 5-year interval.⁶ When financial and access barriers are removed, most women starting a contraceptive will use a LARC, if offered.⁷

Be aware of STDs

STDs are common in this age group. In the United States, chlamydial genital infections reach a peak in women 18 to 25 years old, with a prevalence of about 4%.⁸

Counsel her about exercise and weight loss

Approximately 60% of women older than age 20 are overweight or obese.⁹ The rise in obesity is a key contributing factor to an increase in many diseases, including gestational diabetes, type 2 diabetes mellitus, and hypertension. Successful efforts to reduce the prevalence of obesity through diet and exercise could markedly improve population health.

Don't overlook autoimmune conditions

Many autoimmune diseases reach a peak incidence between ages 19 and 39, and, except for ankylosing spondylitis, are more of a concern for women than men. Systemic lupus erythematosus, lymphocytic thyroiditis, and rheumatoid arthritis occur much more frequently in women than in men, with ratios in the range of 7:1 observed during this age interval.

Keep her immunity up to date

Immunizations recommended in this age group include:

• one Tdap (tetanus toxoid, diphtheria, and pertussis)
• tetanus every 10 years
• influenza annually
• varicella if no evidence of immunity
• HPV for those aged 26 years or younger.

The mature woman: 40–64 years

Transition to postmenopause. The menstrual changes through perimenopause to postmenopause are often accompanied by changes in sleep patterns, vasomotor symptoms, and increasing vaginal dryness.

Open your eyes to a patient's insomnia

Perimenopausal and postmenopausal women report a much higher rate of insomnia than age-matched men.¹⁰ Women with moderate to severe vasomotor symptoms are more likely to report greater nighttime wakefulness and a greater number of nighttime long-awake episodes than women with mild vasomotor symptoms.¹¹ Insomnia can be associated with poor work performance and mood changes.

Hormone therapy: Be conservative

In the past, hormone therapy, with various estrogen and progestin combinations, was recommended to help prevent a number of diseases, including cardiovascular disease (CD) and osteoporosis. Based on clinical trial results, the current recommendation is to limit the use of hormone therapy in postmenopausal women to the treatment of vasomotor symptoms and vaginal symptoms caused by hypoestrogenism. To treat these problems, the lowest doses of hormones that are effective should be used for the shortest periods of time that achieve symptom resolution.

The older woman: 65+ years

Successful aging. Based on observational studies, behavioral and health factors associated with successful aging include more than 12 years of education; high socioeconomic status; absence of diabetes, asthma, stroke, and lower respiratory tract disease; absence of depression; presence of at least five close personal contacts; frequent walking; moderate use of alcohol; and nonsmoking status.¹²

Know her risks, and watch for them

Cardiovascular disease. Among women, CDs cause more deaths than malignant neoplasms, chronic lower respiratory disease, Alzheimer's disease, and accidents combined. Black women have rates of CD approximately 40% greater than white women. Hypertension, hypertriglyceridemia, obesity, and sedentary lifestyle among black women account for a part of this increased risk.

Effective lifestyle interventions for primary CD prevention in women include smoking cessation, a diet such as DASH (Dietary Approaches to Stop Hypertension) rich in fruits and vegetables, regular physical activity, and weight management.¹³

There are important gender differences in aspirin efficacy for primary prevention of stroke and myocardial infarction (MI) in men and women. Among women, aspirin used for primary prevention appears to reduce the risk of stroke but not MI.¹⁴ Among men, aspirin used for primary prevention appears to reduce the risk of MI but not stroke.^15,16 Based on these and other data, the USPSTF has recommended that aspirin not be used to prevent stroke in men but recommends aspirin to prevent stroke among women 55 to 79 years of age when benefits outweigh risks of gastrointestinal bleeding.¹⁷

Atrial fibrillation (AF), a risk factor for stroke, is more common in women than in men. In addition, women with AF who are not anticoagulated are at greater risk for stroke than men with AF who are not anticoagulated.¹⁸ The mechanisms that influence these gender differences are not well characterized.

Respiratory illness. Among women, the prevalence of chronic bronchitis and emphysema increased more than 2.8-fold from 1980 to 2000.¹⁹ These diseases are major contributors to physician office visits, hospitalizations, disability, and death. Tobacco use is the major risk factor that accounts for the marked increase in COPD among women during recent decades, although ambient pollutants in the environment, home, and workplace are also important contributors to COPD development.

Cognitive decline. Alzheimer's disease afflicts approximately twice as many women as men. Part of this difference is due to the greater longevity of women, but additional variables, such as gender differences in neurobiology, are also contributory. The role of estradiol in the development of Alzheimer's disease remains controversial.

Osteoporosis. This disease occurs about five times more frequently in women than in men. Among Medicare patients, the cost of caring for a hip fracture is more than $40,000 in the first year postfracture. Hip fracture is associated with a high risk of rapid health decline. Interventions that successfully prevent hip fracture are associated with a reduced mortality rate.^20,21

A concern at any age

Domestic violence

Domestic violence is common; approximately 5% of women report one episode during the past year and 25% report at least one lifetime episode.²² Domestic violence involves two people: a perpetrator and a victim. In some relationships, a recurrent cycle of violence and reconciliation is observed. Routine, confidential, and private screening is required to detect most cases of domestic violence.

Ask the right question(s). The single question, "At any time, has a partner hit, kicked, or otherwise hurt or threatened you?" can increase the rate of detection. Alternatively, a set of three questions can be used to screen for domestic violence:

1. "Within the past year, have you been hit, slapped, kicked or otherwise physically hurt by someone?"
2. "Within the past year, has anyone forced you to have sexual activity?"
3. In pregnancy: "Since you have been pregnant, have you been hit, slapped, kicked, or otherwise physically hurt by someone?"

Follow-up and refer. If a woman reports that she has suffered or is at risk for domestic violence, document the finding in her medical record. Then try to assess her safety by asking: "Are there guns in the home?", "Have there been threats of suicide or homicide?", "Has there been violence toward children?" Choking, specifically, could be a sign of future escalated violence—as many perpetrators choke their victims prior to further, escalated violence occurring—and should be taken as a threat of homicide. Refer women who report domestic violence to a specialist; often, the best trained and most available experts are experienced social workers.

Sexual assault

About 25% of women report at least one lifetime sexual assault. Most women who report being raped initially receive care in a hospital-based emergency department from nurses who are credentialed in Sexual Assault Nurse Evaluation (SANE) skills.

The initial evaluation includes rapid access to treatment by a specialized clinical team, assessment and treatment of bodily injuries with a focus on genital trauma, psychological assessment and support, pregnancy assessment and prevention, preventive treatment of STDs, and collection of forensic data, including toxicology testing for the presence of date-rape drugs.

When sexual assault is reported, treat for an STD. The Centers for Disease Control and Prevention (CDC) recommends the following approach to prevent and treat STDs in victims of sexual assault²³:

• ceftriaxone 125 mg IM to prevent gonorrhea
• azithromycin 1 g orally as a single dose or doxycycline 100 mg twice daily for 7 days to prevent chlamydia
• metronidazole 2 g orally as a single dose to prevent trichomoniasis
• hepatitis B vaccination, for women not previously vaccinated. (The CDC recommends against the use of hepatitis B immune globulin as the costs are believed to outweigh the benefits.)
• HIV postexposure prophylaxis for 3 to 7 days, with a follow-up visit to consider pros and cons of continued prophylaxis. (The risk of HIV infection following a sexual assault is low.)
• postcoital contraception (for example, levonorgestrel 1.5 mg orally as a single dose).

An antiemetic also should be offered to reduce the risk that the multiple prescribed medications will cause vomiting and nullify prophylaxis efforts. Approximately 2 weeks after the sexual assault the patient should have a pregnancy test and be assessed for ongoing mental health needs. If she did not adhere to the medications or if she shows relevant symptoms, perform follow-up STD testing. Follow-up HIV and syphilis testing can be performed at 12 and 24 weeks following the assault.

Sexual dysfunction

Sexuality is an important part of the human experience. Sexual dysfunction is the inability to participate as desired in a sexual relationship. Problems of sexual dysfunction are best approached from a biopsychosocial framework that recognizes the important contributions of biological, psychological, and social-cultural factors in sexual health. Masters and Johnson posited four stages of sexual response: excitement, plateau, orgasm, and resolution. Building on this linear model, investigators later divided the excitement phase into desire and arousal.

Recent models of sexual response have emphasized a circular model, in which sequential responses overlap and build on previous stimuli. These models also emphasize the importance of emotional intimacy and the quality of the relationship in achieving optimal sexual health.

Approximately 40% of women and 30% of men report sexual dysfunction.²⁴ Common sexual problems reported by heterosexual women include:

• lack of interest in sex
• inability to achieve orgasm
• pain caused by sexual intercourse
• lack of pleasure with sex
• trouble lubricating.

The majority of men and women will not voluntarily report sexual dysfunction to their clinician. To elicit the presence of sexual concerns, you must initiate the conversation.²⁵ You can begin the sexual history by asking, "Do you have any concerns about your sex life?" Additional helpful, open-ended questions include: "Are you having sexual relations currently? With men or women or both?", "If you are not having sex, when did you last have intercourse?", "Are you satisfied with the frequency and quality of your sexual experiences?", "What is the emotional quality and intimacy of your relationship with your sex partner?"

The common sexual disorders in women are categorized as desire, arousal, orgasm, and pain disorders. There are two desire disorders: hypoactive sexual desire disorder and sexual aversion disorder. There are two arousal disorders: female sexual arousal disorder and persistent genital arousal disorder. There are four pain disorders: dyspareunia, vulvodynia, vaginismus, and noncoital nonsexual pain.

Most experts recommend that treatment of female sexual dysfunction include multiple modalities that reflect the complex biopsychosocial factors that cause the problem. For example, a treatment plan might include cognitive behavioral therapy, sex therapy, and appropriate medications.

Mental health issues

Depression, anxiety, bulimia, and anorexia nervosa are more common in women than men. For instance, the lifetime risk of depression in women is approximately 20%, compared with about 10% in men. The gender difference is first observed in adolescence and becomes minimal after age 60. The gender differences are observed across racial and ethnic groups.²⁶

It's on us

As leaders in women's health care, we are uniquely trained to guide, counsel, diagnose, and treat women across their entire lifetime, from adolescence to postmenopause. We are at the vanguard in the effort to continually improve the health of all women.

We want to hear from you! Tell us what you think.

Polycystic ovary syndrome, or PCOS, is an enigmatic condition. It presents with varying levels of severity of those symptoms and conditions associated with it—clinical hyperandrogenism (hirsutism, acne, alopecia), obesity, and menstrual disturbance. Although its exact cause is unknown, at least half of all women with PCOS are overweight or obese. What does obesity and, more specifically, insulin resistance, contribute to the pathogenesis of PCOS, and why is it important to screen your patient with PCOS for insulin resistance?

In part 2 of this 4-part series, which will continue to be posted here on the OBG Management Web site, we address these questions. [Editor’s note: As they are published, future installments of this series will continue to be collected on a single Web page for ease of access.]

The roles of obesity and insulin resistance

Overweight: BMI ≥ 25 kg/m²

Obesity: BMI ≥ 30 kg/m²

Morbid obesity: BMI ≥ 40 kg/m²

PCOS is associated with truncal fat distribution, manifesting as an increased waist-to-hip ratio. According to the Centers for Disease Control and Prevention (CDC), more than one-third of the population was obese in 2009 and 2010.¹ Approximately 50% to 65% of women with PCOS are overweight or obese, and most of them have the truncal fat distribution phenotype. ²

Obesity is associated with an increase in insulin resistance (IR) and hyperinsulinemia. IR can be characterized as impaired action of insulin in the uptake and metabolism of glucose. Impaired insulin action leads to elevated insulin levels. Insulin synergizes with abnormally high secretion of luteinizing hormone (perhaps induced by hyperinsulinemia) to promote excess androgen production by intraovarian theca cells and an arrest of follicular development resulting in chronic anovulation.

In addition, hyperinsulinemia causes a decrease in hepatic sex hormone binding globulin, resulting in free circulating androgens and, thus, hirsutism and acne issues. While this picture tends to be more pronounced in women who have PCOS and are obese, it is important to realize that a nonobese patient with PCOS also may have IR, which suggests that insulin plays a major role in the pathogenesis of this disease.^3,4

Most of the evidence suggests that hyperinsulinemia causes hyperandrogenism and not the reverse. Weight loss and insulin sensitizers are associated with a reduction in androgens, particularly testosterone and androstenedione. Gonadotropin-releasing hormone–analogs, which reduce androgen secretion from the ovaries, do not result in a reduction in insulin.^3,4

Screening for insulin resistance: The rationale

The documented prevalence of IR and type 2 diabetes mellitus (DM) in women with PCOS suggests that impaired glucose tolerance (IGT) is present in 31% to 35% of women with PCOS^5,6—and DM, classified according to World Health Organization (WHO) criteria, is present in 7.5% to 10% of women with PCOS.

The prevalence of IR and DM are considerably lower in women without PCOS. According to the Third National Health and Nutrition Examination Survey, in US women of similar age, the prevalence of IR is 1.6%, and the prevalence of DM is 2.2%.⁷

2003 consensus: Screen for IGT in obese PCOS patients. In view of the high prevalence of IR and IGT, a 2003 PCOS consensus⁸ established that obese women with PCOS should be screened for insulin sensitivity and undergo screening for the metabolic syndrome, including glucose intolerance. For nonobese women, the consensus recommended screening only if additional risk factors are present.

Unfortunately, IGT also occurs independent of obesity. In lean women with PCOS, 5% may have IGT, while 2% are frankly diabetic. Moreover, the conversion from normal glucose tolerance to IGT in patients with PCOS can be as high as 16% per year,⁹ while the conversion rate from IGT to DM among women with PCOS has been reported to be as high as 2% per year.

2007 position statement: Screen for IGT in all PCOS patients. A position statement by the Androgen Excess–PCOS Society on glucose intolerance and PCOS recommends screening for IGT in all PCOS women, regardless of BMI, at least once every 2 years.¹⁰

Screening for insulin resistance: The methods

There are two ways to determine insulin sensitivity:

• direct infusion of IV glucose and/or insulin
• indirect assessment using surrogate markers (such as fasting glucose and insulin, or C-peptide, and oral glucose tolerance test [OGTT]).

Direct infusion of IV glucose or insulin reveals how insulin disposes of glucose from the blood stream; however, this method is expensive, time consuming, and potentially dangerous due to possible hypoglycemia. Indirect assessments are less complex to perform and correlate reasonably well with the results of the more invasive direct measures.

Direct infusion of glucose and insulin

The hyperinsulinemic euglycemic clamp is the gold standard, but drawbacks relegate it to medical research only. This method measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. Numerous blood samplings (every 5 to 10 minutes) are taken to monitor serum glucose so that a steady “fasting” level can be maintained. The degree of insulin resistance is measured by the amount of glucose that is taken up by tissues during the procedure.^11-14

The “clamp” technique is the most scientifically sound method for measuring insulin sensitivity, and it’s the standard against which all other tests are usually compared. Because the clamp technique is expensive, time consuming (about 2 hours), and labor intensive, however, it is not practical and is rarely performed in clinical care. It is primarily used in medical research.

Frequently sampled IV glucose tolerance tests: “minimal model.” The frequently sampled IV glucose tolerance test estimates insulin sensitivity through a computer-based mathematical analysis of the glucose-insulin dynamics. Though this test still requires 11 to 34 blood samples over a 3-hour period, it is less labor intensive than the clamp technique. However, in contrast to the clamp, it does not distinguish between peripheral and hepatic glucose utilization.¹⁵

Direct infusion of insulin

Insulin sensitivity test. This test involves IV infusion of a set glucose load and a fixed-rate infusion of insulin over approximately 3 hours. The mean plasma glucose concentration over the last 30 minutes of the test reflects insulin sensitivity. Although lengthy, the insulin sensitivity test is less labor intensive and requires fewer blood samples than the clamp technique.¹⁶

Insulin tolerance test. This test is a simplified version of the insulin sensitivity test, as it measures the decline in serum glucose after an IV bolus of insulin is administered. Several insulin and glucose levels are sampled over the following 15 minutes. In contrast to the clamp and the minimal model, the insulin tolerance test primarily measures insulin-stimulated uptake of glucose into skeletal muscle, and insulin sensitivity values reflect the rate of decline of log transformed glucose values.¹⁷

Direct infusion of glucose

Continuous infusion of glucose with model assessment. This method utilizes a constant IV glucose infusion; samples for glucose and insulin are drawn at 50, 55, and 60 minutes. A mathematical model is then used to calculate insulin sensitivity. The results are correlated with clamp techniques; however, few laboratories have used this continuous-infusion method for insulin sensitivity testing in women with PCOS.¹⁸

Unfortunately, all of these methods require IV access and multiple venipunctures, making them relatively impractical for office assessment. To overcome these obstacles, alternative tests have been developed including fasting methods and the OGTT, the latter of which does not require IV access and does correlate reasonably well with dynamic clamp techniques.

Fasting methods

Fasting insulin. The measurement of fasting serum insulin is simple and inexpensive. Generally, a fasting level of 30 μU/mL indicates greater insulin resistance in a diabetic individual than in a normoglycemic patient. However, fasting insulin levels may be in the “normal” range in up to 40% of PCOS patients who have impaired glucose tolerance diagnosed by the OGTT. It has been suggested by some investigators that a fasting insulin greater than 20 μU/mL in white women and greater than 23 μU/mL in Mexican-American women probably indicates insulin resistance in women with PCOS. Some have also advocated averaging two or three readings to account for day-to-day variability.^19-21

Fasting plasma glucose. This is a simple blood test taken after 8 hours of fasting. Fasting plasma glucose (FPG) levels are considered normal up to 100 mg/dL (or 5.5 mmol/L). Levels between 100 and 125 mg/dL (5.5 to 7.0 mmol/L) are considered impaired fasting glucose or prediabetes. These levels are considered to be risk factors for DM and its complications. DM is diagnosed when FPG levels are 126 mg/dL (7.0 mmol/L) or higher. A “normal” result on the FPG test is not always reliable. Repeat testing with the OGTT is recommended if risk factors are suggestive for the presence of DM or a prediabetic condition.

Glucose/insulin ratio

The glucose/insulin (G/I) ratio has become very popular since its first description in 1998 as an accurate index of insulin sensitivity in women with PCOS. The ratio of glucose to insulin is easy to calculate, with lower values depicting higher degrees of insulin resistance. A G/I ratio of less than 4.5 has been shown to be sensitive (95%) and specific (84%) for insulin resistance in women with PCOS, compared with a control group. The normal range for G/I ratios may vary in different ethnic groups and have not been fully validated in nonobese patients.^22-25

Homeostatic model assessment

First described in 1985, homeostatic model assessment (HOMA) has been used widely in clinical research to assess insulin sensitivity. Rather than using fasting insulin or a G/I ratio, the product of the fasting values of glucose (expressed as mg/dL) and insulin (expressed as μU/mL) is divided by a constant: I0 x G0 ÷ 405.

The constant 405 should be replaced by 22.5 if glucose is expressed in SI units (mmol/L). Unlike fasting insulin and the G/I ratio, the HOMA calculation compensates for fasting hyperglycemia. The HOMA value correlates well with clamp techniques and has been used frequently to assess changes in insulin sensitivity after treatment. HOMA also has been used to study insulin resistance among PCOS patients of differing ethnic origins.^12,24-26

Quantitative insulin sensitivity check index

Like HOMA, quantitative insulin sensitivity check index (QUICKI) can be applied to normoglycemic and hyperglycemic patients. It is derived by calculating the inverse of the sum of logarithmically expressed values of fasting glucose and insulin: 1 ÷ [log(I0) + log(G0)].

Many investigators believe that QUICKI is superior to HOMA as a way of determining insulin sensitivity, although the two values correlate well. As the SI decreases, QUICKI values decrease.²⁷

Oral glucose tolerance test

As OGTT does not require IV access, it is the current standard in practice for diagnosis of IGT and DM. It provides a better assessment of IGT and DM than fasting techniques because these patients may have normal fasting glucose values despite abnormal 2-hour fasting levels. The OGTT uses a 50-, 75-, or 100-g glucose load and measures glucose and insulin at various intervals over 1 to 3 hours. The WHO currently recommends a 75-g oral dose in all adults. A 50-g dose is used to screen for gestational diabetes over an hour, and the 100-g load over 3 hours if abnormal.²⁸ See TABLE for normal and abnormal values. Insulin sensitivity has been assessed by calculating insulin area under the curve (AUC insulin), AUC glucose/AUC insulin, and by an insulin sensitivity index (ISI) that applies only the glucose and insulin values from 0 and 120 minutes into a complex mathematical formula.^13,25,29-31

Criteria for diagnosis of diabetes

Test for glycosylated hemoglobin

Tests for blood levels of glycosylated hemoglobin, also known as hemoglobin A_1c (HbA_1c) are not currently used for an initial diagnosis because normal HbA_1c levels do not necessarily rule out diabetes, but they are strongly associated with complications of diabetes. The test is not affected by food intake so it can be taken at any time. A normal HbA_1c level is below 7%.

We want to hear from you! Tell us what you think.

Polycystic ovary syndrome, or PCOS, is an enigmatic condition. It presents with varying levels of severity of those symptoms and conditions associated with it—clinical hyperandrogenism (hirsutism, acne, alopecia), obesity, and menstrual disturbance. Although its exact cause is unknown, at least half of all women with PCOS are overweight or obese. What does obesity and, more specifically, insulin resistance, contribute to the pathogenesis of PCOS, and why is it important to screen your patient with PCOS for insulin resistance?

In part 2 of this 4-part series, which will continue to be posted here on the OBG Management Web site, we address these questions. [Editor’s note: As they are published, future installments of this series will continue to be collected on a single Web page for ease of access.]

The roles of obesity and insulin resistance

Overweight: BMI ≥ 25 kg/m²

Obesity: BMI ≥ 30 kg/m²

Morbid obesity: BMI ≥ 40 kg/m²

PCOS is associated with truncal fat distribution, manifesting as an increased waist-to-hip ratio. According to the Centers for Disease Control and Prevention (CDC), more than one-third of the population was obese in 2009 and 2010.¹ Approximately 50% to 65% of women with PCOS are overweight or obese, and most of them have the truncal fat distribution phenotype. ²

Obesity is associated with an increase in insulin resistance (IR) and hyperinsulinemia. IR can be characterized as impaired action of insulin in the uptake and metabolism of glucose. Impaired insulin action leads to elevated insulin levels. Insulin synergizes with abnormally high secretion of luteinizing hormone (perhaps induced by hyperinsulinemia) to promote excess androgen production by intraovarian theca cells and an arrest of follicular development resulting in chronic anovulation.

In addition, hyperinsulinemia causes a decrease in hepatic sex hormone binding globulin, resulting in free circulating androgens and, thus, hirsutism and acne issues. While this picture tends to be more pronounced in women who have PCOS and are obese, it is important to realize that a nonobese patient with PCOS also may have IR, which suggests that insulin plays a major role in the pathogenesis of this disease.^3,4

Most of the evidence suggests that hyperinsulinemia causes hyperandrogenism and not the reverse. Weight loss and insulin sensitizers are associated with a reduction in androgens, particularly testosterone and androstenedione. Gonadotropin-releasing hormone–analogs, which reduce androgen secretion from the ovaries, do not result in a reduction in insulin.^3,4

Screening for insulin resistance: The rationale

The documented prevalence of IR and type 2 diabetes mellitus (DM) in women with PCOS suggests that impaired glucose tolerance (IGT) is present in 31% to 35% of women with PCOS^5,6—and DM, classified according to World Health Organization (WHO) criteria, is present in 7.5% to 10% of women with PCOS.

The prevalence of IR and DM are considerably lower in women without PCOS. According to the Third National Health and Nutrition Examination Survey, in US women of similar age, the prevalence of IR is 1.6%, and the prevalence of DM is 2.2%.⁷

2003 consensus: Screen for IGT in obese PCOS patients. In view of the high prevalence of IR and IGT, a 2003 PCOS consensus⁸ established that obese women with PCOS should be screened for insulin sensitivity and undergo screening for the metabolic syndrome, including glucose intolerance. For nonobese women, the consensus recommended screening only if additional risk factors are present.

Unfortunately, IGT also occurs independent of obesity. In lean women with PCOS, 5% may have IGT, while 2% are frankly diabetic. Moreover, the conversion from normal glucose tolerance to IGT in patients with PCOS can be as high as 16% per year,⁹ while the conversion rate from IGT to DM among women with PCOS has been reported to be as high as 2% per year.

2007 position statement: Screen for IGT in all PCOS patients. A position statement by the Androgen Excess–PCOS Society on glucose intolerance and PCOS recommends screening for IGT in all PCOS women, regardless of BMI, at least once every 2 years.¹⁰

Screening for insulin resistance: The methods

There are two ways to determine insulin sensitivity:

• direct infusion of IV glucose and/or insulin
• indirect assessment using surrogate markers (such as fasting glucose and insulin, or C-peptide, and oral glucose tolerance test [OGTT]).

Direct infusion of IV glucose or insulin reveals how insulin disposes of glucose from the blood stream; however, this method is expensive, time consuming, and potentially dangerous due to possible hypoglycemia. Indirect assessments are less complex to perform and correlate reasonably well with the results of the more invasive direct measures.

Direct infusion of glucose and insulin

The hyperinsulinemic euglycemic clamp is the gold standard, but drawbacks relegate it to medical research only. This method measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. Numerous blood samplings (every 5 to 10 minutes) are taken to monitor serum glucose so that a steady “fasting” level can be maintained. The degree of insulin resistance is measured by the amount of glucose that is taken up by tissues during the procedure.^11-14

The “clamp” technique is the most scientifically sound method for measuring insulin sensitivity, and it’s the standard against which all other tests are usually compared. Because the clamp technique is expensive, time consuming (about 2 hours), and labor intensive, however, it is not practical and is rarely performed in clinical care. It is primarily used in medical research.

Frequently sampled IV glucose tolerance tests: “minimal model.” The frequently sampled IV glucose tolerance test estimates insulin sensitivity through a computer-based mathematical analysis of the glucose-insulin dynamics. Though this test still requires 11 to 34 blood samples over a 3-hour period, it is less labor intensive than the clamp technique. However, in contrast to the clamp, it does not distinguish between peripheral and hepatic glucose utilization.¹⁵

Direct infusion of insulin

Insulin sensitivity test. This test involves IV infusion of a set glucose load and a fixed-rate infusion of insulin over approximately 3 hours. The mean plasma glucose concentration over the last 30 minutes of the test reflects insulin sensitivity. Although lengthy, the insulin sensitivity test is less labor intensive and requires fewer blood samples than the clamp technique.¹⁶

Insulin tolerance test. This test is a simplified version of the insulin sensitivity test, as it measures the decline in serum glucose after an IV bolus of insulin is administered. Several insulin and glucose levels are sampled over the following 15 minutes. In contrast to the clamp and the minimal model, the insulin tolerance test primarily measures insulin-stimulated uptake of glucose into skeletal muscle, and insulin sensitivity values reflect the rate of decline of log transformed glucose values.¹⁷

Direct infusion of glucose

Continuous infusion of glucose with model assessment. This method utilizes a constant IV glucose infusion; samples for glucose and insulin are drawn at 50, 55, and 60 minutes. A mathematical model is then used to calculate insulin sensitivity. The results are correlated with clamp techniques; however, few laboratories have used this continuous-infusion method for insulin sensitivity testing in women with PCOS.¹⁸

Unfortunately, all of these methods require IV access and multiple venipunctures, making them relatively impractical for office assessment. To overcome these obstacles, alternative tests have been developed including fasting methods and the OGTT, the latter of which does not require IV access and does correlate reasonably well with dynamic clamp techniques.

Fasting methods

Fasting insulin. The measurement of fasting serum insulin is simple and inexpensive. Generally, a fasting level of 30 μU/mL indicates greater insulin resistance in a diabetic individual than in a normoglycemic patient. However, fasting insulin levels may be in the “normal” range in up to 40% of PCOS patients who have impaired glucose tolerance diagnosed by the OGTT. It has been suggested by some investigators that a fasting insulin greater than 20 μU/mL in white women and greater than 23 μU/mL in Mexican-American women probably indicates insulin resistance in women with PCOS. Some have also advocated averaging two or three readings to account for day-to-day variability.^19-21

Fasting plasma glucose. This is a simple blood test taken after 8 hours of fasting. Fasting plasma glucose (FPG) levels are considered normal up to 100 mg/dL (or 5.5 mmol/L). Levels between 100 and 125 mg/dL (5.5 to 7.0 mmol/L) are considered impaired fasting glucose or prediabetes. These levels are considered to be risk factors for DM and its complications. DM is diagnosed when FPG levels are 126 mg/dL (7.0 mmol/L) or higher. A “normal” result on the FPG test is not always reliable. Repeat testing with the OGTT is recommended if risk factors are suggestive for the presence of DM or a prediabetic condition.

Glucose/insulin ratio

The glucose/insulin (G/I) ratio has become very popular since its first description in 1998 as an accurate index of insulin sensitivity in women with PCOS. The ratio of glucose to insulin is easy to calculate, with lower values depicting higher degrees of insulin resistance. A G/I ratio of less than 4.5 has been shown to be sensitive (95%) and specific (84%) for insulin resistance in women with PCOS, compared with a control group. The normal range for G/I ratios may vary in different ethnic groups and have not been fully validated in nonobese patients.^22-25

Homeostatic model assessment

First described in 1985, homeostatic model assessment (HOMA) has been used widely in clinical research to assess insulin sensitivity. Rather than using fasting insulin or a G/I ratio, the product of the fasting values of glucose (expressed as mg/dL) and insulin (expressed as μU/mL) is divided by a constant: I0 x G0 ÷ 405.

The constant 405 should be replaced by 22.5 if glucose is expressed in SI units (mmol/L). Unlike fasting insulin and the G/I ratio, the HOMA calculation compensates for fasting hyperglycemia. The HOMA value correlates well with clamp techniques and has been used frequently to assess changes in insulin sensitivity after treatment. HOMA also has been used to study insulin resistance among PCOS patients of differing ethnic origins.^12,24-26

Quantitative insulin sensitivity check index

Like HOMA, quantitative insulin sensitivity check index (QUICKI) can be applied to normoglycemic and hyperglycemic patients. It is derived by calculating the inverse of the sum of logarithmically expressed values of fasting glucose and insulin: 1 ÷ [log(I0) + log(G0)].

Many investigators believe that QUICKI is superior to HOMA as a way of determining insulin sensitivity, although the two values correlate well. As the SI decreases, QUICKI values decrease.²⁷

Oral glucose tolerance test

As OGTT does not require IV access, it is the current standard in practice for diagnosis of IGT and DM. It provides a better assessment of IGT and DM than fasting techniques because these patients may have normal fasting glucose values despite abnormal 2-hour fasting levels. The OGTT uses a 50-, 75-, or 100-g glucose load and measures glucose and insulin at various intervals over 1 to 3 hours. The WHO currently recommends a 75-g oral dose in all adults. A 50-g dose is used to screen for gestational diabetes over an hour, and the 100-g load over 3 hours if abnormal.²⁸ See TABLE for normal and abnormal values. Insulin sensitivity has been assessed by calculating insulin area under the curve (AUC insulin), AUC glucose/AUC insulin, and by an insulin sensitivity index (ISI) that applies only the glucose and insulin values from 0 and 120 minutes into a complex mathematical formula.^13,25,29-31

Criteria for diagnosis of diabetes

Test for glycosylated hemoglobin

Tests for blood levels of glycosylated hemoglobin, also known as hemoglobin A_1c (HbA_1c) are not currently used for an initial diagnosis because normal HbA_1c levels do not necessarily rule out diabetes, but they are strongly associated with complications of diabetes. The test is not affected by food intake so it can be taken at any time. A normal HbA_1c level is below 7%.

We want to hear from you! Tell us what you think.

Polycystic ovary syndrome, or PCOS, is an enigmatic condition. It presents with varying levels of severity of those symptoms and conditions associated with it—clinical hyperandrogenism (hirsutism, acne, alopecia), obesity, and menstrual disturbance. Although its exact cause is unknown, at least half of all women with PCOS are overweight or obese. What does obesity and, more specifically, insulin resistance, contribute to the pathogenesis of PCOS, and why is it important to screen your patient with PCOS for insulin resistance?

In part 2 of this 4-part series, which will continue to be posted here on the OBG Management Web site, we address these questions. [Editor’s note: As they are published, future installments of this series will continue to be collected on a single Web page for ease of access.]

The roles of obesity and insulin resistance

Overweight: BMI ≥ 25 kg/m²

Obesity: BMI ≥ 30 kg/m²

Morbid obesity: BMI ≥ 40 kg/m²

PCOS is associated with truncal fat distribution, manifesting as an increased waist-to-hip ratio. According to the Centers for Disease Control and Prevention (CDC), more than one-third of the population was obese in 2009 and 2010.¹ Approximately 50% to 65% of women with PCOS are overweight or obese, and most of them have the truncal fat distribution phenotype. ²

Obesity is associated with an increase in insulin resistance (IR) and hyperinsulinemia. IR can be characterized as impaired action of insulin in the uptake and metabolism of glucose. Impaired insulin action leads to elevated insulin levels. Insulin synergizes with abnormally high secretion of luteinizing hormone (perhaps induced by hyperinsulinemia) to promote excess androgen production by intraovarian theca cells and an arrest of follicular development resulting in chronic anovulation.

In addition, hyperinsulinemia causes a decrease in hepatic sex hormone binding globulin, resulting in free circulating androgens and, thus, hirsutism and acne issues. While this picture tends to be more pronounced in women who have PCOS and are obese, it is important to realize that a nonobese patient with PCOS also may have IR, which suggests that insulin plays a major role in the pathogenesis of this disease.^3,4

Most of the evidence suggests that hyperinsulinemia causes hyperandrogenism and not the reverse. Weight loss and insulin sensitizers are associated with a reduction in androgens, particularly testosterone and androstenedione. Gonadotropin-releasing hormone–analogs, which reduce androgen secretion from the ovaries, do not result in a reduction in insulin.^3,4

Screening for insulin resistance: The rationale

The documented prevalence of IR and type 2 diabetes mellitus (DM) in women with PCOS suggests that impaired glucose tolerance (IGT) is present in 31% to 35% of women with PCOS^5,6—and DM, classified according to World Health Organization (WHO) criteria, is present in 7.5% to 10% of women with PCOS.

The prevalence of IR and DM are considerably lower in women without PCOS. According to the Third National Health and Nutrition Examination Survey, in US women of similar age, the prevalence of IR is 1.6%, and the prevalence of DM is 2.2%.⁷

2003 consensus: Screen for IGT in obese PCOS patients. In view of the high prevalence of IR and IGT, a 2003 PCOS consensus⁸ established that obese women with PCOS should be screened for insulin sensitivity and undergo screening for the metabolic syndrome, including glucose intolerance. For nonobese women, the consensus recommended screening only if additional risk factors are present.

Unfortunately, IGT also occurs independent of obesity. In lean women with PCOS, 5% may have IGT, while 2% are frankly diabetic. Moreover, the conversion from normal glucose tolerance to IGT in patients with PCOS can be as high as 16% per year,⁹ while the conversion rate from IGT to DM among women with PCOS has been reported to be as high as 2% per year.

2007 position statement: Screen for IGT in all PCOS patients. A position statement by the Androgen Excess–PCOS Society on glucose intolerance and PCOS recommends screening for IGT in all PCOS women, regardless of BMI, at least once every 2 years.¹⁰

Screening for insulin resistance: The methods

There are two ways to determine insulin sensitivity:

• direct infusion of IV glucose and/or insulin
• indirect assessment using surrogate markers (such as fasting glucose and insulin, or C-peptide, and oral glucose tolerance test [OGTT]).

Direct infusion of IV glucose or insulin reveals how insulin disposes of glucose from the blood stream; however, this method is expensive, time consuming, and potentially dangerous due to possible hypoglycemia. Indirect assessments are less complex to perform and correlate reasonably well with the results of the more invasive direct measures.

Direct infusion of glucose and insulin

The hyperinsulinemic euglycemic clamp is the gold standard, but drawbacks relegate it to medical research only. This method measures the amount of glucose necessary to compensate for an increased insulin level without causing hypoglycemia. Numerous blood samplings (every 5 to 10 minutes) are taken to monitor serum glucose so that a steady “fasting” level can be maintained. The degree of insulin resistance is measured by the amount of glucose that is taken up by tissues during the procedure.^11-14

The “clamp” technique is the most scientifically sound method for measuring insulin sensitivity, and it’s the standard against which all other tests are usually compared. Because the clamp technique is expensive, time consuming (about 2 hours), and labor intensive, however, it is not practical and is rarely performed in clinical care. It is primarily used in medical research.

Frequently sampled IV glucose tolerance tests: “minimal model.” The frequently sampled IV glucose tolerance test estimates insulin sensitivity through a computer-based mathematical analysis of the glucose-insulin dynamics. Though this test still requires 11 to 34 blood samples over a 3-hour period, it is less labor intensive than the clamp technique. However, in contrast to the clamp, it does not distinguish between peripheral and hepatic glucose utilization.¹⁵

Direct infusion of insulin

Insulin sensitivity test. This test involves IV infusion of a set glucose load and a fixed-rate infusion of insulin over approximately 3 hours. The mean plasma glucose concentration over the last 30 minutes of the test reflects insulin sensitivity. Although lengthy, the insulin sensitivity test is less labor intensive and requires fewer blood samples than the clamp technique.¹⁶

Insulin tolerance test. This test is a simplified version of the insulin sensitivity test, as it measures the decline in serum glucose after an IV bolus of insulin is administered. Several insulin and glucose levels are sampled over the following 15 minutes. In contrast to the clamp and the minimal model, the insulin tolerance test primarily measures insulin-stimulated uptake of glucose into skeletal muscle, and insulin sensitivity values reflect the rate of decline of log transformed glucose values.¹⁷

Direct infusion of glucose

Continuous infusion of glucose with model assessment. This method utilizes a constant IV glucose infusion; samples for glucose and insulin are drawn at 50, 55, and 60 minutes. A mathematical model is then used to calculate insulin sensitivity. The results are correlated with clamp techniques; however, few laboratories have used this continuous-infusion method for insulin sensitivity testing in women with PCOS.¹⁸

Unfortunately, all of these methods require IV access and multiple venipunctures, making them relatively impractical for office assessment. To overcome these obstacles, alternative tests have been developed including fasting methods and the OGTT, the latter of which does not require IV access and does correlate reasonably well with dynamic clamp techniques.

Fasting methods

Fasting insulin. The measurement of fasting serum insulin is simple and inexpensive. Generally, a fasting level of 30 μU/mL indicates greater insulin resistance in a diabetic individual than in a normoglycemic patient. However, fasting insulin levels may be in the “normal” range in up to 40% of PCOS patients who have impaired glucose tolerance diagnosed by the OGTT. It has been suggested by some investigators that a fasting insulin greater than 20 μU/mL in white women and greater than 23 μU/mL in Mexican-American women probably indicates insulin resistance in women with PCOS. Some have also advocated averaging two or three readings to account for day-to-day variability.^19-21

Fasting plasma glucose. This is a simple blood test taken after 8 hours of fasting. Fasting plasma glucose (FPG) levels are considered normal up to 100 mg/dL (or 5.5 mmol/L). Levels between 100 and 125 mg/dL (5.5 to 7.0 mmol/L) are considered impaired fasting glucose or prediabetes. These levels are considered to be risk factors for DM and its complications. DM is diagnosed when FPG levels are 126 mg/dL (7.0 mmol/L) or higher. A “normal” result on the FPG test is not always reliable. Repeat testing with the OGTT is recommended if risk factors are suggestive for the presence of DM or a prediabetic condition.

Glucose/insulin ratio

The glucose/insulin (G/I) ratio has become very popular since its first description in 1998 as an accurate index of insulin sensitivity in women with PCOS. The ratio of glucose to insulin is easy to calculate, with lower values depicting higher degrees of insulin resistance. A G/I ratio of less than 4.5 has been shown to be sensitive (95%) and specific (84%) for insulin resistance in women with PCOS, compared with a control group. The normal range for G/I ratios may vary in different ethnic groups and have not been fully validated in nonobese patients.^22-25

Homeostatic model assessment

First described in 1985, homeostatic model assessment (HOMA) has been used widely in clinical research to assess insulin sensitivity. Rather than using fasting insulin or a G/I ratio, the product of the fasting values of glucose (expressed as mg/dL) and insulin (expressed as μU/mL) is divided by a constant: I0 x G0 ÷ 405.

The constant 405 should be replaced by 22.5 if glucose is expressed in SI units (mmol/L). Unlike fasting insulin and the G/I ratio, the HOMA calculation compensates for fasting hyperglycemia. The HOMA value correlates well with clamp techniques and has been used frequently to assess changes in insulin sensitivity after treatment. HOMA also has been used to study insulin resistance among PCOS patients of differing ethnic origins.^12,24-26

Quantitative insulin sensitivity check index

Like HOMA, quantitative insulin sensitivity check index (QUICKI) can be applied to normoglycemic and hyperglycemic patients. It is derived by calculating the inverse of the sum of logarithmically expressed values of fasting glucose and insulin: 1 ÷ [log(I0) + log(G0)].

Many investigators believe that QUICKI is superior to HOMA as a way of determining insulin sensitivity, although the two values correlate well. As the SI decreases, QUICKI values decrease.²⁷

Oral glucose tolerance test

As OGTT does not require IV access, it is the current standard in practice for diagnosis of IGT and DM. It provides a better assessment of IGT and DM than fasting techniques because these patients may have normal fasting glucose values despite abnormal 2-hour fasting levels. The OGTT uses a 50-, 75-, or 100-g glucose load and measures glucose and insulin at various intervals over 1 to 3 hours. The WHO currently recommends a 75-g oral dose in all adults. A 50-g dose is used to screen for gestational diabetes over an hour, and the 100-g load over 3 hours if abnormal.²⁸ See TABLE for normal and abnormal values. Insulin sensitivity has been assessed by calculating insulin area under the curve (AUC insulin), AUC glucose/AUC insulin, and by an insulin sensitivity index (ISI) that applies only the glucose and insulin values from 0 and 120 minutes into a complex mathematical formula.^13,25,29-31

Criteria for diagnosis of diabetes

Test for glycosylated hemoglobin

Tests for blood levels of glycosylated hemoglobin, also known as hemoglobin A_1c (HbA_1c) are not currently used for an initial diagnosis because normal HbA_1c levels do not necessarily rule out diabetes, but they are strongly associated with complications of diabetes. The test is not affected by food intake so it can be taken at any time. A normal HbA_1c level is below 7%.

We want to hear from you! Tell us what you think.

The hepatitis C virus (HCV) is estimated to affect 180 million people worldwide, and the CDC estimates that approximately 3.2 million persons in the United States are chronically infected with HCV.^1,2 In recent years, reported HCV-related deaths have outnumbered those attributed to HIV infection.³ Clinicians in almost any practice area are likely to encounter patients affected by HCV.

Infection with HCV is a major risk factor for cirrhosis, a disease associated with significant morbidity and mortality; HCV-associated cirrhosis is considered the leading cause of liver transplantation.⁴

Screening for HCV is important in patients with known risk factors for the disease¹ (see Table 1^1,2,5). Of note, however, the CDC is in the process of expanding its recommendations to one-time screening for all Americans born between 1945 and 1965—an age-group that accounts for more than 75% of cases of HCV infection among US adults.⁶ (Clinicians interested in viewing the draft document for public comment can refer to www.regulations.gov, docket #CDC-2-12-0005.)

PATIENT PRESENTATION/ PATIENT HISTORY

Most patients with hepatitis C present without signs or symptoms of their illness. If symptoms are present, they may include fatigue, pruritus, abdominal pain/ discomfort, arthralgias, or anorexia; results on routine liver function tests may be abnormal.^1,7-9 Liver function may appear normal in patients with HCV, although 30% of patients with a normal alanine aminotransferase (ALT) level may have significant fibrosis.¹⁰ Lichen planus is commonly associated with HCV infection,^9-11 and patients with this condition should be screened for HCV.

HCV infection most commonly presents between the fourth and sixth decades of life. Many patients have had the disease for as long as 20 years by the time they present for treatment—often after abnormal laboratory findings are discovered⁷ (but see "Can Some Patients Defer Treatment?"^7,10,12).

Patients with acute HCV infection usually do not appear jaundiced or exhibit other signs of acute hepatitis. Symptomatic illness occurs in only 20% to 40% of patients with acute hepatitis C.⁷ Patients who present with acute illness (15% to 25% of patients with HCV) typically have an improved prognosis and are less likely to convert to chronicity if they survive the initial symptoms (ie, malaise, weakness, anorexia, jaundice).^2,7 In many such patients, the body appears to mount a full immune response, and patients are often virus-free within weeks.

For 75% to 85% of patients, however, it is believed that the immune system fails to overcome the virus, and chronic infection, with progressive damage to the liver tissue, ensues.⁷ In chronic HCV infection, the rate of progression varies, depending on the HCV genotype, the infected host's genetic factors and lifestyle (including level of alcohol consumption), the extent of liver injury, and possible coinfection (as with HIV or hepatitis B virus [HBV]).^1,7

Cirrhosis and Hepatocellular Carcinoma

Complications of cirrhosis include portal hypertension, ascites, hepatic encephalopathy, esophageal varices, and hepatocellular carcinoma (HCC).¹³ In patients with HCV-related cirrhosis, HCC develops at a rate of 1% to 4% per year, with a twofold to fourfold increased risk among black patients and Asian patients, respectively, compared with whites.⁷ The risk for HCC appears to be reduced in patients who undergo treatment leading to a sustained virologic response (ie, a viral load that is no longer detectable); and the risk is increased in patients with diabetes mellitus and those with HCV genotypes 1b and 3.^14-16

HCC is difficult to treat unless detected in its early stages. It often results in death.¹³

PHYSICAL EXAMINATION

An appropriate physical exam is critical in detecting sequelae of chronic liver disease, which may reflect complications of long-term HCV infection. The patient should be evaluated for the presence of spider angiomas, palmar erythema, scleral icterus, ascites, caput medusae, and evidence of umbilical hernias—all possible signs of advanced liver disease.^8,9

The initial physical exam is also an appropriate time to screen and treat patients for hypertension and diabetes, and to identify disorders that may make them poor candidates for HCV treatment. These conditions include coronary heart disease, untreated cancers or thyroid disease, kidney or autoimmune diseases, and psychiatric illness.^1,17

Evaluation of the skin for "track marks," tattoos or body piercings that may have been applied in prisons, homes, or other nonsterile settings, or nonhealing lesions that may indicate immune compromise or diabetes is important.^5,8 Visual acuity testing and fundoscopic exams are critical to establish a baseline, because treatment with pegylated interferon has the potential to cause visual changes and retinopathy.¹⁸

Laboratory Work-up

Initial testing for HCV includes an HCV antibody test. This serum test is commonly performed as part of a hepatitis panel—testing for hepatitis A virus (HAV), HBV, and HCV. Testing for hepatitis D and E is not routinely recommended unless the patient routinely travels to the Mediterranean Basin, the Middle East, Central Asia, or West Africa (where hepatitis D is most prevalent¹⁹) or the patient is pregnant (because during the third trimester, hepatitis E infection carries a mortality rate of 20% and can be transmitted to the fetus²⁰).

If immunity to HAV and HBV are not shown on laboratory findings, it is critical to vaccinate the HCV-positive patient against these diseases. Coinfection with HAV and HCV can progress to a fulminant form of hepatitis and poor hepatic function; coinfection with HBV and HCV is associated with severe liver disease and an increased risk for HCC.^21,22

The patient with positive results on the HCV antibody screen should be tested next with a quantitative HCV RNA assay to confirm the presence of active infection (ie, viral load).¹ Detection of virus is considered indicative of active disease.

It is possible for a patient with positive HCV antibody test results to have no circulating virus detected on HCV RNA testing. Perhaps 15% to 25% of patients are able to clear HCV infection spontaneously within weeks to months after infection.⁷

Testing Considerations Before Treatment

Several assays are available to identify the patient's HCV genotype. It is essential to obtain this information before agents, dosing, and duration are determined, as the regimen will be tailored to the patient's HCV genotype.¹ There are six major known HCV genotypes (numbered 1 through 6) and at least 50 minor subtypes (eg, 1a, 2b, 3a).^1,23

Also to be considered before initiating HCV treatment is screening for autoimmune hepatitis.¹⁷ Appropriate tests include the anti-actin antibody, anti-smooth muscle antibody, antinuclear antibody, and anti-liver kidney microsomal antibody tests.^24,25 Additionally, ceruloplasmin testing should be ordered along with the iron studies and ferritin levels obtained at the patient's first visit, to screen for Wilson's disease, a disorder of copper metabolism, and hemochromatosis, a disorder of iron metabolism.

The risks associated with HAV or HBV coinfection have been described; patients with HCV and HAV, HBV, or HIV are at greater risk for disease progression to cirrhosis and/or HCC than are mono-infected patients.^1,21,22,26 HIV testing is routinely recommended for patients with HCV, with repeat testing during treatment if the patient maintains any risk factors for HIV exposure. Patients with HCV who are found to be coinfected with HIV must be treated urgently, but therapeutic components must be selected with considerable care: Serious interactions are possible among the effective agents, and antiretroviral drugs are associated with hepatotoxicity.^1,27

Before HCV treatment begins, it is essential to obtain baseline values: liver function testing (aspartate aminotransferase, ALT, alkaline phosphatase, bilirubin), coagulation testing (prothrombin time and partial thromboplastin time), and thyroid testing (thyroid-stimulating hormone, triiodothyronine, thyroxine),¹ as changes may occur as a result of anti-HCV therapy. It is also important to establish a baseline complete blood count (CBC) and electrolyte levels in order to identify, and later monitor, the presence of anemia, thrombocytopenia, and renal or other abnormalities.

Finally, it is important to screen the patient early for HCC by testing for serum alphafetoprotein (AFP, ie, tumor marker).²⁸ Serum AFP must then be monitored at six-month intervals (with a recommended threshold of 400 ng/mL, but even readings as modest as 6 to 20 ng/mL) for elevations that may indicate HCC.^29,30

Liver Studies

In addition to the recommended AFP monitoring, the patient should undergo an imaging study of the liver twice yearly. Ultrasound is the most cost-effective screening tool for most patients (with high specificity but varying sensitivity); when combined with a serum AFP reading of 10 ng/mL or greater, ultrasound has a sensitivity of 100% for detection of HCC.²⁹ However, if lesions are found, or if a patient has known cirrhosis, CT or MRI is more accurate in detecting small lesions of the liver (specificity, 100%).²⁹

Liver biopsy is recommended for certain patients to stage liver fibrosis; biopsy may not be necessary, for example, in patients with genotypes 2 and 3, as 80% of these patients react to standard therapy with sustained virologic response.¹ Detection of advanced fibrosis or cirrhosis increases the urgency for treatment to avert associated complications.³¹

Thanks to radiologic guidance, the risk for liver biopsy-related complications has been reduced; less than 1% of patients, according to 2008 study results, required hospitalization because of postprocedural pain or bleeding³²; these are risks for which patients should be prepared,¹ in addition to possible perforation of the bowel or lung, bile leak, or hematoma formation.³³ Less than 10% of patients require analgesia two hours after the procedure,³⁴ although prophylactic analgesia (as with sublingual tramadol and oral lorazepam) has been found helpful in reducing pain and anxiety.³⁵

TREATMENT/MANAGEMENT

According to information from the CDC and practice guidelines from the American Association for the Study of Liver Diseases (AASLD),^1,2 early diagnosis of HCV and treatment with currently available interventions can lead to cures in 75% of cases; otherwise, serious, life-threatening complications can be expected. In patients treated for HCV infection, cure (or sustained virologic response) is defined by an undetectable viral load, 24 weeks after completion of therapy.¹ Patients with these test results are no longer able to transmit the virus to others.

For the past decade, pegylated interferon (or peginterferon) combined with ribavirin has been considered the standard of care for HCV; treatment response rates, depending on race and genotype, can range from 35% to 80%.^36,37 Two forms of peginterferon, alfa-2a and alfa-2b, are FDA approved for treatment of chronic hepatitis C; both forms are administered subcutaneously in combination with oral ribavirin.^1,38

The choice between peginterferon alfa-2a and alfa-2b and the recommended duration of treatment are dependent on the patient's HCV genotype (see Table 2^1,39-45) and prior exposure to treatment. These complex regimens are best managed by specialists in gastroenterology, hepatology, or infectious disease—clinicians who are familiar with the agents' associated adverse effects, the elements of attentive monitoring, and protocols for dosing adjustments.⁴⁶

As noted in the AASLD guidelines,¹ alcohol consumption constitutes a risk for worsening fibrosis and possibly for HCC. Additionally, drinking in excess may facilitate replication of HCV RNA, interfering with therapy.

Thus, patients should be urged to discontinue alcohol use during treatment for HCV—or at least restrict it to an occasional drink.

New Agents to Improve Cure Rates

HCV genotype 1 accounts for 70% to 75% of cases in the US, but with current standard treatment, a sustained virologic response is achieved in only 45% to 50% of these patients³⁷ (including 30% of black patients and 50% of whites).^1,36,38 However, adding one of two new protease inhibitors to the current peginterferon/ribavirin regimen has the potential to increase sustained virologic response rates to as high as 90% to 95% in early virologic responders with genotype 1 infection, both treatment-naïve and previously treated; and in some patients, to shorten treatment to 24 weeks.^41,42,44,45 Both boceprevir and telaprevir were approved by the FDA in May 2011.

Both agents are given for 12 weeks during standard peginterferon/ribavirin therapy. Depending on the patient's viral response, the overall regimen may be shortened or extended. Neither telaprevir nor boceprevir is administered as monotherapy,^47,48 nor are they ever administered together. As with any protease inhibitor, resuming treatment after the agent has been stopped incurs a risk for drug resistance.⁴⁰

Both new agents are taken every 7 to 9 hours, with a meal or snack.^47,48 The telaprevir dose should be taken with non-low-fat food.⁴⁷

Drug interactions are common. Patients also being treated for HIV and those being treated for HCV genotype 1 infection with either of the two new protease inhibitors must very carefully communicate any prescription drug changes to their treating provider. Substances of greatest concern act via the cytochrome P450 3A (CYP3A) pathway. Examples include ritonavir, St. John's wort, statins, and daily-dosed sildenafil (as used to treat patients with pulmonary hypertension).

Package inserts accompanying all agents used should be reviewed for monitoring parameters and associated recommendations.

Monitoring for Treatment Effectiveness and Complications

Patients are closely monitored for treatment effectiveness by repeated measurements of HCV RNA (ie, weeks 4, 12, 24, then at four- to 12-week intervals; at end of treatment; and 24 weeks after treatment ends). A viral load not detectable at week 4 indicates a good chance for a cure.¹ If at week 12 the viral load remains detectable, the patient with HCV genotype 1 is unlikely to respond to triple therapy; similarly, dual therapy is not likely to produce a cure in patients with HCV genotype 2 or 3. Without a 2-log drop in viral load by week 12, the patient has only an 8% chance of achieving a sustained virologic response.^49-51 In these cases, treatment should be discontinued or modified.⁵¹

Regular visits and frequent blood testing make it possible to avoid potential disease- and treatment-related complications. At a minimum, it is recommended that a CBC, serum creatinine, and ALT level be measured at weeks 2, 4, 8, 12, 16, 20, and 24 of therapy.¹ If significant abnormalities are detected (eg, anemia, thrombocytopenia, neutropenia), the clinician may decide to monitor the patient more closely. Measures of liver and kidney function, electrolytes, and coagulation times are part of the recommended monitoring parameters at regular intervals. In addition, interferon therapy is associated with thyroid dysfunction, so relevant monitoring is advised every 12 weeks.¹

Anemia, neutropenia, thrombocytopenia, and other hematologic complications are known adverse effects of HCV therapy—particularly in cirrhotic patients.^1,52 Ribavirin use (especially aggressive use, as for patients with recurrent infection or post-liver transplantation⁵³) is associated with hemolytic anemia,⁵⁴ as is protease inhibitor use.^41,45 In cases of profound anemia, dosing reduction or treatment discontinuation may be necessary. Severe cases of hemolysis may require transfusion, but treatment with epoietin alfa has been found helpful in some patients.^52,53 Conventional iron supplementation is not an effective treatment for hemolytic anemia resulting from ribavirin use.

For patients with low absolute neutrophil counts, treatment dosing reduction was once standard management.^45,52 More recently, the use of epoietin alfa or a granulocyte colony-stimulating factor (eg, filgrastim) has been found helpful in raising neutrophil counts.⁵²

Intervention for thrombocytopenia is not typically undertaken unless the total platelet count indicates a risk for spontaneous bleeding. In some patients, a new oral thrombopoietin mimetic called eltrombopag may reduce the need for dose reduction or early termination of therapy.⁵²

Ribavirin is a major teratogen. This agent is listed in pregnancy category X, and its label carries a black box warning advising patients to avoid pregnancy while undergoing therapy and for six months following therapy. It has such a high potential for teratogenicity that male patients are even advised not to impregnate their female partners while on therapy or six months following therapy.⁵⁴ Pregnant women should never handle ribavirin. It is important to educate medical professionals and office staff about this risk.

For management of other adverse reactions to one or more components of HCV treatment, see Table 3.^{1,41,43,45,55-57}

PATIENT EDUCATION/FOLLOW-UP DISCUSSION

Patient education is critical to successful treatment for HCV. Patients should be encouraged to avoid viral transmission to sexual partners by using condoms. They should also be advised to avoid sharing razors or toothbrushes with others in the home.¹ Any patient with known HCV, HIV, or HBV should avoid undergoing body piercing or tattooing in any nonprofessional, nonsterile setting, where transmission may occur.⁵ Even successfully treated patients retain an HCV antibody and will test positive for HCV, making them ineligible to donate blood.

Six months after treatment, a viral load is drawn. If no active virus is found, patients will not need monitoring or follow-up labs unless they have known cirrhosis. Fibrosis is reversible in some patients following HCV treatment. However, if active disease is found at the six-month posttreatment follow-up visit, then the treatment was not effective, and the patient is considered a responder-relapser. Many such patients then consider enrolling in a drug trial or awaiting the potential approval of new treatments.

Herbal therapies, such as milk thistle and licorice root, have been widely tried by patients with HCV infection. The literature is mixed regarding the effectiveness of these substances or their potential for reducing liver function testing abnormalities. To date, no herbal compound has been proven to eradicate the virus. Most hepatologists encourage patients who take interferon, ribavirin, and/or protease inhibitors to avoid herbal or OTC substances with any potential for drug interactions or other complications.

ON THE HORIZON

Promising developments suggest a brightening future for patients with HCV infection. Researchers throughout the world are currently investigating new combinations of agents, effective against a wider range of genotypes and subtypes, that can control HCV infection without the emergence of drug-resistant strains. The near future may see more protease inhibitors added to current regimens and other direct-acting antivirals possibly replacing old treatment components. As is true of HIV, a vaccine for HCV will be difficult to develop; but in the meantime, new drug combinations will be created with a goal of sustained virologic response rates nearing 100% and ever-shorter treatment regimens.^37,58

CONCLUSION

Since signs or symptoms are often not seen in patients infected with hepatitis C, it is important for primary care providers to question patients regarding known risk factors. At-risk patients should be screened using antibody testing, followed by confirmation of any positive results by HCV RNA testing. The patient's HCV genotype must be identified next, as it plays a key role in the therapeutic decisions to be made.

Because HCV therapy is complex, it is best managed by specialists who are experienced in all the aspects of each patient's regimen and who remain abreast of new therapeutic developments. Nevertheless, primary care providers can serve their patients well by acting as knowledgeable, supportive members of the health care team, accompanying their patients through the challenges of treatment and follow-up.

The hepatitis C virus (HCV) is estimated to affect 180 million people worldwide, and the CDC estimates that approximately 3.2 million persons in the United States are chronically infected with HCV.^1,2 In recent years, reported HCV-related deaths have outnumbered those attributed to HIV infection.³ Clinicians in almost any practice area are likely to encounter patients affected by HCV.

Infection with HCV is a major risk factor for cirrhosis, a disease associated with significant morbidity and mortality; HCV-associated cirrhosis is considered the leading cause of liver transplantation.⁴

Screening for HCV is important in patients with known risk factors for the disease¹ (see Table 1^1,2,5). Of note, however, the CDC is in the process of expanding its recommendations to one-time screening for all Americans born between 1945 and 1965—an age-group that accounts for more than 75% of cases of HCV infection among US adults.⁶ (Clinicians interested in viewing the draft document for public comment can refer to www.regulations.gov, docket #CDC-2-12-0005.)

PATIENT PRESENTATION/ PATIENT HISTORY

Most patients with hepatitis C present without signs or symptoms of their illness. If symptoms are present, they may include fatigue, pruritus, abdominal pain/ discomfort, arthralgias, or anorexia; results on routine liver function tests may be abnormal.^1,7-9 Liver function may appear normal in patients with HCV, although 30% of patients with a normal alanine aminotransferase (ALT) level may have significant fibrosis.¹⁰ Lichen planus is commonly associated with HCV infection,^9-11 and patients with this condition should be screened for HCV.

HCV infection most commonly presents between the fourth and sixth decades of life. Many patients have had the disease for as long as 20 years by the time they present for treatment—often after abnormal laboratory findings are discovered⁷ (but see "Can Some Patients Defer Treatment?"^7,10,12).

Patients with acute HCV infection usually do not appear jaundiced or exhibit other signs of acute hepatitis. Symptomatic illness occurs in only 20% to 40% of patients with acute hepatitis C.⁷ Patients who present with acute illness (15% to 25% of patients with HCV) typically have an improved prognosis and are less likely to convert to chronicity if they survive the initial symptoms (ie, malaise, weakness, anorexia, jaundice).^2,7 In many such patients, the body appears to mount a full immune response, and patients are often virus-free within weeks.

For 75% to 85% of patients, however, it is believed that the immune system fails to overcome the virus, and chronic infection, with progressive damage to the liver tissue, ensues.⁷ In chronic HCV infection, the rate of progression varies, depending on the HCV genotype, the infected host's genetic factors and lifestyle (including level of alcohol consumption), the extent of liver injury, and possible coinfection (as with HIV or hepatitis B virus [HBV]).^1,7

Cirrhosis and Hepatocellular Carcinoma

Complications of cirrhosis include portal hypertension, ascites, hepatic encephalopathy, esophageal varices, and hepatocellular carcinoma (HCC).¹³ In patients with HCV-related cirrhosis, HCC develops at a rate of 1% to 4% per year, with a twofold to fourfold increased risk among black patients and Asian patients, respectively, compared with whites.⁷ The risk for HCC appears to be reduced in patients who undergo treatment leading to a sustained virologic response (ie, a viral load that is no longer detectable); and the risk is increased in patients with diabetes mellitus and those with HCV genotypes 1b and 3.^14-16

HCC is difficult to treat unless detected in its early stages. It often results in death.¹³

PHYSICAL EXAMINATION

An appropriate physical exam is critical in detecting sequelae of chronic liver disease, which may reflect complications of long-term HCV infection. The patient should be evaluated for the presence of spider angiomas, palmar erythema, scleral icterus, ascites, caput medusae, and evidence of umbilical hernias—all possible signs of advanced liver disease.^8,9

The initial physical exam is also an appropriate time to screen and treat patients for hypertension and diabetes, and to identify disorders that may make them poor candidates for HCV treatment. These conditions include coronary heart disease, untreated cancers or thyroid disease, kidney or autoimmune diseases, and psychiatric illness.^1,17

Evaluation of the skin for "track marks," tattoos or body piercings that may have been applied in prisons, homes, or other nonsterile settings, or nonhealing lesions that may indicate immune compromise or diabetes is important.^5,8 Visual acuity testing and fundoscopic exams are critical to establish a baseline, because treatment with pegylated interferon has the potential to cause visual changes and retinopathy.¹⁸

Laboratory Work-up

Initial testing for HCV includes an HCV antibody test. This serum test is commonly performed as part of a hepatitis panel—testing for hepatitis A virus (HAV), HBV, and HCV. Testing for hepatitis D and E is not routinely recommended unless the patient routinely travels to the Mediterranean Basin, the Middle East, Central Asia, or West Africa (where hepatitis D is most prevalent¹⁹) or the patient is pregnant (because during the third trimester, hepatitis E infection carries a mortality rate of 20% and can be transmitted to the fetus²⁰).

If immunity to HAV and HBV are not shown on laboratory findings, it is critical to vaccinate the HCV-positive patient against these diseases. Coinfection with HAV and HCV can progress to a fulminant form of hepatitis and poor hepatic function; coinfection with HBV and HCV is associated with severe liver disease and an increased risk for HCC.^21,22

The patient with positive results on the HCV antibody screen should be tested next with a quantitative HCV RNA assay to confirm the presence of active infection (ie, viral load).¹ Detection of virus is considered indicative of active disease.

It is possible for a patient with positive HCV antibody test results to have no circulating virus detected on HCV RNA testing. Perhaps 15% to 25% of patients are able to clear HCV infection spontaneously within weeks to months after infection.⁷

Testing Considerations Before Treatment

Several assays are available to identify the patient's HCV genotype. It is essential to obtain this information before agents, dosing, and duration are determined, as the regimen will be tailored to the patient's HCV genotype.¹ There are six major known HCV genotypes (numbered 1 through 6) and at least 50 minor subtypes (eg, 1a, 2b, 3a).^1,23

Also to be considered before initiating HCV treatment is screening for autoimmune hepatitis.¹⁷ Appropriate tests include the anti-actin antibody, anti-smooth muscle antibody, antinuclear antibody, and anti-liver kidney microsomal antibody tests.^24,25 Additionally, ceruloplasmin testing should be ordered along with the iron studies and ferritin levels obtained at the patient's first visit, to screen for Wilson's disease, a disorder of copper metabolism, and hemochromatosis, a disorder of iron metabolism.

The risks associated with HAV or HBV coinfection have been described; patients with HCV and HAV, HBV, or HIV are at greater risk for disease progression to cirrhosis and/or HCC than are mono-infected patients.^1,21,22,26 HIV testing is routinely recommended for patients with HCV, with repeat testing during treatment if the patient maintains any risk factors for HIV exposure. Patients with HCV who are found to be coinfected with HIV must be treated urgently, but therapeutic components must be selected with considerable care: Serious interactions are possible among the effective agents, and antiretroviral drugs are associated with hepatotoxicity.^1,27

Before HCV treatment begins, it is essential to obtain baseline values: liver function testing (aspartate aminotransferase, ALT, alkaline phosphatase, bilirubin), coagulation testing (prothrombin time and partial thromboplastin time), and thyroid testing (thyroid-stimulating hormone, triiodothyronine, thyroxine),¹ as changes may occur as a result of anti-HCV therapy. It is also important to establish a baseline complete blood count (CBC) and electrolyte levels in order to identify, and later monitor, the presence of anemia, thrombocytopenia, and renal or other abnormalities.

Finally, it is important to screen the patient early for HCC by testing for serum alphafetoprotein (AFP, ie, tumor marker).²⁸ Serum AFP must then be monitored at six-month intervals (with a recommended threshold of 400 ng/mL, but even readings as modest as 6 to 20 ng/mL) for elevations that may indicate HCC.^29,30

Liver Studies

In addition to the recommended AFP monitoring, the patient should undergo an imaging study of the liver twice yearly. Ultrasound is the most cost-effective screening tool for most patients (with high specificity but varying sensitivity); when combined with a serum AFP reading of 10 ng/mL or greater, ultrasound has a sensitivity of 100% for detection of HCC.²⁹ However, if lesions are found, or if a patient has known cirrhosis, CT or MRI is more accurate in detecting small lesions of the liver (specificity, 100%).²⁹

Liver biopsy is recommended for certain patients to stage liver fibrosis; biopsy may not be necessary, for example, in patients with genotypes 2 and 3, as 80% of these patients react to standard therapy with sustained virologic response.¹ Detection of advanced fibrosis or cirrhosis increases the urgency for treatment to avert associated complications.³¹

Thanks to radiologic guidance, the risk for liver biopsy-related complications has been reduced; less than 1% of patients, according to 2008 study results, required hospitalization because of postprocedural pain or bleeding³²; these are risks for which patients should be prepared,¹ in addition to possible perforation of the bowel or lung, bile leak, or hematoma formation.³³ Less than 10% of patients require analgesia two hours after the procedure,³⁴ although prophylactic analgesia (as with sublingual tramadol and oral lorazepam) has been found helpful in reducing pain and anxiety.³⁵

TREATMENT/MANAGEMENT

According to information from the CDC and practice guidelines from the American Association for the Study of Liver Diseases (AASLD),^1,2 early diagnosis of HCV and treatment with currently available interventions can lead to cures in 75% of cases; otherwise, serious, life-threatening complications can be expected. In patients treated for HCV infection, cure (or sustained virologic response) is defined by an undetectable viral load, 24 weeks after completion of therapy.¹ Patients with these test results are no longer able to transmit the virus to others.

For the past decade, pegylated interferon (or peginterferon) combined with ribavirin has been considered the standard of care for HCV; treatment response rates, depending on race and genotype, can range from 35% to 80%.^36,37 Two forms of peginterferon, alfa-2a and alfa-2b, are FDA approved for treatment of chronic hepatitis C; both forms are administered subcutaneously in combination with oral ribavirin.^1,38

The choice between peginterferon alfa-2a and alfa-2b and the recommended duration of treatment are dependent on the patient's HCV genotype (see Table 2^1,39-45) and prior exposure to treatment. These complex regimens are best managed by specialists in gastroenterology, hepatology, or infectious disease—clinicians who are familiar with the agents' associated adverse effects, the elements of attentive monitoring, and protocols for dosing adjustments.⁴⁶

As noted in the AASLD guidelines,¹ alcohol consumption constitutes a risk for worsening fibrosis and possibly for HCC. Additionally, drinking in excess may facilitate replication of HCV RNA, interfering with therapy.

Thus, patients should be urged to discontinue alcohol use during treatment for HCV—or at least restrict it to an occasional drink.

New Agents to Improve Cure Rates

HCV genotype 1 accounts for 70% to 75% of cases in the US, but with current standard treatment, a sustained virologic response is achieved in only 45% to 50% of these patients³⁷ (including 30% of black patients and 50% of whites).^1,36,38 However, adding one of two new protease inhibitors to the current peginterferon/ribavirin regimen has the potential to increase sustained virologic response rates to as high as 90% to 95% in early virologic responders with genotype 1 infection, both treatment-naïve and previously treated; and in some patients, to shorten treatment to 24 weeks.^41,42,44,45 Both boceprevir and telaprevir were approved by the FDA in May 2011.

Both agents are given for 12 weeks during standard peginterferon/ribavirin therapy. Depending on the patient's viral response, the overall regimen may be shortened or extended. Neither telaprevir nor boceprevir is administered as monotherapy,^47,48 nor are they ever administered together. As with any protease inhibitor, resuming treatment after the agent has been stopped incurs a risk for drug resistance.⁴⁰

Both new agents are taken every 7 to 9 hours, with a meal or snack.^47,48 The telaprevir dose should be taken with non-low-fat food.⁴⁷

Drug interactions are common. Patients also being treated for HIV and those being treated for HCV genotype 1 infection with either of the two new protease inhibitors must very carefully communicate any prescription drug changes to their treating provider. Substances of greatest concern act via the cytochrome P450 3A (CYP3A) pathway. Examples include ritonavir, St. John's wort, statins, and daily-dosed sildenafil (as used to treat patients with pulmonary hypertension).

Package inserts accompanying all agents used should be reviewed for monitoring parameters and associated recommendations.

Monitoring for Treatment Effectiveness and Complications

Patients are closely monitored for treatment effectiveness by repeated measurements of HCV RNA (ie, weeks 4, 12, 24, then at four- to 12-week intervals; at end of treatment; and 24 weeks after treatment ends). A viral load not detectable at week 4 indicates a good chance for a cure.¹ If at week 12 the viral load remains detectable, the patient with HCV genotype 1 is unlikely to respond to triple therapy; similarly, dual therapy is not likely to produce a cure in patients with HCV genotype 2 or 3. Without a 2-log drop in viral load by week 12, the patient has only an 8% chance of achieving a sustained virologic response.^49-51 In these cases, treatment should be discontinued or modified.⁵¹

Regular visits and frequent blood testing make it possible to avoid potential disease- and treatment-related complications. At a minimum, it is recommended that a CBC, serum creatinine, and ALT level be measured at weeks 2, 4, 8, 12, 16, 20, and 24 of therapy.¹ If significant abnormalities are detected (eg, anemia, thrombocytopenia, neutropenia), the clinician may decide to monitor the patient more closely. Measures of liver and kidney function, electrolytes, and coagulation times are part of the recommended monitoring parameters at regular intervals. In addition, interferon therapy is associated with thyroid dysfunction, so relevant monitoring is advised every 12 weeks.¹

Anemia, neutropenia, thrombocytopenia, and other hematologic complications are known adverse effects of HCV therapy—particularly in cirrhotic patients.^1,52 Ribavirin use (especially aggressive use, as for patients with recurrent infection or post-liver transplantation⁵³) is associated with hemolytic anemia,⁵⁴ as is protease inhibitor use.^41,45 In cases of profound anemia, dosing reduction or treatment discontinuation may be necessary. Severe cases of hemolysis may require transfusion, but treatment with epoietin alfa has been found helpful in some patients.^52,53 Conventional iron supplementation is not an effective treatment for hemolytic anemia resulting from ribavirin use.

For patients with low absolute neutrophil counts, treatment dosing reduction was once standard management.^45,52 More recently, the use of epoietin alfa or a granulocyte colony-stimulating factor (eg, filgrastim) has been found helpful in raising neutrophil counts.⁵²

Intervention for thrombocytopenia is not typically undertaken unless the total platelet count indicates a risk for spontaneous bleeding. In some patients, a new oral thrombopoietin mimetic called eltrombopag may reduce the need for dose reduction or early termination of therapy.⁵²

Ribavirin is a major teratogen. This agent is listed in pregnancy category X, and its label carries a black box warning advising patients to avoid pregnancy while undergoing therapy and for six months following therapy. It has such a high potential for teratogenicity that male patients are even advised not to impregnate their female partners while on therapy or six months following therapy.⁵⁴ Pregnant women should never handle ribavirin. It is important to educate medical professionals and office staff about this risk.

For management of other adverse reactions to one or more components of HCV treatment, see Table 3.^{1,41,43,45,55-57}

PATIENT EDUCATION/FOLLOW-UP DISCUSSION

Patient education is critical to successful treatment for HCV. Patients should be encouraged to avoid viral transmission to sexual partners by using condoms. They should also be advised to avoid sharing razors or toothbrushes with others in the home.¹ Any patient with known HCV, HIV, or HBV should avoid undergoing body piercing or tattooing in any nonprofessional, nonsterile setting, where transmission may occur.⁵ Even successfully treated patients retain an HCV antibody and will test positive for HCV, making them ineligible to donate blood.

Six months after treatment, a viral load is drawn. If no active virus is found, patients will not need monitoring or follow-up labs unless they have known cirrhosis. Fibrosis is reversible in some patients following HCV treatment. However, if active disease is found at the six-month posttreatment follow-up visit, then the treatment was not effective, and the patient is considered a responder-relapser. Many such patients then consider enrolling in a drug trial or awaiting the potential approval of new treatments.

Herbal therapies, such as milk thistle and licorice root, have been widely tried by patients with HCV infection. The literature is mixed regarding the effectiveness of these substances or their potential for reducing liver function testing abnormalities. To date, no herbal compound has been proven to eradicate the virus. Most hepatologists encourage patients who take interferon, ribavirin, and/or protease inhibitors to avoid herbal or OTC substances with any potential for drug interactions or other complications.

ON THE HORIZON

Promising developments suggest a brightening future for patients with HCV infection. Researchers throughout the world are currently investigating new combinations of agents, effective against a wider range of genotypes and subtypes, that can control HCV infection without the emergence of drug-resistant strains. The near future may see more protease inhibitors added to current regimens and other direct-acting antivirals possibly replacing old treatment components. As is true of HIV, a vaccine for HCV will be difficult to develop; but in the meantime, new drug combinations will be created with a goal of sustained virologic response rates nearing 100% and ever-shorter treatment regimens.^37,58

CONCLUSION

Since signs or symptoms are often not seen in patients infected with hepatitis C, it is important for primary care providers to question patients regarding known risk factors. At-risk patients should be screened using antibody testing, followed by confirmation of any positive results by HCV RNA testing. The patient's HCV genotype must be identified next, as it plays a key role in the therapeutic decisions to be made.

Because HCV therapy is complex, it is best managed by specialists who are experienced in all the aspects of each patient's regimen and who remain abreast of new therapeutic developments. Nevertheless, primary care providers can serve their patients well by acting as knowledgeable, supportive members of the health care team, accompanying their patients through the challenges of treatment and follow-up.

The hepatitis C virus (HCV) is estimated to affect 180 million people worldwide, and the CDC estimates that approximately 3.2 million persons in the United States are chronically infected with HCV.^1,2 In recent years, reported HCV-related deaths have outnumbered those attributed to HIV infection.³ Clinicians in almost any practice area are likely to encounter patients affected by HCV.

Infection with HCV is a major risk factor for cirrhosis, a disease associated with significant morbidity and mortality; HCV-associated cirrhosis is considered the leading cause of liver transplantation.⁴

Screening for HCV is important in patients with known risk factors for the disease¹ (see Table 1^1,2,5). Of note, however, the CDC is in the process of expanding its recommendations to one-time screening for all Americans born between 1945 and 1965—an age-group that accounts for more than 75% of cases of HCV infection among US adults.⁶ (Clinicians interested in viewing the draft document for public comment can refer to www.regulations.gov, docket #CDC-2-12-0005.)

PATIENT PRESENTATION/ PATIENT HISTORY

Most patients with hepatitis C present without signs or symptoms of their illness. If symptoms are present, they may include fatigue, pruritus, abdominal pain/ discomfort, arthralgias, or anorexia; results on routine liver function tests may be abnormal.^1,7-9 Liver function may appear normal in patients with HCV, although 30% of patients with a normal alanine aminotransferase (ALT) level may have significant fibrosis.¹⁰ Lichen planus is commonly associated with HCV infection,^9-11 and patients with this condition should be screened for HCV.

HCV infection most commonly presents between the fourth and sixth decades of life. Many patients have had the disease for as long as 20 years by the time they present for treatment—often after abnormal laboratory findings are discovered⁷ (but see "Can Some Patients Defer Treatment?"^7,10,12).

Patients with acute HCV infection usually do not appear jaundiced or exhibit other signs of acute hepatitis. Symptomatic illness occurs in only 20% to 40% of patients with acute hepatitis C.⁷ Patients who present with acute illness (15% to 25% of patients with HCV) typically have an improved prognosis and are less likely to convert to chronicity if they survive the initial symptoms (ie, malaise, weakness, anorexia, jaundice).^2,7 In many such patients, the body appears to mount a full immune response, and patients are often virus-free within weeks.

For 75% to 85% of patients, however, it is believed that the immune system fails to overcome the virus, and chronic infection, with progressive damage to the liver tissue, ensues.⁷ In chronic HCV infection, the rate of progression varies, depending on the HCV genotype, the infected host's genetic factors and lifestyle (including level of alcohol consumption), the extent of liver injury, and possible coinfection (as with HIV or hepatitis B virus [HBV]).^1,7

Cirrhosis and Hepatocellular Carcinoma

Complications of cirrhosis include portal hypertension, ascites, hepatic encephalopathy, esophageal varices, and hepatocellular carcinoma (HCC).¹³ In patients with HCV-related cirrhosis, HCC develops at a rate of 1% to 4% per year, with a twofold to fourfold increased risk among black patients and Asian patients, respectively, compared with whites.⁷ The risk for HCC appears to be reduced in patients who undergo treatment leading to a sustained virologic response (ie, a viral load that is no longer detectable); and the risk is increased in patients with diabetes mellitus and those with HCV genotypes 1b and 3.^14-16

HCC is difficult to treat unless detected in its early stages. It often results in death.¹³

PHYSICAL EXAMINATION

An appropriate physical exam is critical in detecting sequelae of chronic liver disease, which may reflect complications of long-term HCV infection. The patient should be evaluated for the presence of spider angiomas, palmar erythema, scleral icterus, ascites, caput medusae, and evidence of umbilical hernias—all possible signs of advanced liver disease.^8,9

The initial physical exam is also an appropriate time to screen and treat patients for hypertension and diabetes, and to identify disorders that may make them poor candidates for HCV treatment. These conditions include coronary heart disease, untreated cancers or thyroid disease, kidney or autoimmune diseases, and psychiatric illness.^1,17

Evaluation of the skin for "track marks," tattoos or body piercings that may have been applied in prisons, homes, or other nonsterile settings, or nonhealing lesions that may indicate immune compromise or diabetes is important.^5,8 Visual acuity testing and fundoscopic exams are critical to establish a baseline, because treatment with pegylated interferon has the potential to cause visual changes and retinopathy.¹⁸

Laboratory Work-up

Initial testing for HCV includes an HCV antibody test. This serum test is commonly performed as part of a hepatitis panel—testing for hepatitis A virus (HAV), HBV, and HCV. Testing for hepatitis D and E is not routinely recommended unless the patient routinely travels to the Mediterranean Basin, the Middle East, Central Asia, or West Africa (where hepatitis D is most prevalent¹⁹) or the patient is pregnant (because during the third trimester, hepatitis E infection carries a mortality rate of 20% and can be transmitted to the fetus²⁰).

If immunity to HAV and HBV are not shown on laboratory findings, it is critical to vaccinate the HCV-positive patient against these diseases. Coinfection with HAV and HCV can progress to a fulminant form of hepatitis and poor hepatic function; coinfection with HBV and HCV is associated with severe liver disease and an increased risk for HCC.^21,22

The patient with positive results on the HCV antibody screen should be tested next with a quantitative HCV RNA assay to confirm the presence of active infection (ie, viral load).¹ Detection of virus is considered indicative of active disease.

It is possible for a patient with positive HCV antibody test results to have no circulating virus detected on HCV RNA testing. Perhaps 15% to 25% of patients are able to clear HCV infection spontaneously within weeks to months after infection.⁷

Testing Considerations Before Treatment

Several assays are available to identify the patient's HCV genotype. It is essential to obtain this information before agents, dosing, and duration are determined, as the regimen will be tailored to the patient's HCV genotype.¹ There are six major known HCV genotypes (numbered 1 through 6) and at least 50 minor subtypes (eg, 1a, 2b, 3a).^1,23

Also to be considered before initiating HCV treatment is screening for autoimmune hepatitis.¹⁷ Appropriate tests include the anti-actin antibody, anti-smooth muscle antibody, antinuclear antibody, and anti-liver kidney microsomal antibody tests.^24,25 Additionally, ceruloplasmin testing should be ordered along with the iron studies and ferritin levels obtained at the patient's first visit, to screen for Wilson's disease, a disorder of copper metabolism, and hemochromatosis, a disorder of iron metabolism.

The risks associated with HAV or HBV coinfection have been described; patients with HCV and HAV, HBV, or HIV are at greater risk for disease progression to cirrhosis and/or HCC than are mono-infected patients.^1,21,22,26 HIV testing is routinely recommended for patients with HCV, with repeat testing during treatment if the patient maintains any risk factors for HIV exposure. Patients with HCV who are found to be coinfected with HIV must be treated urgently, but therapeutic components must be selected with considerable care: Serious interactions are possible among the effective agents, and antiretroviral drugs are associated with hepatotoxicity.^1,27

Before HCV treatment begins, it is essential to obtain baseline values: liver function testing (aspartate aminotransferase, ALT, alkaline phosphatase, bilirubin), coagulation testing (prothrombin time and partial thromboplastin time), and thyroid testing (thyroid-stimulating hormone, triiodothyronine, thyroxine),¹ as changes may occur as a result of anti-HCV therapy. It is also important to establish a baseline complete blood count (CBC) and electrolyte levels in order to identify, and later monitor, the presence of anemia, thrombocytopenia, and renal or other abnormalities.

Finally, it is important to screen the patient early for HCC by testing for serum alphafetoprotein (AFP, ie, tumor marker).²⁸ Serum AFP must then be monitored at six-month intervals (with a recommended threshold of 400 ng/mL, but even readings as modest as 6 to 20 ng/mL) for elevations that may indicate HCC.^29,30

Liver Studies

In addition to the recommended AFP monitoring, the patient should undergo an imaging study of the liver twice yearly. Ultrasound is the most cost-effective screening tool for most patients (with high specificity but varying sensitivity); when combined with a serum AFP reading of 10 ng/mL or greater, ultrasound has a sensitivity of 100% for detection of HCC.²⁹ However, if lesions are found, or if a patient has known cirrhosis, CT or MRI is more accurate in detecting small lesions of the liver (specificity, 100%).²⁹

Liver biopsy is recommended for certain patients to stage liver fibrosis; biopsy may not be necessary, for example, in patients with genotypes 2 and 3, as 80% of these patients react to standard therapy with sustained virologic response.¹ Detection of advanced fibrosis or cirrhosis increases the urgency for treatment to avert associated complications.³¹

Thanks to radiologic guidance, the risk for liver biopsy-related complications has been reduced; less than 1% of patients, according to 2008 study results, required hospitalization because of postprocedural pain or bleeding³²; these are risks for which patients should be prepared,¹ in addition to possible perforation of the bowel or lung, bile leak, or hematoma formation.³³ Less than 10% of patients require analgesia two hours after the procedure,³⁴ although prophylactic analgesia (as with sublingual tramadol and oral lorazepam) has been found helpful in reducing pain and anxiety.³⁵

TREATMENT/MANAGEMENT

According to information from the CDC and practice guidelines from the American Association for the Study of Liver Diseases (AASLD),^1,2 early diagnosis of HCV and treatment with currently available interventions can lead to cures in 75% of cases; otherwise, serious, life-threatening complications can be expected. In patients treated for HCV infection, cure (or sustained virologic response) is defined by an undetectable viral load, 24 weeks after completion of therapy.¹ Patients with these test results are no longer able to transmit the virus to others.

For the past decade, pegylated interferon (or peginterferon) combined with ribavirin has been considered the standard of care for HCV; treatment response rates, depending on race and genotype, can range from 35% to 80%.^36,37 Two forms of peginterferon, alfa-2a and alfa-2b, are FDA approved for treatment of chronic hepatitis C; both forms are administered subcutaneously in combination with oral ribavirin.^1,38

The choice between peginterferon alfa-2a and alfa-2b and the recommended duration of treatment are dependent on the patient's HCV genotype (see Table 2^1,39-45) and prior exposure to treatment. These complex regimens are best managed by specialists in gastroenterology, hepatology, or infectious disease—clinicians who are familiar with the agents' associated adverse effects, the elements of attentive monitoring, and protocols for dosing adjustments.⁴⁶

As noted in the AASLD guidelines,¹ alcohol consumption constitutes a risk for worsening fibrosis and possibly for HCC. Additionally, drinking in excess may facilitate replication of HCV RNA, interfering with therapy.

Thus, patients should be urged to discontinue alcohol use during treatment for HCV—or at least restrict it to an occasional drink.

New Agents to Improve Cure Rates

HCV genotype 1 accounts for 70% to 75% of cases in the US, but with current standard treatment, a sustained virologic response is achieved in only 45% to 50% of these patients³⁷ (including 30% of black patients and 50% of whites).^1,36,38 However, adding one of two new protease inhibitors to the current peginterferon/ribavirin regimen has the potential to increase sustained virologic response rates to as high as 90% to 95% in early virologic responders with genotype 1 infection, both treatment-naïve and previously treated; and in some patients, to shorten treatment to 24 weeks.^41,42,44,45 Both boceprevir and telaprevir were approved by the FDA in May 2011.

Both agents are given for 12 weeks during standard peginterferon/ribavirin therapy. Depending on the patient's viral response, the overall regimen may be shortened or extended. Neither telaprevir nor boceprevir is administered as monotherapy,^47,48 nor are they ever administered together. As with any protease inhibitor, resuming treatment after the agent has been stopped incurs a risk for drug resistance.⁴⁰

Both new agents are taken every 7 to 9 hours, with a meal or snack.^47,48 The telaprevir dose should be taken with non-low-fat food.⁴⁷

Drug interactions are common. Patients also being treated for HIV and those being treated for HCV genotype 1 infection with either of the two new protease inhibitors must very carefully communicate any prescription drug changes to their treating provider. Substances of greatest concern act via the cytochrome P450 3A (CYP3A) pathway. Examples include ritonavir, St. John's wort, statins, and daily-dosed sildenafil (as used to treat patients with pulmonary hypertension).

Package inserts accompanying all agents used should be reviewed for monitoring parameters and associated recommendations.

Monitoring for Treatment Effectiveness and Complications

Patients are closely monitored for treatment effectiveness by repeated measurements of HCV RNA (ie, weeks 4, 12, 24, then at four- to 12-week intervals; at end of treatment; and 24 weeks after treatment ends). A viral load not detectable at week 4 indicates a good chance for a cure.¹ If at week 12 the viral load remains detectable, the patient with HCV genotype 1 is unlikely to respond to triple therapy; similarly, dual therapy is not likely to produce a cure in patients with HCV genotype 2 or 3. Without a 2-log drop in viral load by week 12, the patient has only an 8% chance of achieving a sustained virologic response.^49-51 In these cases, treatment should be discontinued or modified.⁵¹

Regular visits and frequent blood testing make it possible to avoid potential disease- and treatment-related complications. At a minimum, it is recommended that a CBC, serum creatinine, and ALT level be measured at weeks 2, 4, 8, 12, 16, 20, and 24 of therapy.¹ If significant abnormalities are detected (eg, anemia, thrombocytopenia, neutropenia), the clinician may decide to monitor the patient more closely. Measures of liver and kidney function, electrolytes, and coagulation times are part of the recommended monitoring parameters at regular intervals. In addition, interferon therapy is associated with thyroid dysfunction, so relevant monitoring is advised every 12 weeks.¹

Anemia, neutropenia, thrombocytopenia, and other hematologic complications are known adverse effects of HCV therapy—particularly in cirrhotic patients.^1,52 Ribavirin use (especially aggressive use, as for patients with recurrent infection or post-liver transplantation⁵³) is associated with hemolytic anemia,⁵⁴ as is protease inhibitor use.^41,45 In cases of profound anemia, dosing reduction or treatment discontinuation may be necessary. Severe cases of hemolysis may require transfusion, but treatment with epoietin alfa has been found helpful in some patients.^52,53 Conventional iron supplementation is not an effective treatment for hemolytic anemia resulting from ribavirin use.

For patients with low absolute neutrophil counts, treatment dosing reduction was once standard management.^45,52 More recently, the use of epoietin alfa or a granulocyte colony-stimulating factor (eg, filgrastim) has been found helpful in raising neutrophil counts.⁵²

Intervention for thrombocytopenia is not typically undertaken unless the total platelet count indicates a risk for spontaneous bleeding. In some patients, a new oral thrombopoietin mimetic called eltrombopag may reduce the need for dose reduction or early termination of therapy.⁵²

Ribavirin is a major teratogen. This agent is listed in pregnancy category X, and its label carries a black box warning advising patients to avoid pregnancy while undergoing therapy and for six months following therapy. It has such a high potential for teratogenicity that male patients are even advised not to impregnate their female partners while on therapy or six months following therapy.⁵⁴ Pregnant women should never handle ribavirin. It is important to educate medical professionals and office staff about this risk.

For management of other adverse reactions to one or more components of HCV treatment, see Table 3.^{1,41,43,45,55-57}

PATIENT EDUCATION/FOLLOW-UP DISCUSSION

Patient education is critical to successful treatment for HCV. Patients should be encouraged to avoid viral transmission to sexual partners by using condoms. They should also be advised to avoid sharing razors or toothbrushes with others in the home.¹ Any patient with known HCV, HIV, or HBV should avoid undergoing body piercing or tattooing in any nonprofessional, nonsterile setting, where transmission may occur.⁵ Even successfully treated patients retain an HCV antibody and will test positive for HCV, making them ineligible to donate blood.

Six months after treatment, a viral load is drawn. If no active virus is found, patients will not need monitoring or follow-up labs unless they have known cirrhosis. Fibrosis is reversible in some patients following HCV treatment. However, if active disease is found at the six-month posttreatment follow-up visit, then the treatment was not effective, and the patient is considered a responder-relapser. Many such patients then consider enrolling in a drug trial or awaiting the potential approval of new treatments.

Herbal therapies, such as milk thistle and licorice root, have been widely tried by patients with HCV infection. The literature is mixed regarding the effectiveness of these substances or their potential for reducing liver function testing abnormalities. To date, no herbal compound has been proven to eradicate the virus. Most hepatologists encourage patients who take interferon, ribavirin, and/or protease inhibitors to avoid herbal or OTC substances with any potential for drug interactions or other complications.

ON THE HORIZON

Promising developments suggest a brightening future for patients with HCV infection. Researchers throughout the world are currently investigating new combinations of agents, effective against a wider range of genotypes and subtypes, that can control HCV infection without the emergence of drug-resistant strains. The near future may see more protease inhibitors added to current regimens and other direct-acting antivirals possibly replacing old treatment components. As is true of HIV, a vaccine for HCV will be difficult to develop; but in the meantime, new drug combinations will be created with a goal of sustained virologic response rates nearing 100% and ever-shorter treatment regimens.^37,58

CONCLUSION

Since signs or symptoms are often not seen in patients infected with hepatitis C, it is important for primary care providers to question patients regarding known risk factors. At-risk patients should be screened using antibody testing, followed by confirmation of any positive results by HCV RNA testing. The patient's HCV genotype must be identified next, as it plays a key role in the therapeutic decisions to be made.

Because HCV therapy is complex, it is best managed by specialists who are experienced in all the aspects of each patient's regimen and who remain abreast of new therapeutic developments. Nevertheless, primary care providers can serve their patients well by acting as knowledgeable, supportive members of the health care team, accompanying their patients through the challenges of treatment and follow-up.

Infantile hypertrophic pyloric stenosis (IHPS) is a common yet treatable condition in young infants, characterized by forceful vomiting after feeding as a result of hypertrophy of the pyloric muscle. Without proper diagnosis and surgical intervention, IHPS can eventually lead to dehydration, weight loss, and electrolyte disturbances, including the classic finding of hypochloremic alkalosis.^1,2

IHPS occurs in two to four of every 1,000 births and is most common among white male infants.^3,4 It develops between the first three to five weeks of life but rarely after age 12 weeks.^1,2,5 IHPS is characterized by hypertrophy of the pyloric muscle (see figure), which eventually leads to gastric outlet obstruction.^6,7

Because IHPS presents with symptoms that resemble those associated with other gastrointestinal disturbances, such as gastroesophageal reflux disease (GERD), it can be misdiagnosed in its early stages.¹ Once it is identified, however, surgical correction by pyloromyotomy is considered curative, with a very low mortality rate (ie, 0.1%) and incidence recurrence in only 1% of patients. Typically, treated infants recover quickly and can begin feeding within hours after surgery.^3,8

Although the etiology of IHPS remains unknown, providers can quickly recognize the signs and symptoms of IHPS in order for surgical treatment to be scheduled in a timely manner.

PATIENT PRESENTATION
Typically, an infant with IHPS will have a period of normal feeding for the first two to three weeks of life, followed by onset of nonbilious vomiting soon after feeding. Vomiting may become increasingly frequent and forceful—possibly described as “projectile.” Despite stomach distention, affected infants seem to have an insatiable appetite and may cry inconsolably. Depending on the duration of symptoms, patients may suffer significant weight loss, even falling below birth weight. In severe cases, a scaphoid abdomen and protruding ribcage may be present.^1,2

Atypical Presentations
Premature infants with IHPS and those with certain medical or surgical conditions may present atypically. Vomiting may be less forceful, and the classic finding of visible gastric peristalsis may or may not be present.⁹ Researchers have documented cases in which hospitalized premature infants had nonprojectile vomiting, weight loss, and lethargy that were erroneously attributed to sepsis. IHPS should have been considered over sepsis when the infants’ clinical condition improved rapidly with rehydration, and when metabolic alkalosis (rather than acidosis) was identified.^1,10,11

Projectile vomiting may not occur in infants with congenital anomalies that affect swallowing, such as cleft lip/palate or central nervous system disturbances. In infants who have recently undergone gastrointestinal (GI) surgery, IHPS may be misdiagnosed as adhesions or obstruction at an anastomotic site.^1,10

RISK FACTORS
Despite the fact that IHPS is a relatively common condition, the etiology remains unknown. Research findings indicate that IHPS is not present at birth. Several hypotheses exist about potential risk factors, including genetics, use of macrolide antibiotics, and mechanical or environmental factors.⁶ IHPS has been associated with certain genetic conditions, including Cornelia de Lange syndrome and Smith-Lemli-Opitz syndrome, as well as chromosomal abnormalities, such as the translocation of chromosomes 8 and 17, and partial trisomy of chromosome 9.^6,12

According to Chung,¹³ additional research has implicated the genetic loci IHPS1, also known as nitric oxide synthase 1 (NOS1), which encodes the gene for neuronal nitric oxide synthase (nNOS). This is the key enzyme for production of nitric oxide, which mediates relaxation of the pyloric smooth muscle.¹³

In a study by Mahon et al,¹² an increased risk for IHPS was confirmed in young infants for whom systemic erythromycin had been prescribed as prophylactic treatment for pertussis. This may result from the agent’s motilin-like effects on antral smooth-muscle function.¹³

Mechanical defects, such as abnormal innervation of the pyloric muscle and neonatal hypergastrinemia and hyperacidity, have also been implicated.⁶ Infant sleeping position has been investigated as a possible environmental factor in the development of IHPS, correlating the decline in sudden infant death syndrome (attributed to decreased prone sleep position) with a decline in IHPS in recent years. However, no conclusive evidence has been shown to support this hypothesis.¹³

DIFFERENTIAL DIAGNOSIS
Typically, infants with nonbilious vomiting have either IHPS or GERD. Two factors to consider when evaluating the infant are its age and whether emesis is bilious or nonbilious. IHPS rarely causes bilious vomiting and most frequently occurs in infants between ages 3 and 6 weeks. Other GI disturbances that cause nonbilious emesis include adrenal crisis, gastroenteritis, pylorospasm, hiatal hernia, and preampullary duodenal stenosis.² Malrotation or midgut volvulus may also be considered in the differential¹⁴ (see table^1,2,14-16).

DIAGNOSIS
The diagnosis of IHPS is often made based on the history and physical exam. Imaging studies and labs can confirm the diagnosis, and surgery is usually deferred until dehydration has been addressed and any electrolyte disturbances corrected.^1,17

Physical Examination
The infant may appear underweight and dehydrated, with visible peristaltic waves across the upper abdomen prior to emesis. Severe illness may be indicated in an underweight infant with the classic scaphoid abdomen.¹⁸

Palpation of an olive-shaped mass in the upper left quadrant of the epigastric region is pathognomonic for IHPS; the mass may be found more easily after emesis has occurred.¹⁹ To facilitate palpation, the hips can first be flexed to relax the abdominal wall. Next, the examiner should palpate gently for the “olive” in the space midway between the umbilicus and the xiphoid, between the two rectus muscles.³ All other findings in the physical exam should be within normal limits.

Imaging and Laboratory

Studies
An experienced provider can make a diagnosis of IHPS based on clinical examination alone in 60% to 80% of cases.²⁰ However, most surgeons require the diagnosis to be confirmed with one of the following imaging studies before surgery.¹⁹

The diagnosis of IHPS can be confirmed by an upper GI series, but this is not commonly ordered as the primary diagnostic study. Ultrasound has become the modality of choice⁹; it can be used to quantify the size of an elongated, thickened pyloric muscle. The hypertrophied pylorus ranges in length from 14 to 16 mm, with thickness measuring more than 3.0 to 3.5 mm.^1,19,21

An upper GI contrast study is rarely used for diagnosis of IHPS, but when this test is ordered to detect other gastrointestinal disease processes (eg, malrotation), IHPS may be identified incidentally.¹⁹ During an upper GI study, contrast material is propelled through the pyloric mucosa, and the string sign or the double-track sign may be visualized, revealing the mucosal filling defect.²

Abdominal x-ray may reveal a dilated stomach or a blockage, with a possible finding of gas in the gastric bubble but extending no further into the intestine.¹⁹

A study by Hernanz-Schulman² was conducted to quantify the sensitivities and specificities associated with different diagnostic tools and the clinician’s experience and proficiency in using them. According to this study, palpation by a surgeon has a sensitivity of 31% to 99% and a specificity of 85% to 99% for detection of the pathognomonic olive-shaped mass. Ultrasound performed by an experienced technician has 97% to 100% sensitivity and 99% to 100% specificity for detecting IHPS. An upper GI series has 90% to 100% sensitivity and 99.5% specificity.

Venous blood gas and electrolyte levels are both helpful in making a diagnosis of IHPS.^19,22 In a study by Oakley and Barnett,²² the following lab values were found useful in confirming the presence of pyloric stenosis: pH > 7.45; chloride 3 mEq/L. Sodium and potassium deficits may also be present.^2,22

Before treatment is considered, the degree of dehydration must be determined by clinical examination and urinary output, as well as serum bicarbonate and chloride levels.³ Other laboratory tests to be ordered include urinalysis and a complete blood count (including platelets).

TREATMENT/MANAGEMENT
Initial management of vomiting in children should begin with fluid replacement if the patient appears dehydrated or if lab findings suggest an electrolyte imbalance. If surgery is later deemed necessary, this will reduce the risk for postoperative apnea.^1,23

If IHPS is suspected, a pediatric surgery consult should be obtained. Before anesthesia is considered, serum bicarbonate should be measured with results no higher than 28 mEq/L, and the serum chloride level should be at least 100 mEq/L.³ Imaging, such as ultrasound or the upper GI series, may be ordered to confirm the diagnosis.

Surgical correction by a pyloromyotomy is curative. Presurgical gastric decompression via nasogastric tube placement will reduce the risk for postoperative vomiting and gastritis.²⁰

Surgery
Although a variety of nonsurgical interventions, including oral and IV atropine and balloon dilation, have been described in the literature,^3,24-26 the preferred treatment for IHPS is surgical intervention. Surgical correction has been so consistently successful (that is, provided the procedure is performed by a pediatric surgeon or other surgeon with appropriate experience³) that the treatment of choice for IHPS is the Ramstedt pyloromyotomy, which was first performed in 1912.^6,27,28

Although the approach may differ based on the individual surgeon’s preference, the pyloric muscle is pulled through an incision in the abdominal wall. A longitudinal incision is made through the muscle with blunt dissection to the submucosa on the anterior surface of the pylorus. The pylorus is then returned to the abdominal cavity, and the abdominal incision is sutured.^3,20

The laparoscopic approach, first described in the literature in the mid-1990s,²⁹ is gaining popularity among surgeons, although recent studies have demonstrated that open and laparoscopic procedures are comparably safe and effective for the management of IHPS.^30-33 Results from a recent study by Jia et al³⁰ indicate that the laparoscopic approach results in reduced postoperative emesis, shorter length of hospital stay, and shorter recovery times; Hall et al³¹ emphasize the advantages of laparoscopic pyloromyotomy and recommend it over open surgery in facilities with experienced surgeons.

In follow-up ultrasound studies, hypertrophy of the pyloric muscle was reportedly resolved between two and 12 weeks after pyloromyotomy.³⁴

Postoperative Care
The gastric tube can be removed and oral fluids reintroduced slowly at the surgeon’s discretion, between 8 and 12 hours after surgery. Postoperative vomiting is common (occurring in up to 80% of patients) but should resolve within 24 hours. Mild emesis should not delay the refeeding schedule.³

Patients should be evaluated by the surgeon one to two weeks following surgery unless the infant shows signs of infection (ie, fever, erythema, edema, bleeding, purulent drainage, excess pain, decreased fluid or nutritional intake). Follow-up imaging and laboratory studies are not indicated in an otherwise healthy infant.²⁰

CONCLUSION
Early detection of IHPS, a condition characterized by hypertrophy of the pyloric muscle that results in gastric obstruction and projectile vomiting, can prevent complications of dehydration, malnutrition, and electrolyte disturbances. Surgery by open or laparoscopic pyloromyotomy is curative. Knowing the key physical exam findings, laboratory values, and typical patient history in IHPS enhances the clinician’s ability to make a timely diagnosis.

REFERENCES
1. Olivé AP, Endom EE. Infantile hypertrophic pyloric stenosis (2011). www.uptodate.com/contents/infan tile-hypertrophic-pyloric-stenosis. Accessed August 20, 2012.

2. Hernanz-Schulman M. Infantile hypertrophic pyloric stenosis. Radiology. 2003;227(2):319-331.

3. Aspelund G, Langer JC. Current management of hypertrophic pyloric stenosis. Semin Pediatr Surg. 2007;16(1):27-33.

4. To T, Wajja A, Wales PW, Langer JC. Population demographic indicators associated with incidence of pyloric stenosis. Arch Pediatr Adolesc Med. 2005;159(6):520-525.

5. MacMahon B. The continuing enigma of pyloric stenosis of infancy: a review. Epidemiology. 2006; 17(2):195-201.

6. Panteli C. New insights into the pathogenesis of infantile pyloric stenosis. Pediatr Surg Int. 2009;25 (12):1043-1052.

7. Stone CK, Humphries RL, eds. Current Medical Diagnosis and Treatment: Emergency Medicine. 7th ed. Chapter 50. Pediatric emergencies (2008). http://accessmedicine.com/resourceTOC.aspx?resource ID=718. Accessed August 20, 2012.

8. Hulka F, Harrison MW, Campbell TJ, Campbell JR. Complications of pyloromyotomy for infantile hypertrophic pyloric stenosis. Am J Surg. 1997;173 (5):450-452.

9. Shaoul R, Enav B, Steiner Z, et al. Clinical presentation of pyloric stenosis: the change is in our hands. Isr Med Assoc J. 2004;6(3):134-137.

10. Weinstein MM, Seibert JJ, Ehrenberg A. Six atypical presentations of congenital hypertrophic pyloric stenosis. Clin Pediatr. 1979;18(2):120-122.

11. Eyal O, Asia A, Yorgenson U, et al. Atypical infantile hypertrophic pyloric stenosis [in Hebrew]. Harefuah. 1999;136(2):113-114, 175.

12. Mahon BE, Rosenman MB, Kleiman MB. Maternal and infant use of erythromycin and other macrolide antibiotics as risk factors for infantile hypertrophic pyloric stenosis. J Pediatr. 2001;139(3):380-384.

13. Chung E. Infantile hypertrophic pyloric stenosis: genes and environment. Arch Dis Child. 2008;93 (12):1003-1004.

14. Gilbertson-Dahdal DL, Dutta S, Varich LJ, Barth RA. Neonatal malrotation with midgut volvulus mimicking duodenal atresia. AJR Am J Roentgenol. 2009;192(5):1269-1271.

15. Schmedel W, Ashe L, Kuznicki K. A 24-day-old child with projectile vomiting. J Emerg Nurs. 2009; 35(2):163-164.

16. Iijima T, Okamatsu T, Matsumura M, Yatsuzuka M. Hypertrophic pyloric stenosis associated with hiatal hernia. J Pediatr Surg. 1996;31(2):277-279.

17. Nakayama DK, Taylor LA. Hypertrophic pyloric stenosis in infancy: an analysis of treatment outcome. N C Med J. 1998;59(5):310-313.

18. Irish MS, Pearl RH, Caty M, Glick PL. The approach to common abdominal diagnoses in infants and children. Pediatr Clin North Am. 1998; 45(4):729-772.

19. Askew N. An overview of infantile hypertrophic pyloric stenosis: literature review. Paediatric Nurs. 2010;22(8):27-30.

20. Rudolph CD. Infantile hypertrophic pyloric stenosis. In: Rudolph CD, Rudolph AM, eds. Rudolph’s Pediatrics. 21st ed. New York, NY: McGraw-Hill; 2002:1402-1403.

21. Hallam D, Hansen B, Bødker B, et al. Pyloric size in normal infants and in infants suspected of having hypertrophic pyloric stenosis. Acta Radiol. 2005;36(3):261.

22. Oakley EA, Barnett PL. Is acid base determination an accurate predictor of pyloric stenosis? J Paediatr Child Health. 2000;36(6):587-589.

23. Steven IM, Allen TH, Sweeney DB. Congenital hypertrophic pyloric stenosis: the anaesthetist’s view. Anaesth Intensive Care. 1973;1(6):544-546.

24. Singh UK, Kumar R, Prasad R. Oral atropine sulfate for infantile hypertrophic pyloric stenosis. Indian Pediatr. 2005;42(5):473-476.

25. Nagita A, Yamaguchi J, Amemoto K, et al. Management and ultrasonographic appearance of infantile hypertrophic pyloric stenosis with intravenous atropine sulfate. J Pediatr Gastroenterol Nutr. 1996;23(2):172-177.

26. Ogawa Y, Higashimoto U, Nishijima E, et al. Successful endoscopic balloon dilatation for hypertrophic pyloric stenosis. J Pediatr Surg. 1996;31(12):1712-1714.

27. Langer JC, To T. Does pediatric surgical specialty training affect outcome after Ramstedt pyloromyotomy? A population-based study. Pediatrics. 2004;113(5):1342-1347.

28. Pollock WF, Norris WJ. Dr. Conrad Ramstedt and pyloromyotomy. Surgery. 1957;42(5):966-970.

29. Najmaldin A, Tan HL. Early experience with laparoscopic pyloromyotomy for infantile hypertrophic pyloric stenosis. J Pediatr Surg. 1995;30(1):37-38.

30. Jia WQ, Tian JH, Yang KH, et al. Open versus laparoscopic pyloromyotomy for pyloric stenosis: a meta-analysis of randomized controlled trials. Eur J Pediatr Surg. 2011;21(2):77-81.

31. Hall NJ, Pacilli M, Eaton S, et al. Recovery after open versus laparoscopic pyloromyotomy for pyloric stenosis: a double-blind multicentre randomised controlled trial. Lancet. 2009;373(9661):390-398.

32. Adibe OO, Nichol PF, Flake AAW, Mattei P. Comparison of outcomes after laparoscopic and open pyloromyotomy at a high-volume pediatric teaching hospital. J Pediatr Surg. 2006;41(10):1676-1678.

33. St. Peter SD, Holcomb GW, Calkins CM, et al. Open versus laparoscopic pyloromyotomy for pyloric stenosis: a prospective, randomized trial. Ann Surg. 2006;244(3):363-370.

34. Okorie NM, Dickson JA, Carver RA, Steiner GM. What happens to the pylorus after pyloromyotomy? Arch Dis Child. 1988;63(11):1339-1341.

Infantile hypertrophic pyloric stenosis (IHPS) is a common yet treatable condition in young infants, characterized by forceful vomiting after feeding as a result of hypertrophy of the pyloric muscle. Without proper diagnosis and surgical intervention, IHPS can eventually lead to dehydration, weight loss, and electrolyte disturbances, including the classic finding of hypochloremic alkalosis.^1,2

IHPS occurs in two to four of every 1,000 births and is most common among white male infants.^3,4 It develops between the first three to five weeks of life but rarely after age 12 weeks.^1,2,5 IHPS is characterized by hypertrophy of the pyloric muscle (see figure), which eventually leads to gastric outlet obstruction.^6,7

Because IHPS presents with symptoms that resemble those associated with other gastrointestinal disturbances, such as gastroesophageal reflux disease (GERD), it can be misdiagnosed in its early stages.¹ Once it is identified, however, surgical correction by pyloromyotomy is considered curative, with a very low mortality rate (ie, 0.1%) and incidence recurrence in only 1% of patients. Typically, treated infants recover quickly and can begin feeding within hours after surgery.^3,8

Although the etiology of IHPS remains unknown, providers can quickly recognize the signs and symptoms of IHPS in order for surgical treatment to be scheduled in a timely manner.

PATIENT PRESENTATION
Typically, an infant with IHPS will have a period of normal feeding for the first two to three weeks of life, followed by onset of nonbilious vomiting soon after feeding. Vomiting may become increasingly frequent and forceful—possibly described as “projectile.” Despite stomach distention, affected infants seem to have an insatiable appetite and may cry inconsolably. Depending on the duration of symptoms, patients may suffer significant weight loss, even falling below birth weight. In severe cases, a scaphoid abdomen and protruding ribcage may be present.^1,2

Atypical Presentations
Premature infants with IHPS and those with certain medical or surgical conditions may present atypically. Vomiting may be less forceful, and the classic finding of visible gastric peristalsis may or may not be present.⁹ Researchers have documented cases in which hospitalized premature infants had nonprojectile vomiting, weight loss, and lethargy that were erroneously attributed to sepsis. IHPS should have been considered over sepsis when the infants’ clinical condition improved rapidly with rehydration, and when metabolic alkalosis (rather than acidosis) was identified.^1,10,11

Projectile vomiting may not occur in infants with congenital anomalies that affect swallowing, such as cleft lip/palate or central nervous system disturbances. In infants who have recently undergone gastrointestinal (GI) surgery, IHPS may be misdiagnosed as adhesions or obstruction at an anastomotic site.^1,10

RISK FACTORS
Despite the fact that IHPS is a relatively common condition, the etiology remains unknown. Research findings indicate that IHPS is not present at birth. Several hypotheses exist about potential risk factors, including genetics, use of macrolide antibiotics, and mechanical or environmental factors.⁶ IHPS has been associated with certain genetic conditions, including Cornelia de Lange syndrome and Smith-Lemli-Opitz syndrome, as well as chromosomal abnormalities, such as the translocation of chromosomes 8 and 17, and partial trisomy of chromosome 9.^6,12

According to Chung,¹³ additional research has implicated the genetic loci IHPS1, also known as nitric oxide synthase 1 (NOS1), which encodes the gene for neuronal nitric oxide synthase (nNOS). This is the key enzyme for production of nitric oxide, which mediates relaxation of the pyloric smooth muscle.¹³

In a study by Mahon et al,¹² an increased risk for IHPS was confirmed in young infants for whom systemic erythromycin had been prescribed as prophylactic treatment for pertussis. This may result from the agent’s motilin-like effects on antral smooth-muscle function.¹³

Mechanical defects, such as abnormal innervation of the pyloric muscle and neonatal hypergastrinemia and hyperacidity, have also been implicated.⁶ Infant sleeping position has been investigated as a possible environmental factor in the development of IHPS, correlating the decline in sudden infant death syndrome (attributed to decreased prone sleep position) with a decline in IHPS in recent years. However, no conclusive evidence has been shown to support this hypothesis.¹³

DIFFERENTIAL DIAGNOSIS
Typically, infants with nonbilious vomiting have either IHPS or GERD. Two factors to consider when evaluating the infant are its age and whether emesis is bilious or nonbilious. IHPS rarely causes bilious vomiting and most frequently occurs in infants between ages 3 and 6 weeks. Other GI disturbances that cause nonbilious emesis include adrenal crisis, gastroenteritis, pylorospasm, hiatal hernia, and preampullary duodenal stenosis.² Malrotation or midgut volvulus may also be considered in the differential¹⁴ (see table^1,2,14-16).

DIAGNOSIS
The diagnosis of IHPS is often made based on the history and physical exam. Imaging studies and labs can confirm the diagnosis, and surgery is usually deferred until dehydration has been addressed and any electrolyte disturbances corrected.^1,17

Physical Examination
The infant may appear underweight and dehydrated, with visible peristaltic waves across the upper abdomen prior to emesis. Severe illness may be indicated in an underweight infant with the classic scaphoid abdomen.¹⁸

Palpation of an olive-shaped mass in the upper left quadrant of the epigastric region is pathognomonic for IHPS; the mass may be found more easily after emesis has occurred.¹⁹ To facilitate palpation, the hips can first be flexed to relax the abdominal wall. Next, the examiner should palpate gently for the “olive” in the space midway between the umbilicus and the xiphoid, between the two rectus muscles.³ All other findings in the physical exam should be within normal limits.

Imaging and Laboratory

Studies
An experienced provider can make a diagnosis of IHPS based on clinical examination alone in 60% to 80% of cases.²⁰ However, most surgeons require the diagnosis to be confirmed with one of the following imaging studies before surgery.¹⁹

The diagnosis of IHPS can be confirmed by an upper GI series, but this is not commonly ordered as the primary diagnostic study. Ultrasound has become the modality of choice⁹; it can be used to quantify the size of an elongated, thickened pyloric muscle. The hypertrophied pylorus ranges in length from 14 to 16 mm, with thickness measuring more than 3.0 to 3.5 mm.^1,19,21

An upper GI contrast study is rarely used for diagnosis of IHPS, but when this test is ordered to detect other gastrointestinal disease processes (eg, malrotation), IHPS may be identified incidentally.¹⁹ During an upper GI study, contrast material is propelled through the pyloric mucosa, and the string sign or the double-track sign may be visualized, revealing the mucosal filling defect.²

Abdominal x-ray may reveal a dilated stomach or a blockage, with a possible finding of gas in the gastric bubble but extending no further into the intestine.¹⁹

A study by Hernanz-Schulman² was conducted to quantify the sensitivities and specificities associated with different diagnostic tools and the clinician’s experience and proficiency in using them. According to this study, palpation by a surgeon has a sensitivity of 31% to 99% and a specificity of 85% to 99% for detection of the pathognomonic olive-shaped mass. Ultrasound performed by an experienced technician has 97% to 100% sensitivity and 99% to 100% specificity for detecting IHPS. An upper GI series has 90% to 100% sensitivity and 99.5% specificity.

Venous blood gas and electrolyte levels are both helpful in making a diagnosis of IHPS.^19,22 In a study by Oakley and Barnett,²² the following lab values were found useful in confirming the presence of pyloric stenosis: pH > 7.45; chloride 3 mEq/L. Sodium and potassium deficits may also be present.^2,22

Before treatment is considered, the degree of dehydration must be determined by clinical examination and urinary output, as well as serum bicarbonate and chloride levels.³ Other laboratory tests to be ordered include urinalysis and a complete blood count (including platelets).

TREATMENT/MANAGEMENT
Initial management of vomiting in children should begin with fluid replacement if the patient appears dehydrated or if lab findings suggest an electrolyte imbalance. If surgery is later deemed necessary, this will reduce the risk for postoperative apnea.^1,23

If IHPS is suspected, a pediatric surgery consult should be obtained. Before anesthesia is considered, serum bicarbonate should be measured with results no higher than 28 mEq/L, and the serum chloride level should be at least 100 mEq/L.³ Imaging, such as ultrasound or the upper GI series, may be ordered to confirm the diagnosis.

Surgical correction by a pyloromyotomy is curative. Presurgical gastric decompression via nasogastric tube placement will reduce the risk for postoperative vomiting and gastritis.²⁰

Surgery
Although a variety of nonsurgical interventions, including oral and IV atropine and balloon dilation, have been described in the literature,^3,24-26 the preferred treatment for IHPS is surgical intervention. Surgical correction has been so consistently successful (that is, provided the procedure is performed by a pediatric surgeon or other surgeon with appropriate experience³) that the treatment of choice for IHPS is the Ramstedt pyloromyotomy, which was first performed in 1912.^6,27,28

Although the approach may differ based on the individual surgeon’s preference, the pyloric muscle is pulled through an incision in the abdominal wall. A longitudinal incision is made through the muscle with blunt dissection to the submucosa on the anterior surface of the pylorus. The pylorus is then returned to the abdominal cavity, and the abdominal incision is sutured.^3,20

The laparoscopic approach, first described in the literature in the mid-1990s,²⁹ is gaining popularity among surgeons, although recent studies have demonstrated that open and laparoscopic procedures are comparably safe and effective for the management of IHPS.^30-33 Results from a recent study by Jia et al³⁰ indicate that the laparoscopic approach results in reduced postoperative emesis, shorter length of hospital stay, and shorter recovery times; Hall et al³¹ emphasize the advantages of laparoscopic pyloromyotomy and recommend it over open surgery in facilities with experienced surgeons.

In follow-up ultrasound studies, hypertrophy of the pyloric muscle was reportedly resolved between two and 12 weeks after pyloromyotomy.³⁴

Postoperative Care
The gastric tube can be removed and oral fluids reintroduced slowly at the surgeon’s discretion, between 8 and 12 hours after surgery. Postoperative vomiting is common (occurring in up to 80% of patients) but should resolve within 24 hours. Mild emesis should not delay the refeeding schedule.³

Patients should be evaluated by the surgeon one to two weeks following surgery unless the infant shows signs of infection (ie, fever, erythema, edema, bleeding, purulent drainage, excess pain, decreased fluid or nutritional intake). Follow-up imaging and laboratory studies are not indicated in an otherwise healthy infant.²⁰

CONCLUSION
Early detection of IHPS, a condition characterized by hypertrophy of the pyloric muscle that results in gastric obstruction and projectile vomiting, can prevent complications of dehydration, malnutrition, and electrolyte disturbances. Surgery by open or laparoscopic pyloromyotomy is curative. Knowing the key physical exam findings, laboratory values, and typical patient history in IHPS enhances the clinician’s ability to make a timely diagnosis.

REFERENCES
1. Olivé AP, Endom EE. Infantile hypertrophic pyloric stenosis (2011). www.uptodate.com/contents/infan tile-hypertrophic-pyloric-stenosis. Accessed August 20, 2012.

2. Hernanz-Schulman M. Infantile hypertrophic pyloric stenosis. Radiology. 2003;227(2):319-331.

3. Aspelund G, Langer JC. Current management of hypertrophic pyloric stenosis. Semin Pediatr Surg. 2007;16(1):27-33.

4. To T, Wajja A, Wales PW, Langer JC. Population demographic indicators associated with incidence of pyloric stenosis. Arch Pediatr Adolesc Med. 2005;159(6):520-525.

5. MacMahon B. The continuing enigma of pyloric stenosis of infancy: a review. Epidemiology. 2006; 17(2):195-201.

6. Panteli C. New insights into the pathogenesis of infantile pyloric stenosis. Pediatr Surg Int. 2009;25 (12):1043-1052.

7. Stone CK, Humphries RL, eds. Current Medical Diagnosis and Treatment: Emergency Medicine. 7th ed. Chapter 50. Pediatric emergencies (2008). http://accessmedicine.com/resourceTOC.aspx?resource ID=718. Accessed August 20, 2012.

8. Hulka F, Harrison MW, Campbell TJ, Campbell JR. Complications of pyloromyotomy for infantile hypertrophic pyloric stenosis. Am J Surg. 1997;173 (5):450-452.

9. Shaoul R, Enav B, Steiner Z, et al. Clinical presentation of pyloric stenosis: the change is in our hands. Isr Med Assoc J. 2004;6(3):134-137.

10. Weinstein MM, Seibert JJ, Ehrenberg A. Six atypical presentations of congenital hypertrophic pyloric stenosis. Clin Pediatr. 1979;18(2):120-122.

11. Eyal O, Asia A, Yorgenson U, et al. Atypical infantile hypertrophic pyloric stenosis [in Hebrew]. Harefuah. 1999;136(2):113-114, 175.

12. Mahon BE, Rosenman MB, Kleiman MB. Maternal and infant use of erythromycin and other macrolide antibiotics as risk factors for infantile hypertrophic pyloric stenosis. J Pediatr. 2001;139(3):380-384.

13. Chung E. Infantile hypertrophic pyloric stenosis: genes and environment. Arch Dis Child. 2008;93 (12):1003-1004.

14. Gilbertson-Dahdal DL, Dutta S, Varich LJ, Barth RA. Neonatal malrotation with midgut volvulus mimicking duodenal atresia. AJR Am J Roentgenol. 2009;192(5):1269-1271.

15. Schmedel W, Ashe L, Kuznicki K. A 24-day-old child with projectile vomiting. J Emerg Nurs. 2009; 35(2):163-164.

16. Iijima T, Okamatsu T, Matsumura M, Yatsuzuka M. Hypertrophic pyloric stenosis associated with hiatal hernia. J Pediatr Surg. 1996;31(2):277-279.

17. Nakayama DK, Taylor LA. Hypertrophic pyloric stenosis in infancy: an analysis of treatment outcome. N C Med J. 1998;59(5):310-313.

18. Irish MS, Pearl RH, Caty M, Glick PL. The approach to common abdominal diagnoses in infants and children. Pediatr Clin North Am. 1998; 45(4):729-772.

19. Askew N. An overview of infantile hypertrophic pyloric stenosis: literature review. Paediatric Nurs. 2010;22(8):27-30.

20. Rudolph CD. Infantile hypertrophic pyloric stenosis. In: Rudolph CD, Rudolph AM, eds. Rudolph’s Pediatrics. 21st ed. New York, NY: McGraw-Hill; 2002:1402-1403.

21. Hallam D, Hansen B, Bødker B, et al. Pyloric size in normal infants and in infants suspected of having hypertrophic pyloric stenosis. Acta Radiol. 2005;36(3):261.

22. Oakley EA, Barnett PL. Is acid base determination an accurate predictor of pyloric stenosis? J Paediatr Child Health. 2000;36(6):587-589.

23. Steven IM, Allen TH, Sweeney DB. Congenital hypertrophic pyloric stenosis: the anaesthetist’s view. Anaesth Intensive Care. 1973;1(6):544-546.

24. Singh UK, Kumar R, Prasad R. Oral atropine sulfate for infantile hypertrophic pyloric stenosis. Indian Pediatr. 2005;42(5):473-476.

25. Nagita A, Yamaguchi J, Amemoto K, et al. Management and ultrasonographic appearance of infantile hypertrophic pyloric stenosis with intravenous atropine sulfate. J Pediatr Gastroenterol Nutr. 1996;23(2):172-177.

26. Ogawa Y, Higashimoto U, Nishijima E, et al. Successful endoscopic balloon dilatation for hypertrophic pyloric stenosis. J Pediatr Surg. 1996;31(12):1712-1714.

27. Langer JC, To T. Does pediatric surgical specialty training affect outcome after Ramstedt pyloromyotomy? A population-based study. Pediatrics. 2004;113(5):1342-1347.

28. Pollock WF, Norris WJ. Dr. Conrad Ramstedt and pyloromyotomy. Surgery. 1957;42(5):966-970.

29. Najmaldin A, Tan HL. Early experience with laparoscopic pyloromyotomy for infantile hypertrophic pyloric stenosis. J Pediatr Surg. 1995;30(1):37-38.

30. Jia WQ, Tian JH, Yang KH, et al. Open versus laparoscopic pyloromyotomy for pyloric stenosis: a meta-analysis of randomized controlled trials. Eur J Pediatr Surg. 2011;21(2):77-81.

31. Hall NJ, Pacilli M, Eaton S, et al. Recovery after open versus laparoscopic pyloromyotomy for pyloric stenosis: a double-blind multicentre randomised controlled trial. Lancet. 2009;373(9661):390-398.

32. Adibe OO, Nichol PF, Flake AAW, Mattei P. Comparison of outcomes after laparoscopic and open pyloromyotomy at a high-volume pediatric teaching hospital. J Pediatr Surg. 2006;41(10):1676-1678.

33. St. Peter SD, Holcomb GW, Calkins CM, et al. Open versus laparoscopic pyloromyotomy for pyloric stenosis: a prospective, randomized trial. Ann Surg. 2006;244(3):363-370.

34. Okorie NM, Dickson JA, Carver RA, Steiner GM. What happens to the pylorus after pyloromyotomy? Arch Dis Child. 1988;63(11):1339-1341.

Infantile hypertrophic pyloric stenosis (IHPS) is a common yet treatable condition in young infants, characterized by forceful vomiting after feeding as a result of hypertrophy of the pyloric muscle. Without proper diagnosis and surgical intervention, IHPS can eventually lead to dehydration, weight loss, and electrolyte disturbances, including the classic finding of hypochloremic alkalosis.^1,2

IHPS occurs in two to four of every 1,000 births and is most common among white male infants.^3,4 It develops between the first three to five weeks of life but rarely after age 12 weeks.^1,2,5 IHPS is characterized by hypertrophy of the pyloric muscle (see figure), which eventually leads to gastric outlet obstruction.^6,7

Because IHPS presents with symptoms that resemble those associated with other gastrointestinal disturbances, such as gastroesophageal reflux disease (GERD), it can be misdiagnosed in its early stages.¹ Once it is identified, however, surgical correction by pyloromyotomy is considered curative, with a very low mortality rate (ie, 0.1%) and incidence recurrence in only 1% of patients. Typically, treated infants recover quickly and can begin feeding within hours after surgery.^3,8

Although the etiology of IHPS remains unknown, providers can quickly recognize the signs and symptoms of IHPS in order for surgical treatment to be scheduled in a timely manner.

PATIENT PRESENTATION
Typically, an infant with IHPS will have a period of normal feeding for the first two to three weeks of life, followed by onset of nonbilious vomiting soon after feeding. Vomiting may become increasingly frequent and forceful—possibly described as “projectile.” Despite stomach distention, affected infants seem to have an insatiable appetite and may cry inconsolably. Depending on the duration of symptoms, patients may suffer significant weight loss, even falling below birth weight. In severe cases, a scaphoid abdomen and protruding ribcage may be present.^1,2

Atypical Presentations
Premature infants with IHPS and those with certain medical or surgical conditions may present atypically. Vomiting may be less forceful, and the classic finding of visible gastric peristalsis may or may not be present.⁹ Researchers have documented cases in which hospitalized premature infants had nonprojectile vomiting, weight loss, and lethargy that were erroneously attributed to sepsis. IHPS should have been considered over sepsis when the infants’ clinical condition improved rapidly with rehydration, and when metabolic alkalosis (rather than acidosis) was identified.^1,10,11

Projectile vomiting may not occur in infants with congenital anomalies that affect swallowing, such as cleft lip/palate or central nervous system disturbances. In infants who have recently undergone gastrointestinal (GI) surgery, IHPS may be misdiagnosed as adhesions or obstruction at an anastomotic site.^1,10

RISK FACTORS
Despite the fact that IHPS is a relatively common condition, the etiology remains unknown. Research findings indicate that IHPS is not present at birth. Several hypotheses exist about potential risk factors, including genetics, use of macrolide antibiotics, and mechanical or environmental factors.⁶ IHPS has been associated with certain genetic conditions, including Cornelia de Lange syndrome and Smith-Lemli-Opitz syndrome, as well as chromosomal abnormalities, such as the translocation of chromosomes 8 and 17, and partial trisomy of chromosome 9.^6,12

According to Chung,¹³ additional research has implicated the genetic loci IHPS1, also known as nitric oxide synthase 1 (NOS1), which encodes the gene for neuronal nitric oxide synthase (nNOS). This is the key enzyme for production of nitric oxide, which mediates relaxation of the pyloric smooth muscle.¹³

In a study by Mahon et al,¹² an increased risk for IHPS was confirmed in young infants for whom systemic erythromycin had been prescribed as prophylactic treatment for pertussis. This may result from the agent’s motilin-like effects on antral smooth-muscle function.¹³

Mechanical defects, such as abnormal innervation of the pyloric muscle and neonatal hypergastrinemia and hyperacidity, have also been implicated.⁶ Infant sleeping position has been investigated as a possible environmental factor in the development of IHPS, correlating the decline in sudden infant death syndrome (attributed to decreased prone sleep position) with a decline in IHPS in recent years. However, no conclusive evidence has been shown to support this hypothesis.¹³

DIFFERENTIAL DIAGNOSIS
Typically, infants with nonbilious vomiting have either IHPS or GERD. Two factors to consider when evaluating the infant are its age and whether emesis is bilious or nonbilious. IHPS rarely causes bilious vomiting and most frequently occurs in infants between ages 3 and 6 weeks. Other GI disturbances that cause nonbilious emesis include adrenal crisis, gastroenteritis, pylorospasm, hiatal hernia, and preampullary duodenal stenosis.² Malrotation or midgut volvulus may also be considered in the differential¹⁴ (see table^1,2,14-16).

DIAGNOSIS
The diagnosis of IHPS is often made based on the history and physical exam. Imaging studies and labs can confirm the diagnosis, and surgery is usually deferred until dehydration has been addressed and any electrolyte disturbances corrected.^1,17

Physical Examination
The infant may appear underweight and dehydrated, with visible peristaltic waves across the upper abdomen prior to emesis. Severe illness may be indicated in an underweight infant with the classic scaphoid abdomen.¹⁸

Palpation of an olive-shaped mass in the upper left quadrant of the epigastric region is pathognomonic for IHPS; the mass may be found more easily after emesis has occurred.¹⁹ To facilitate palpation, the hips can first be flexed to relax the abdominal wall. Next, the examiner should palpate gently for the “olive” in the space midway between the umbilicus and the xiphoid, between the two rectus muscles.³ All other findings in the physical exam should be within normal limits.

Imaging and Laboratory

Studies
An experienced provider can make a diagnosis of IHPS based on clinical examination alone in 60% to 80% of cases.²⁰ However, most surgeons require the diagnosis to be confirmed with one of the following imaging studies before surgery.¹⁹

The diagnosis of IHPS can be confirmed by an upper GI series, but this is not commonly ordered as the primary diagnostic study. Ultrasound has become the modality of choice⁹; it can be used to quantify the size of an elongated, thickened pyloric muscle. The hypertrophied pylorus ranges in length from 14 to 16 mm, with thickness measuring more than 3.0 to 3.5 mm.^1,19,21

An upper GI contrast study is rarely used for diagnosis of IHPS, but when this test is ordered to detect other gastrointestinal disease processes (eg, malrotation), IHPS may be identified incidentally.¹⁹ During an upper GI study, contrast material is propelled through the pyloric mucosa, and the string sign or the double-track sign may be visualized, revealing the mucosal filling defect.²

Abdominal x-ray may reveal a dilated stomach or a blockage, with a possible finding of gas in the gastric bubble but extending no further into the intestine.¹⁹

A study by Hernanz-Schulman² was conducted to quantify the sensitivities and specificities associated with different diagnostic tools and the clinician’s experience and proficiency in using them. According to this study, palpation by a surgeon has a sensitivity of 31% to 99% and a specificity of 85% to 99% for detection of the pathognomonic olive-shaped mass. Ultrasound performed by an experienced technician has 97% to 100% sensitivity and 99% to 100% specificity for detecting IHPS. An upper GI series has 90% to 100% sensitivity and 99.5% specificity.

Venous blood gas and electrolyte levels are both helpful in making a diagnosis of IHPS.^19,22 In a study by Oakley and Barnett,²² the following lab values were found useful in confirming the presence of pyloric stenosis: pH > 7.45; chloride 3 mEq/L. Sodium and potassium deficits may also be present.^2,22

Before treatment is considered, the degree of dehydration must be determined by clinical examination and urinary output, as well as serum bicarbonate and chloride levels.³ Other laboratory tests to be ordered include urinalysis and a complete blood count (including platelets).

TREATMENT/MANAGEMENT
Initial management of vomiting in children should begin with fluid replacement if the patient appears dehydrated or if lab findings suggest an electrolyte imbalance. If surgery is later deemed necessary, this will reduce the risk for postoperative apnea.^1,23

If IHPS is suspected, a pediatric surgery consult should be obtained. Before anesthesia is considered, serum bicarbonate should be measured with results no higher than 28 mEq/L, and the serum chloride level should be at least 100 mEq/L.³ Imaging, such as ultrasound or the upper GI series, may be ordered to confirm the diagnosis.

Surgical correction by a pyloromyotomy is curative. Presurgical gastric decompression via nasogastric tube placement will reduce the risk for postoperative vomiting and gastritis.²⁰

Surgery
Although a variety of nonsurgical interventions, including oral and IV atropine and balloon dilation, have been described in the literature,^3,24-26 the preferred treatment for IHPS is surgical intervention. Surgical correction has been so consistently successful (that is, provided the procedure is performed by a pediatric surgeon or other surgeon with appropriate experience³) that the treatment of choice for IHPS is the Ramstedt pyloromyotomy, which was first performed in 1912.^6,27,28

Although the approach may differ based on the individual surgeon’s preference, the pyloric muscle is pulled through an incision in the abdominal wall. A longitudinal incision is made through the muscle with blunt dissection to the submucosa on the anterior surface of the pylorus. The pylorus is then returned to the abdominal cavity, and the abdominal incision is sutured.^3,20

The laparoscopic approach, first described in the literature in the mid-1990s,²⁹ is gaining popularity among surgeons, although recent studies have demonstrated that open and laparoscopic procedures are comparably safe and effective for the management of IHPS.^30-33 Results from a recent study by Jia et al³⁰ indicate that the laparoscopic approach results in reduced postoperative emesis, shorter length of hospital stay, and shorter recovery times; Hall et al³¹ emphasize the advantages of laparoscopic pyloromyotomy and recommend it over open surgery in facilities with experienced surgeons.

In follow-up ultrasound studies, hypertrophy of the pyloric muscle was reportedly resolved between two and 12 weeks after pyloromyotomy.³⁴

Postoperative Care
The gastric tube can be removed and oral fluids reintroduced slowly at the surgeon’s discretion, between 8 and 12 hours after surgery. Postoperative vomiting is common (occurring in up to 80% of patients) but should resolve within 24 hours. Mild emesis should not delay the refeeding schedule.³

Patients should be evaluated by the surgeon one to two weeks following surgery unless the infant shows signs of infection (ie, fever, erythema, edema, bleeding, purulent drainage, excess pain, decreased fluid or nutritional intake). Follow-up imaging and laboratory studies are not indicated in an otherwise healthy infant.²⁰

CONCLUSION
Early detection of IHPS, a condition characterized by hypertrophy of the pyloric muscle that results in gastric obstruction and projectile vomiting, can prevent complications of dehydration, malnutrition, and electrolyte disturbances. Surgery by open or laparoscopic pyloromyotomy is curative. Knowing the key physical exam findings, laboratory values, and typical patient history in IHPS enhances the clinician’s ability to make a timely diagnosis.

REFERENCES
1. Olivé AP, Endom EE. Infantile hypertrophic pyloric stenosis (2011). www.uptodate.com/contents/infan tile-hypertrophic-pyloric-stenosis. Accessed August 20, 2012.

2. Hernanz-Schulman M. Infantile hypertrophic pyloric stenosis. Radiology. 2003;227(2):319-331.

3. Aspelund G, Langer JC. Current management of hypertrophic pyloric stenosis. Semin Pediatr Surg. 2007;16(1):27-33.

4. To T, Wajja A, Wales PW, Langer JC. Population demographic indicators associated with incidence of pyloric stenosis. Arch Pediatr Adolesc Med. 2005;159(6):520-525.

5. MacMahon B. The continuing enigma of pyloric stenosis of infancy: a review. Epidemiology. 2006; 17(2):195-201.

6. Panteli C. New insights into the pathogenesis of infantile pyloric stenosis. Pediatr Surg Int. 2009;25 (12):1043-1052.

7. Stone CK, Humphries RL, eds. Current Medical Diagnosis and Treatment: Emergency Medicine. 7th ed. Chapter 50. Pediatric emergencies (2008). http://accessmedicine.com/resourceTOC.aspx?resource ID=718. Accessed August 20, 2012.

8. Hulka F, Harrison MW, Campbell TJ, Campbell JR. Complications of pyloromyotomy for infantile hypertrophic pyloric stenosis. Am J Surg. 1997;173 (5):450-452.

9. Shaoul R, Enav B, Steiner Z, et al. Clinical presentation of pyloric stenosis: the change is in our hands. Isr Med Assoc J. 2004;6(3):134-137.

10. Weinstein MM, Seibert JJ, Ehrenberg A. Six atypical presentations of congenital hypertrophic pyloric stenosis. Clin Pediatr. 1979;18(2):120-122.

11. Eyal O, Asia A, Yorgenson U, et al. Atypical infantile hypertrophic pyloric stenosis [in Hebrew]. Harefuah. 1999;136(2):113-114, 175.

12. Mahon BE, Rosenman MB, Kleiman MB. Maternal and infant use of erythromycin and other macrolide antibiotics as risk factors for infantile hypertrophic pyloric stenosis. J Pediatr. 2001;139(3):380-384.

13. Chung E. Infantile hypertrophic pyloric stenosis: genes and environment. Arch Dis Child. 2008;93 (12):1003-1004.

14. Gilbertson-Dahdal DL, Dutta S, Varich LJ, Barth RA. Neonatal malrotation with midgut volvulus mimicking duodenal atresia. AJR Am J Roentgenol. 2009;192(5):1269-1271.

15. Schmedel W, Ashe L, Kuznicki K. A 24-day-old child with projectile vomiting. J Emerg Nurs. 2009; 35(2):163-164.

16. Iijima T, Okamatsu T, Matsumura M, Yatsuzuka M. Hypertrophic pyloric stenosis associated with hiatal hernia. J Pediatr Surg. 1996;31(2):277-279.

17. Nakayama DK, Taylor LA. Hypertrophic pyloric stenosis in infancy: an analysis of treatment outcome. N C Med J. 1998;59(5):310-313.

18. Irish MS, Pearl RH, Caty M, Glick PL. The approach to common abdominal diagnoses in infants and children. Pediatr Clin North Am. 1998; 45(4):729-772.

19. Askew N. An overview of infantile hypertrophic pyloric stenosis: literature review. Paediatric Nurs. 2010;22(8):27-30.

20. Rudolph CD. Infantile hypertrophic pyloric stenosis. In: Rudolph CD, Rudolph AM, eds. Rudolph’s Pediatrics. 21st ed. New York, NY: McGraw-Hill; 2002:1402-1403.

21. Hallam D, Hansen B, Bødker B, et al. Pyloric size in normal infants and in infants suspected of having hypertrophic pyloric stenosis. Acta Radiol. 2005;36(3):261.

22. Oakley EA, Barnett PL. Is acid base determination an accurate predictor of pyloric stenosis? J Paediatr Child Health. 2000;36(6):587-589.

23. Steven IM, Allen TH, Sweeney DB. Congenital hypertrophic pyloric stenosis: the anaesthetist’s view. Anaesth Intensive Care. 1973;1(6):544-546.

24. Singh UK, Kumar R, Prasad R. Oral atropine sulfate for infantile hypertrophic pyloric stenosis. Indian Pediatr. 2005;42(5):473-476.

25. Nagita A, Yamaguchi J, Amemoto K, et al. Management and ultrasonographic appearance of infantile hypertrophic pyloric stenosis with intravenous atropine sulfate. J Pediatr Gastroenterol Nutr. 1996;23(2):172-177.

26. Ogawa Y, Higashimoto U, Nishijima E, et al. Successful endoscopic balloon dilatation for hypertrophic pyloric stenosis. J Pediatr Surg. 1996;31(12):1712-1714.

27. Langer JC, To T. Does pediatric surgical specialty training affect outcome after Ramstedt pyloromyotomy? A population-based study. Pediatrics. 2004;113(5):1342-1347.

28. Pollock WF, Norris WJ. Dr. Conrad Ramstedt and pyloromyotomy. Surgery. 1957;42(5):966-970.

29. Najmaldin A, Tan HL. Early experience with laparoscopic pyloromyotomy for infantile hypertrophic pyloric stenosis. J Pediatr Surg. 1995;30(1):37-38.

30. Jia WQ, Tian JH, Yang KH, et al. Open versus laparoscopic pyloromyotomy for pyloric stenosis: a meta-analysis of randomized controlled trials. Eur J Pediatr Surg. 2011;21(2):77-81.

31. Hall NJ, Pacilli M, Eaton S, et al. Recovery after open versus laparoscopic pyloromyotomy for pyloric stenosis: a double-blind multicentre randomised controlled trial. Lancet. 2009;373(9661):390-398.

32. Adibe OO, Nichol PF, Flake AAW, Mattei P. Comparison of outcomes after laparoscopic and open pyloromyotomy at a high-volume pediatric teaching hospital. J Pediatr Surg. 2006;41(10):1676-1678.

33. St. Peter SD, Holcomb GW, Calkins CM, et al. Open versus laparoscopic pyloromyotomy for pyloric stenosis: a prospective, randomized trial. Ann Surg. 2006;244(3):363-370.

34. Okorie NM, Dickson JA, Carver RA, Steiner GM. What happens to the pylorus after pyloromyotomy? Arch Dis Child. 1988;63(11):1339-1341.