1-Minute Consult

Yes, by using a pre-visit questionnaire that zeroes in on weight history, eating habits, and level of physical activity. This information will lay the foundation for effective weight loss counseling and interventions consistent with intensive behavioral therapy for obesity, reimbursable by Medicare.¹

See related editorial

More than one-third of US adults are obese.³ And even though the rate of obesity in adults has leveled off since 2009,³ more needs to be done to bend the arc of the national obesity trend. Clinicians tend to focus on the complications of obesity (coronary artery disease, type 2 diabetes, hypertension, hyperlipidemia) rather than on early identification and intervention of obesity itself.^4–6 A national study of outpatient visits showed that only 29% of visits by patients who were obese according to their body mass index (BMI) had a documented diagnosis of obesity, suggesting a profound under­diagnosis of obesity.⁷ According to one study, primary care doctors lack the level of comfort and counseling experience needed to provide obesity and weight loss counseling.⁸ Yet recent changes to Medicare reimbursement encourage obesity screening and management by covering up to 20 visits for intensive behavioral therapy to treat obesity.¹

We offer the following targeted approach to counseling, achievable within the context of a primary care visit and based on recent evidence, including the 2013 joint guidelines for the treatment of obesity of the American College of Cardiology, the American Heart Association Task Force on Practice Guidelines, and the Obesity Society.²

START WITH SCREENING

Measure the patient’s height and weight with the patient wearing light clothing and no shoes, and calculate the BMI as the weight in kilograms divided by the square of the height in meters. A BMI of 30 kg/m² or greater defines obesity.

OBTAIN AN OBESITY HISTORY

According to the 2013 joint guidelines,² when obtaining a thorough obesity history, the physician should do the following:

• Obtain information about weight the patient has gained and lost over time and previous weight loss efforts
• Ask the patient about eating habits, including number of meals per day, and the contents of a typical breakfast, lunch, and dinner; we recommend also asking about the number of daily beverages high in sugar
• Quantify the type and amount of physical activity performed within a specific time period.

This information can be obtained in advance of an office visit through either an electronic medical record portal or a pre-visit questionnaire (eg, http://onlinelibrary.wiley.com/doi/10.1038/oby.2002.205/full).

Also assess the patient’s risk of cardiovascular and obesity-related comorbidities. The waist circumference for patients with a BMI between 25 and 35 kg/m² provides additional information on risk: eg, a waist circumference greater than 88 cm for women and greater than 102 cm for men indicates increased cardiometabolic risk.²

SUGGEST SPECIFIC GOALS

Use a shared decision-making process to arrive at a set of incremental goals centered around the following evidence-based targets²:

• Weight loss: 3% to 5% of baseline weight within 6 months
• 6-month commitment to a weight loss intervention
• Exercise: at least 150 minutes of moderate aerobic activity per week
• More vegetables, fewer carbohydrates, and less protein, according to the American Diabetes Association’s “Create your plate” plan⁹
• Mediterranean diet.¹⁰

Use motivational interviewing techniques along with the obesity history to negotiate goals. Exercise-related goals should consider the patient’s cardiovascular and musculoskeletal comorbidities.

The most effective weight loss treatment consists of in-person consultations in which comprehensive lifestyle interventions are included. The components of an effective intervention (Table 1) include a reduced-calorie diet, aerobic physical activity, and behavioral strategies to meaningfully support these changes.²

We recommend addressing potential barriers to initiating and maintaining weight-loss interventions, and revisiting them during follow-up visits. Barriers include the following:

Depression

Adults with depression are more likely to be obese than adults without depression, and the age-adjusted percentage of adults who are obese increases as depression severity increases.¹¹

Access to healthy foods

Limited access to healthy food choices can lead to poor diets and higher levels of obesity.¹² Local grocery store websites and nutrition specialists can help identify a range of healthy and affordable food to sustain a dietary intervention.

Medications associated with weight gain

Certain diabetic medications, contraceptives, tricyclic antidepressants, atypical antipsychotics, antiseizure drugs, and glucocorticoids promote weight gain and may have alternatives that do not promote weight gain.¹³

ARRANGE FOLLOW-UP AND REFERRALS

The literature supports frequent in-person sessions as the basis for a successful weight loss intervention (ie, ≥ 14 sessions in 6 months).² Medicare beneficiaries are eligible for 14 covered visits in the first 6 months and become eligible for an additional monthly visit over the course of 6 subsequent months if a weight loss goal of 3 kg is met in the first 6-month period.

Nutritionists, dieticians, and behavioral psychologists are often instrumental in comprehensive weight loss interventions. Anti­obesity drugs help curb appetite, promote weight loss, help enhance adherence to lifestyle modifications, and make it easier for patients to start a program of physical activity.¹⁴

The joint 2013 guidelines² recommend referral for bariatric surgery for adults with a BMI 40 kg/m² or higher, or for adults with a BMI 35 kg/m² or higher and obesity-related comorbidities who have not responded to behavioral treatment (with or without pharmacotherapy).

A growing body of evidence promotes the use of group support sessions such as shared medical appointments to encourage healthy eating and physical activity.¹⁵

OBESITY COUNSELING IS ACHIEVABLE AND REIMBURSABLE

To receive reimbursement from Medicare for obesity counseling, the information listed under “assess” and “advise” in Table 1 should be obtained in the initial visit; and follow-up visits should be used to address items under “agree,” “assist,” and “arrange.” Up to 20 visits are eligible for reimbursement when patients meet the goal of a 3-kg weight loss in the first 6 months (or 14 visits).

Yes, by using a pre-visit questionnaire that zeroes in on weight history, eating habits, and level of physical activity. This information will lay the foundation for effective weight loss counseling and interventions consistent with intensive behavioral therapy for obesity, reimbursable by Medicare.¹

See related editorial

More than one-third of US adults are obese.³ And even though the rate of obesity in adults has leveled off since 2009,³ more needs to be done to bend the arc of the national obesity trend. Clinicians tend to focus on the complications of obesity (coronary artery disease, type 2 diabetes, hypertension, hyperlipidemia) rather than on early identification and intervention of obesity itself.^4–6 A national study of outpatient visits showed that only 29% of visits by patients who were obese according to their body mass index (BMI) had a documented diagnosis of obesity, suggesting a profound under­diagnosis of obesity.⁷ According to one study, primary care doctors lack the level of comfort and counseling experience needed to provide obesity and weight loss counseling.⁸ Yet recent changes to Medicare reimbursement encourage obesity screening and management by covering up to 20 visits for intensive behavioral therapy to treat obesity.¹

We offer the following targeted approach to counseling, achievable within the context of a primary care visit and based on recent evidence, including the 2013 joint guidelines for the treatment of obesity of the American College of Cardiology, the American Heart Association Task Force on Practice Guidelines, and the Obesity Society.²

START WITH SCREENING

Measure the patient’s height and weight with the patient wearing light clothing and no shoes, and calculate the BMI as the weight in kilograms divided by the square of the height in meters. A BMI of 30 kg/m² or greater defines obesity.

OBTAIN AN OBESITY HISTORY

According to the 2013 joint guidelines,² when obtaining a thorough obesity history, the physician should do the following:

• Obtain information about weight the patient has gained and lost over time and previous weight loss efforts
• Ask the patient about eating habits, including number of meals per day, and the contents of a typical breakfast, lunch, and dinner; we recommend also asking about the number of daily beverages high in sugar
• Quantify the type and amount of physical activity performed within a specific time period.

This information can be obtained in advance of an office visit through either an electronic medical record portal or a pre-visit questionnaire (eg, http://onlinelibrary.wiley.com/doi/10.1038/oby.2002.205/full).

Also assess the patient’s risk of cardiovascular and obesity-related comorbidities. The waist circumference for patients with a BMI between 25 and 35 kg/m² provides additional information on risk: eg, a waist circumference greater than 88 cm for women and greater than 102 cm for men indicates increased cardiometabolic risk.²

SUGGEST SPECIFIC GOALS

Use a shared decision-making process to arrive at a set of incremental goals centered around the following evidence-based targets²:

• Weight loss: 3% to 5% of baseline weight within 6 months
• 6-month commitment to a weight loss intervention
• Exercise: at least 150 minutes of moderate aerobic activity per week
• More vegetables, fewer carbohydrates, and less protein, according to the American Diabetes Association’s “Create your plate” plan⁹
• Mediterranean diet.¹⁰

Use motivational interviewing techniques along with the obesity history to negotiate goals. Exercise-related goals should consider the patient’s cardiovascular and musculoskeletal comorbidities.

The most effective weight loss treatment consists of in-person consultations in which comprehensive lifestyle interventions are included. The components of an effective intervention (Table 1) include a reduced-calorie diet, aerobic physical activity, and behavioral strategies to meaningfully support these changes.²

We recommend addressing potential barriers to initiating and maintaining weight-loss interventions, and revisiting them during follow-up visits. Barriers include the following:

Depression

Adults with depression are more likely to be obese than adults without depression, and the age-adjusted percentage of adults who are obese increases as depression severity increases.¹¹

Access to healthy foods

Limited access to healthy food choices can lead to poor diets and higher levels of obesity.¹² Local grocery store websites and nutrition specialists can help identify a range of healthy and affordable food to sustain a dietary intervention.

Medications associated with weight gain

Certain diabetic medications, contraceptives, tricyclic antidepressants, atypical antipsychotics, antiseizure drugs, and glucocorticoids promote weight gain and may have alternatives that do not promote weight gain.¹³

ARRANGE FOLLOW-UP AND REFERRALS

The literature supports frequent in-person sessions as the basis for a successful weight loss intervention (ie, ≥ 14 sessions in 6 months).² Medicare beneficiaries are eligible for 14 covered visits in the first 6 months and become eligible for an additional monthly visit over the course of 6 subsequent months if a weight loss goal of 3 kg is met in the first 6-month period.

Nutritionists, dieticians, and behavioral psychologists are often instrumental in comprehensive weight loss interventions. Anti­obesity drugs help curb appetite, promote weight loss, help enhance adherence to lifestyle modifications, and make it easier for patients to start a program of physical activity.¹⁴

The joint 2013 guidelines² recommend referral for bariatric surgery for adults with a BMI 40 kg/m² or higher, or for adults with a BMI 35 kg/m² or higher and obesity-related comorbidities who have not responded to behavioral treatment (with or without pharmacotherapy).

A growing body of evidence promotes the use of group support sessions such as shared medical appointments to encourage healthy eating and physical activity.¹⁵

OBESITY COUNSELING IS ACHIEVABLE AND REIMBURSABLE

To receive reimbursement from Medicare for obesity counseling, the information listed under “assess” and “advise” in Table 1 should be obtained in the initial visit; and follow-up visits should be used to address items under “agree,” “assist,” and “arrange.” Up to 20 visits are eligible for reimbursement when patients meet the goal of a 3-kg weight loss in the first 6 months (or 14 visits).

Yes, by using a pre-visit questionnaire that zeroes in on weight history, eating habits, and level of physical activity. This information will lay the foundation for effective weight loss counseling and interventions consistent with intensive behavioral therapy for obesity, reimbursable by Medicare.¹

See related editorial

More than one-third of US adults are obese.³ And even though the rate of obesity in adults has leveled off since 2009,³ more needs to be done to bend the arc of the national obesity trend. Clinicians tend to focus on the complications of obesity (coronary artery disease, type 2 diabetes, hypertension, hyperlipidemia) rather than on early identification and intervention of obesity itself.^4–6 A national study of outpatient visits showed that only 29% of visits by patients who were obese according to their body mass index (BMI) had a documented diagnosis of obesity, suggesting a profound under­diagnosis of obesity.⁷ According to one study, primary care doctors lack the level of comfort and counseling experience needed to provide obesity and weight loss counseling.⁸ Yet recent changes to Medicare reimbursement encourage obesity screening and management by covering up to 20 visits for intensive behavioral therapy to treat obesity.¹

We offer the following targeted approach to counseling, achievable within the context of a primary care visit and based on recent evidence, including the 2013 joint guidelines for the treatment of obesity of the American College of Cardiology, the American Heart Association Task Force on Practice Guidelines, and the Obesity Society.²

START WITH SCREENING

Measure the patient’s height and weight with the patient wearing light clothing and no shoes, and calculate the BMI as the weight in kilograms divided by the square of the height in meters. A BMI of 30 kg/m² or greater defines obesity.

OBTAIN AN OBESITY HISTORY

According to the 2013 joint guidelines,² when obtaining a thorough obesity history, the physician should do the following:

• Obtain information about weight the patient has gained and lost over time and previous weight loss efforts
• Ask the patient about eating habits, including number of meals per day, and the contents of a typical breakfast, lunch, and dinner; we recommend also asking about the number of daily beverages high in sugar
• Quantify the type and amount of physical activity performed within a specific time period.

This information can be obtained in advance of an office visit through either an electronic medical record portal or a pre-visit questionnaire (eg, http://onlinelibrary.wiley.com/doi/10.1038/oby.2002.205/full).

Also assess the patient’s risk of cardiovascular and obesity-related comorbidities. The waist circumference for patients with a BMI between 25 and 35 kg/m² provides additional information on risk: eg, a waist circumference greater than 88 cm for women and greater than 102 cm for men indicates increased cardiometabolic risk.²

SUGGEST SPECIFIC GOALS

Use a shared decision-making process to arrive at a set of incremental goals centered around the following evidence-based targets²:

• Weight loss: 3% to 5% of baseline weight within 6 months
• 6-month commitment to a weight loss intervention
• Exercise: at least 150 minutes of moderate aerobic activity per week
• More vegetables, fewer carbohydrates, and less protein, according to the American Diabetes Association’s “Create your plate” plan⁹
• Mediterranean diet.¹⁰

Use motivational interviewing techniques along with the obesity history to negotiate goals. Exercise-related goals should consider the patient’s cardiovascular and musculoskeletal comorbidities.

The most effective weight loss treatment consists of in-person consultations in which comprehensive lifestyle interventions are included. The components of an effective intervention (Table 1) include a reduced-calorie diet, aerobic physical activity, and behavioral strategies to meaningfully support these changes.²

We recommend addressing potential barriers to initiating and maintaining weight-loss interventions, and revisiting them during follow-up visits. Barriers include the following:

Depression

Adults with depression are more likely to be obese than adults without depression, and the age-adjusted percentage of adults who are obese increases as depression severity increases.¹¹

Access to healthy foods

Limited access to healthy food choices can lead to poor diets and higher levels of obesity.¹² Local grocery store websites and nutrition specialists can help identify a range of healthy and affordable food to sustain a dietary intervention.

Medications associated with weight gain

Certain diabetic medications, contraceptives, tricyclic antidepressants, atypical antipsychotics, antiseizure drugs, and glucocorticoids promote weight gain and may have alternatives that do not promote weight gain.¹³

ARRANGE FOLLOW-UP AND REFERRALS

The literature supports frequent in-person sessions as the basis for a successful weight loss intervention (ie, ≥ 14 sessions in 6 months).² Medicare beneficiaries are eligible for 14 covered visits in the first 6 months and become eligible for an additional monthly visit over the course of 6 subsequent months if a weight loss goal of 3 kg is met in the first 6-month period.

Nutritionists, dieticians, and behavioral psychologists are often instrumental in comprehensive weight loss interventions. Anti­obesity drugs help curb appetite, promote weight loss, help enhance adherence to lifestyle modifications, and make it easier for patients to start a program of physical activity.¹⁴

The joint 2013 guidelines² recommend referral for bariatric surgery for adults with a BMI 40 kg/m² or higher, or for adults with a BMI 35 kg/m² or higher and obesity-related comorbidities who have not responded to behavioral treatment (with or without pharmacotherapy).

A growing body of evidence promotes the use of group support sessions such as shared medical appointments to encourage healthy eating and physical activity.¹⁵

OBESITY COUNSELING IS ACHIEVABLE AND REIMBURSABLE

To receive reimbursement from Medicare for obesity counseling, the information listed under “assess” and “advise” in Table 1 should be obtained in the initial visit; and follow-up visits should be used to address items under “agree,” “assist,” and “arrange.” Up to 20 visits are eligible for reimbursement when patients meet the goal of a 3-kg weight loss in the first 6 months (or 14 visits).

Since the first successful pregnancy in a kidney transplant recipient in 1958,¹ hundreds of kidney recipients have had successful pregnancies. Chronic kidney disease disrupts the hypothalamic-pituitary-gonadal axis, lead­ing to anovulation and infertility. However, within 6 months of kidney transplant, the hypothalamic-pituitary-gonadal axis and sex hormone levels return to normal,² and the renal allograft is able to adapt to the various physiologic changes of pregnancy.³

Successful pregnancy after kidney transplant requires a team approach to care that includes the primary care physician, a transplant nephrologist, and an obstetrician with expertise in high-risk pregnancies. But equally important is educating and counseling the patient about the risks and challenges. This should begin at the first pretransplant visit.⁴

Below are answers to questions often asked by renal transplant recipients who wish to become pregnant.

WHAT IS THE IDEAL TIME TO BECOME PREGNANT AFTER KIDNEY TRANSPLANT?

Mycophenolate mofetil and sirolimus are contraindicated in pregnancy and should be stopped at least 6 weeks before conception. Mycophenolate mofetil increases the risk of congenital malformations and spontaneous abortion. Data on sirolimus from clinical studies are limited, but in animal studies it is associated with delay in ossification of skeletal structure and with an increase in fetal mortality.⁷

WHAT INCREASES THE RISK OF A POOR PREGNANCY OUTCOME AFTER RENAL TRANSPLANT?

Risk factors for poor maternal and fetal outcomes include an elevated prepregnancy serum creatinine level (≥ 1.4 mg/dL), hypertension, and proteinuria (≥ 500 mg/24 hours). Younger age at transplant and at conception is associated with better pregnancy outcome.^5,8

WHAT ARE THE POSSIBLE MATERNAL COMPLICATIONS?

Kidney transplant recipients who become pregnant have a risk of developing preeclampsia 6 times higher than normal, and the incidence rate ranges between 24% and 38%.^9,10 The risk of cesarean delivery is 5 times higher  than in the general population, and the incidence rate is 43% to 64%.^10,11

Low-dose aspirin reduces the risk of preeclampsia and should be prescribed to all pregnant women who are kidney transplant recipients. Angiotensin-converting enzyme inhibitors are contraindicated due to the risk of teratogenic effects, ie, pulmonary hypoplasia and oligohydramnios.⁴

Women who become pregnant after kidney transplant are at greater risk of preterm delivery (40% to 60% higher risk), having a baby with low birth weight (42% to 46% higher risk), and intrauterine growth restriction (30% to 50% higher risk). But the risk of perinatal mortality is not increased in the absence of the above-mentioned risk factors.^10,11

DOES PREGNANCY INCREASE THE RISK OF GRAFT FAILURE?

Pregnancy does not increase the risk of allograft loss as long as the patient has a prepregnancy serum creatinine below 1.4 mg/dL, no hypertension, and urine protein excretion less than 500 mg/24 hours.¹²

WHAT CHANGES TO IMMUNE SUPPRESSION ARE REQUIRED BEFORE AND DURING PREGNANCY?

Careful management of immunosuppression is critical in renal transplant recipients before and during pregnancy because of the risks of teratogenicity and other adverse effects.

As stated above, mycophenolate mofetil and sirolimus are teratogenic and should be stopped 6 weeks before conception. The recommended maintenance immunosuppression during pregnancy includes calcineurin inhibitors (tacrolimus and cyclosporine), azathioprine, and low-dose prednisone.

A 20% to 25% increase in the dose of calcineurin inhibitor is required during pregnancy due to an increase in metabolic activity of cytochrome P450 and an increase in the volume of distribution.^5,6,13 However, this dosing increase requires more frequent monitoring throughout the pregnancy to ensure the safest possible therapeutic levels.

DOES PREGNANCY INCREASE THE RISK OF INFECTION?

Because of their immunosuppressed state, renal transplant recipients are prone to infection; the incidence rate of urinary tract infection is as high as 40% due to mild reflux and pregnancy-related dilation of ureters and collecting ducts.⁶ Women should be screened for urinary tract infection at every visit with urine dipstick testing and with urine culture every 4 weeks. Antibiotics such as nitrofurantoin, amoxicillin, and cephalexin are safe to treat urinary tract infection during pregnancy.⁶

IS BREAST-FEEDING SAFE IN RENAL TRANSPLANT RECIPIENTS?

Breast-feeding is considered safe for women with renal transplant who are on prednisone, azathioprine, cyclosporine, and tacrolimus. Women should avoid breast-feeding if they are taking mycophenolate mofetil, sirolimus, everolimus, or belatacept, as clinical data on safety are not adequate.¹⁴

Since the first successful pregnancy in a kidney transplant recipient in 1958,¹ hundreds of kidney recipients have had successful pregnancies. Chronic kidney disease disrupts the hypothalamic-pituitary-gonadal axis, lead­ing to anovulation and infertility. However, within 6 months of kidney transplant, the hypothalamic-pituitary-gonadal axis and sex hormone levels return to normal,² and the renal allograft is able to adapt to the various physiologic changes of pregnancy.³

Successful pregnancy after kidney transplant requires a team approach to care that includes the primary care physician, a transplant nephrologist, and an obstetrician with expertise in high-risk pregnancies. But equally important is educating and counseling the patient about the risks and challenges. This should begin at the first pretransplant visit.⁴

Below are answers to questions often asked by renal transplant recipients who wish to become pregnant.

WHAT IS THE IDEAL TIME TO BECOME PREGNANT AFTER KIDNEY TRANSPLANT?

Mycophenolate mofetil and sirolimus are contraindicated in pregnancy and should be stopped at least 6 weeks before conception. Mycophenolate mofetil increases the risk of congenital malformations and spontaneous abortion. Data on sirolimus from clinical studies are limited, but in animal studies it is associated with delay in ossification of skeletal structure and with an increase in fetal mortality.⁷

WHAT INCREASES THE RISK OF A POOR PREGNANCY OUTCOME AFTER RENAL TRANSPLANT?

Risk factors for poor maternal and fetal outcomes include an elevated prepregnancy serum creatinine level (≥ 1.4 mg/dL), hypertension, and proteinuria (≥ 500 mg/24 hours). Younger age at transplant and at conception is associated with better pregnancy outcome.^5,8

WHAT ARE THE POSSIBLE MATERNAL COMPLICATIONS?

Kidney transplant recipients who become pregnant have a risk of developing preeclampsia 6 times higher than normal, and the incidence rate ranges between 24% and 38%.^9,10 The risk of cesarean delivery is 5 times higher  than in the general population, and the incidence rate is 43% to 64%.^10,11

Low-dose aspirin reduces the risk of preeclampsia and should be prescribed to all pregnant women who are kidney transplant recipients. Angiotensin-converting enzyme inhibitors are contraindicated due to the risk of teratogenic effects, ie, pulmonary hypoplasia and oligohydramnios.⁴

Women who become pregnant after kidney transplant are at greater risk of preterm delivery (40% to 60% higher risk), having a baby with low birth weight (42% to 46% higher risk), and intrauterine growth restriction (30% to 50% higher risk). But the risk of perinatal mortality is not increased in the absence of the above-mentioned risk factors.^10,11

DOES PREGNANCY INCREASE THE RISK OF GRAFT FAILURE?

Pregnancy does not increase the risk of allograft loss as long as the patient has a prepregnancy serum creatinine below 1.4 mg/dL, no hypertension, and urine protein excretion less than 500 mg/24 hours.¹²

WHAT CHANGES TO IMMUNE SUPPRESSION ARE REQUIRED BEFORE AND DURING PREGNANCY?

Careful management of immunosuppression is critical in renal transplant recipients before and during pregnancy because of the risks of teratogenicity and other adverse effects.

As stated above, mycophenolate mofetil and sirolimus are teratogenic and should be stopped 6 weeks before conception. The recommended maintenance immunosuppression during pregnancy includes calcineurin inhibitors (tacrolimus and cyclosporine), azathioprine, and low-dose prednisone.

A 20% to 25% increase in the dose of calcineurin inhibitor is required during pregnancy due to an increase in metabolic activity of cytochrome P450 and an increase in the volume of distribution.^5,6,13 However, this dosing increase requires more frequent monitoring throughout the pregnancy to ensure the safest possible therapeutic levels.

DOES PREGNANCY INCREASE THE RISK OF INFECTION?

Because of their immunosuppressed state, renal transplant recipients are prone to infection; the incidence rate of urinary tract infection is as high as 40% due to mild reflux and pregnancy-related dilation of ureters and collecting ducts.⁶ Women should be screened for urinary tract infection at every visit with urine dipstick testing and with urine culture every 4 weeks. Antibiotics such as nitrofurantoin, amoxicillin, and cephalexin are safe to treat urinary tract infection during pregnancy.⁶

IS BREAST-FEEDING SAFE IN RENAL TRANSPLANT RECIPIENTS?

Breast-feeding is considered safe for women with renal transplant who are on prednisone, azathioprine, cyclosporine, and tacrolimus. Women should avoid breast-feeding if they are taking mycophenolate mofetil, sirolimus, everolimus, or belatacept, as clinical data on safety are not adequate.¹⁴

Since the first successful pregnancy in a kidney transplant recipient in 1958,¹ hundreds of kidney recipients have had successful pregnancies. Chronic kidney disease disrupts the hypothalamic-pituitary-gonadal axis, lead­ing to anovulation and infertility. However, within 6 months of kidney transplant, the hypothalamic-pituitary-gonadal axis and sex hormone levels return to normal,² and the renal allograft is able to adapt to the various physiologic changes of pregnancy.³

Successful pregnancy after kidney transplant requires a team approach to care that includes the primary care physician, a transplant nephrologist, and an obstetrician with expertise in high-risk pregnancies. But equally important is educating and counseling the patient about the risks and challenges. This should begin at the first pretransplant visit.⁴

Below are answers to questions often asked by renal transplant recipients who wish to become pregnant.

WHAT IS THE IDEAL TIME TO BECOME PREGNANT AFTER KIDNEY TRANSPLANT?

Mycophenolate mofetil and sirolimus are contraindicated in pregnancy and should be stopped at least 6 weeks before conception. Mycophenolate mofetil increases the risk of congenital malformations and spontaneous abortion. Data on sirolimus from clinical studies are limited, but in animal studies it is associated with delay in ossification of skeletal structure and with an increase in fetal mortality.⁷

WHAT INCREASES THE RISK OF A POOR PREGNANCY OUTCOME AFTER RENAL TRANSPLANT?

Risk factors for poor maternal and fetal outcomes include an elevated prepregnancy serum creatinine level (≥ 1.4 mg/dL), hypertension, and proteinuria (≥ 500 mg/24 hours). Younger age at transplant and at conception is associated with better pregnancy outcome.^5,8

WHAT ARE THE POSSIBLE MATERNAL COMPLICATIONS?

Kidney transplant recipients who become pregnant have a risk of developing preeclampsia 6 times higher than normal, and the incidence rate ranges between 24% and 38%.^9,10 The risk of cesarean delivery is 5 times higher  than in the general population, and the incidence rate is 43% to 64%.^10,11

Low-dose aspirin reduces the risk of preeclampsia and should be prescribed to all pregnant women who are kidney transplant recipients. Angiotensin-converting enzyme inhibitors are contraindicated due to the risk of teratogenic effects, ie, pulmonary hypoplasia and oligohydramnios.⁴

Women who become pregnant after kidney transplant are at greater risk of preterm delivery (40% to 60% higher risk), having a baby with low birth weight (42% to 46% higher risk), and intrauterine growth restriction (30% to 50% higher risk). But the risk of perinatal mortality is not increased in the absence of the above-mentioned risk factors.^10,11

DOES PREGNANCY INCREASE THE RISK OF GRAFT FAILURE?

Pregnancy does not increase the risk of allograft loss as long as the patient has a prepregnancy serum creatinine below 1.4 mg/dL, no hypertension, and urine protein excretion less than 500 mg/24 hours.¹²

WHAT CHANGES TO IMMUNE SUPPRESSION ARE REQUIRED BEFORE AND DURING PREGNANCY?

Careful management of immunosuppression is critical in renal transplant recipients before and during pregnancy because of the risks of teratogenicity and other adverse effects.

As stated above, mycophenolate mofetil and sirolimus are teratogenic and should be stopped 6 weeks before conception. The recommended maintenance immunosuppression during pregnancy includes calcineurin inhibitors (tacrolimus and cyclosporine), azathioprine, and low-dose prednisone.

A 20% to 25% increase in the dose of calcineurin inhibitor is required during pregnancy due to an increase in metabolic activity of cytochrome P450 and an increase in the volume of distribution.^5,6,13 However, this dosing increase requires more frequent monitoring throughout the pregnancy to ensure the safest possible therapeutic levels.

DOES PREGNANCY INCREASE THE RISK OF INFECTION?

Because of their immunosuppressed state, renal transplant recipients are prone to infection; the incidence rate of urinary tract infection is as high as 40% due to mild reflux and pregnancy-related dilation of ureters and collecting ducts.⁶ Women should be screened for urinary tract infection at every visit with urine dipstick testing and with urine culture every 4 weeks. Antibiotics such as nitrofurantoin, amoxicillin, and cephalexin are safe to treat urinary tract infection during pregnancy.⁶

IS BREAST-FEEDING SAFE IN RENAL TRANSPLANT RECIPIENTS?

Breast-feeding is considered safe for women with renal transplant who are on prednisone, azathioprine, cyclosporine, and tacrolimus. Women should avoid breast-feeding if they are taking mycophenolate mofetil, sirolimus, everolimus, or belatacept, as clinical data on safety are not adequate.¹⁴

Azithromycin is prescribed for a variety of acute respiratory and nonrespiratory infections. However, it is also used in several chronic respiratory diseases.

MECHANISM OF ACTION

Macrolide antibiotics like azithromycin inhibit bacterial growth and replication by interrupting protein synthesis. But azithromycin also has immunomodulatory properties.¹

In the acute phase of inflammation, azithromycin exerts an initial neutrophil degranulation effect and enhances the oxidative response that is primed by particulate stimulus, which could facilitate its antibacterial effects. In the late phase, it down-regulates the oxidative burst and increases apoptosis of neutrophils to promote healing without compromising immunity. Azithromycin also attenuates airway mucus hypersecretion, improves ciliary function, and promotes pulmonary epithelial cell healing.^2,3

Collectively, these effects make the drug effective in many chronic inflammatory lung conditions (Table 1).

CYSTIC FIBROSIS

Cystic fibrosis is a genetic disease affecting many organs, but its effect on the upper and lower airways has the greatest impact on quality of life and survival. Impaired mucociliary clearance and repeated respiratory infections contribute to chronic inflammation and a progressive decline in lung function.^4,5

A 2012 Cochrane review of 5 studies in 549 patients found that, compared with those taking placebo, patients taking azithromycin 250–500 mg 3 times a week had improvement in forced expiratory volume in 1 second (FEV₁). The mean difference at 6 months was 3.97% (95% cofidence interval [CI] 1.74– 6.19). Patients on azithromycin were free from pulmonary exacerbation approximately twice as long as patients on placebo (odds ratio 1.96, 95% CI 1.15–3.33).^6,7

The Cystic Fibrosis Foundation recommends long-term azithromycin therapy to improve lung function and reduce exacerbations in patients age 6 or older who have persistent Pseudomonas aeruginosa airway cultures (level of evidence: fair).⁸

DIFFUSE PANBRONCHIOLITIS

Diffuse panbronchiolitis, or diffuse chronic inflammatory bronchiolitis and sinusitis, is seen mainly in patients of Asian descent.⁹ In the past, the mortality rate was greater than 90%, but between 1970 and 1979 the 10-year survival rate increased by more than 40% with chronic macrolide therapy, ie, with erythromycin.^10,11

Later retrospective studies of azithromycin 500 mg 3 times a week showed results comparable to those with erythromycin, with improvement in symptoms, lung function, arterial partial pressure of oxygen, and radiologic findings, as well as fewer adverse effects.¹² These benefits justify the current recommendation for azithromycin as the mainstay of therapy in diffuse panbronchiolitis.

BRONCHIOLITIS OBLITERANS SYNDROME

Bronchiolitis obliterans syndrome is an airflow limitation that arises without infection or imaging evidence of bronchiolitis in patients who received allogeneic hematopoietic stem cell or lung transplant. It occurs in 50% of lung transplant recipients as a form of chronic graft rejection and in 6% to 20% of allogeneic stem cell transplant recipients as a manifestation of chronic graft-vs-host disease.^13,14

Azithromycin has been used in its management. A meta-analysis of lung transplant recipients found a significant improvement in the survival rate and overall lung function after an average of 7 months of treatment with azithromycin, with a mean increase in FEV₁ of 8.8% (95% CI 5.1–12.47, P < .001).¹⁴ The evidence currently supports long-term azithromycin 250 mg 3 times a week after lung transplant to reduce any decline in lung function and to lower the mortality rate.^14,15

In allogeneic stem cell transplant recipients, the evidence for long-term azithromycin treatment is sparse. A recent prospective multicenter study evaluated the effect of an azithromycin-based regimen (fluticasone, azithromycin, and montelukast, plus a steroid pulse) in stem cell recipients with bronchiolitis obliterans syndrome during the first 3 months after diagnosis. In the treated group, 6% had a drop in FEV₁ of more than 10% at 3-month follow-up compared with 40% of historical controls (95% CI 1%–19%, P < .001). Also, treatment resulted in a 50% reduction in the dose of systemic steroids and a substantial improvement in functional status.¹⁶

Given the limited options in the management of these patients and until further studies are available, azithromycin 3 times weekly is suggested.

NON-CYSTIC FIBROSIS BRONCHIECTASIS

Non-cystic fibrosis bronchiectasis is a chronic inflammatory lung condition characterized by irreversible dilation of the bronchi and bronchioles due to a variety of causes including recurrent or old infection, immunodeficiency, autoimmune conditions, and connective tissue disease; it can also be idiopathic.¹⁷

Altenburg et al,¹⁸ in a randomized, double-blind, placebo-controlled trial, found that azithromycin 250 mg 3 times a week for 12 months reduced the number of exacerbations  from a median number of 2 per patient with placebo to 0 per patient with azithromycin (P < .001). At 3 months, the FEV₁ as a percent of predicted had increased by 1.03% in the azithromycin group and decreased by 0.10% in the placebo group (P = .047). The number needed to treat with azithromycin to maintain clinical stability was 3.0.

Wong et al¹⁹ randomized patients to receive azithromycin 500 mg 3 times a week or placebo for 6 months. The rate of exacerbations was 0.59 per patient in the azithromycin group and 1.57 per patient in the placebo group (P < .0001). The FEV₁ remained unchanged from baseline in the azithromycin group while decreasing in the placebo group, but the difference was not significant.

EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of death, poor quality of life, and healthcare expenditures.²⁰ Prevention is therefore of the utmost importance.

Several studies have shown that azithromycin prophylaxis can reduce acute exacerbations of COPD. A recent meta-analysis showed that long-term macrolide prophylaxis significantly reduced exacerbations compared with rates in controls (risk ratio = 0.70, 95% CI 0.56–0.87, P < .01) and increased the median time to first COPD exacerbation by more than 90 days (P < .01).²¹ Long-term azithromycin therapy may be considered in selected patients who have frequent exacerbations despite optimal maintenance inhaler therapy.

PROPHYLAXIS IN IMMUNODEFICIENCY

Disseminated Mycobacterium avium complex (MAC) is an opportunistic infection most commonly occurring in patients with acquired immunodeficiency syndrome with CD4 counts below 50 cells/µL.^22,23

In a double-blinded, randomized trial, patients who received azithromycin had a 47% reduction in the incidence of MAC infection.

Given the long half-life of azithromycin, it is effective with once-weekly dosing of 1,200 mg.²³ Ideally, patients are placed on a prophylactic agent for disseminated MAC infection until the CD4 count reaches 100 cells/µL and remains at or above this level for 3 consecutive months.²⁴

ADVERSE EFFECTS AND PRECAUTIONS

Long-term azithromycin therapy may produce bacterial resistance; the risk has been estimated at 2.7 times greater in patients who are on long-term azithromycin treatment.²⁵ Also, patients at risk for MAC infection, such as those with cystic fibrosis, should be screened for it before starting treatment in order to prevent resistance to azithromycin.

The US Food and Drug Administration warns that azithromycin can lead to a prolonged corrected QT interval and potential fatal arrhythmias such as torsades de pointes. Major reviews have largely agreed that arrhythmias are more pronounced in patients with a coexisting cardiac risk factor such as existing QT-interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or arrhythmias, or who are on class IA and III antiarrhythmic drugs.^26–28

Other potential adverse effects of long-term azithromycin treatment are gastrointestinal symptoms and hearing impairment.^29,30 A review of potential drug interactions is advised when patients are placed on long-term azithromycin therapy.

Although azithromycin is generally well tolerated, long-term treatment should be individualized and the benefits weighed against the risks. Patients should be monitored during treatment for any of the above adverse effects.

Azithromycin is prescribed for a variety of acute respiratory and nonrespiratory infections. However, it is also used in several chronic respiratory diseases.

MECHANISM OF ACTION

Macrolide antibiotics like azithromycin inhibit bacterial growth and replication by interrupting protein synthesis. But azithromycin also has immunomodulatory properties.¹

In the acute phase of inflammation, azithromycin exerts an initial neutrophil degranulation effect and enhances the oxidative response that is primed by particulate stimulus, which could facilitate its antibacterial effects. In the late phase, it down-regulates the oxidative burst and increases apoptosis of neutrophils to promote healing without compromising immunity. Azithromycin also attenuates airway mucus hypersecretion, improves ciliary function, and promotes pulmonary epithelial cell healing.^2,3

Collectively, these effects make the drug effective in many chronic inflammatory lung conditions (Table 1).

CYSTIC FIBROSIS

Cystic fibrosis is a genetic disease affecting many organs, but its effect on the upper and lower airways has the greatest impact on quality of life and survival. Impaired mucociliary clearance and repeated respiratory infections contribute to chronic inflammation and a progressive decline in lung function.^4,5

A 2012 Cochrane review of 5 studies in 549 patients found that, compared with those taking placebo, patients taking azithromycin 250–500 mg 3 times a week had improvement in forced expiratory volume in 1 second (FEV₁). The mean difference at 6 months was 3.97% (95% cofidence interval [CI] 1.74– 6.19). Patients on azithromycin were free from pulmonary exacerbation approximately twice as long as patients on placebo (odds ratio 1.96, 95% CI 1.15–3.33).^6,7

The Cystic Fibrosis Foundation recommends long-term azithromycin therapy to improve lung function and reduce exacerbations in patients age 6 or older who have persistent Pseudomonas aeruginosa airway cultures (level of evidence: fair).⁸

DIFFUSE PANBRONCHIOLITIS

Diffuse panbronchiolitis, or diffuse chronic inflammatory bronchiolitis and sinusitis, is seen mainly in patients of Asian descent.⁹ In the past, the mortality rate was greater than 90%, but between 1970 and 1979 the 10-year survival rate increased by more than 40% with chronic macrolide therapy, ie, with erythromycin.^10,11

Later retrospective studies of azithromycin 500 mg 3 times a week showed results comparable to those with erythromycin, with improvement in symptoms, lung function, arterial partial pressure of oxygen, and radiologic findings, as well as fewer adverse effects.¹² These benefits justify the current recommendation for azithromycin as the mainstay of therapy in diffuse panbronchiolitis.

BRONCHIOLITIS OBLITERANS SYNDROME

Bronchiolitis obliterans syndrome is an airflow limitation that arises without infection or imaging evidence of bronchiolitis in patients who received allogeneic hematopoietic stem cell or lung transplant. It occurs in 50% of lung transplant recipients as a form of chronic graft rejection and in 6% to 20% of allogeneic stem cell transplant recipients as a manifestation of chronic graft-vs-host disease.^13,14

Azithromycin has been used in its management. A meta-analysis of lung transplant recipients found a significant improvement in the survival rate and overall lung function after an average of 7 months of treatment with azithromycin, with a mean increase in FEV₁ of 8.8% (95% CI 5.1–12.47, P < .001).¹⁴ The evidence currently supports long-term azithromycin 250 mg 3 times a week after lung transplant to reduce any decline in lung function and to lower the mortality rate.^14,15

In allogeneic stem cell transplant recipients, the evidence for long-term azithromycin treatment is sparse. A recent prospective multicenter study evaluated the effect of an azithromycin-based regimen (fluticasone, azithromycin, and montelukast, plus a steroid pulse) in stem cell recipients with bronchiolitis obliterans syndrome during the first 3 months after diagnosis. In the treated group, 6% had a drop in FEV₁ of more than 10% at 3-month follow-up compared with 40% of historical controls (95% CI 1%–19%, P < .001). Also, treatment resulted in a 50% reduction in the dose of systemic steroids and a substantial improvement in functional status.¹⁶

Given the limited options in the management of these patients and until further studies are available, azithromycin 3 times weekly is suggested.

NON-CYSTIC FIBROSIS BRONCHIECTASIS

Non-cystic fibrosis bronchiectasis is a chronic inflammatory lung condition characterized by irreversible dilation of the bronchi and bronchioles due to a variety of causes including recurrent or old infection, immunodeficiency, autoimmune conditions, and connective tissue disease; it can also be idiopathic.¹⁷

Altenburg et al,¹⁸ in a randomized, double-blind, placebo-controlled trial, found that azithromycin 250 mg 3 times a week for 12 months reduced the number of exacerbations  from a median number of 2 per patient with placebo to 0 per patient with azithromycin (P < .001). At 3 months, the FEV₁ as a percent of predicted had increased by 1.03% in the azithromycin group and decreased by 0.10% in the placebo group (P = .047). The number needed to treat with azithromycin to maintain clinical stability was 3.0.

Wong et al¹⁹ randomized patients to receive azithromycin 500 mg 3 times a week or placebo for 6 months. The rate of exacerbations was 0.59 per patient in the azithromycin group and 1.57 per patient in the placebo group (P < .0001). The FEV₁ remained unchanged from baseline in the azithromycin group while decreasing in the placebo group, but the difference was not significant.

EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of death, poor quality of life, and healthcare expenditures.²⁰ Prevention is therefore of the utmost importance.

Several studies have shown that azithromycin prophylaxis can reduce acute exacerbations of COPD. A recent meta-analysis showed that long-term macrolide prophylaxis significantly reduced exacerbations compared with rates in controls (risk ratio = 0.70, 95% CI 0.56–0.87, P < .01) and increased the median time to first COPD exacerbation by more than 90 days (P < .01).²¹ Long-term azithromycin therapy may be considered in selected patients who have frequent exacerbations despite optimal maintenance inhaler therapy.

PROPHYLAXIS IN IMMUNODEFICIENCY

Disseminated Mycobacterium avium complex (MAC) is an opportunistic infection most commonly occurring in patients with acquired immunodeficiency syndrome with CD4 counts below 50 cells/µL.^22,23

In a double-blinded, randomized trial, patients who received azithromycin had a 47% reduction in the incidence of MAC infection.

Given the long half-life of azithromycin, it is effective with once-weekly dosing of 1,200 mg.²³ Ideally, patients are placed on a prophylactic agent for disseminated MAC infection until the CD4 count reaches 100 cells/µL and remains at or above this level for 3 consecutive months.²⁴

ADVERSE EFFECTS AND PRECAUTIONS

Long-term azithromycin therapy may produce bacterial resistance; the risk has been estimated at 2.7 times greater in patients who are on long-term azithromycin treatment.²⁵ Also, patients at risk for MAC infection, such as those with cystic fibrosis, should be screened for it before starting treatment in order to prevent resistance to azithromycin.

The US Food and Drug Administration warns that azithromycin can lead to a prolonged corrected QT interval and potential fatal arrhythmias such as torsades de pointes. Major reviews have largely agreed that arrhythmias are more pronounced in patients with a coexisting cardiac risk factor such as existing QT-interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or arrhythmias, or who are on class IA and III antiarrhythmic drugs.^26–28

Other potential adverse effects of long-term azithromycin treatment are gastrointestinal symptoms and hearing impairment.^29,30 A review of potential drug interactions is advised when patients are placed on long-term azithromycin therapy.

Although azithromycin is generally well tolerated, long-term treatment should be individualized and the benefits weighed against the risks. Patients should be monitored during treatment for any of the above adverse effects.

Azithromycin is prescribed for a variety of acute respiratory and nonrespiratory infections. However, it is also used in several chronic respiratory diseases.

MECHANISM OF ACTION

Macrolide antibiotics like azithromycin inhibit bacterial growth and replication by interrupting protein synthesis. But azithromycin also has immunomodulatory properties.¹

In the acute phase of inflammation, azithromycin exerts an initial neutrophil degranulation effect and enhances the oxidative response that is primed by particulate stimulus, which could facilitate its antibacterial effects. In the late phase, it down-regulates the oxidative burst and increases apoptosis of neutrophils to promote healing without compromising immunity. Azithromycin also attenuates airway mucus hypersecretion, improves ciliary function, and promotes pulmonary epithelial cell healing.^2,3

Collectively, these effects make the drug effective in many chronic inflammatory lung conditions (Table 1).

CYSTIC FIBROSIS

Cystic fibrosis is a genetic disease affecting many organs, but its effect on the upper and lower airways has the greatest impact on quality of life and survival. Impaired mucociliary clearance and repeated respiratory infections contribute to chronic inflammation and a progressive decline in lung function.^4,5

A 2012 Cochrane review of 5 studies in 549 patients found that, compared with those taking placebo, patients taking azithromycin 250–500 mg 3 times a week had improvement in forced expiratory volume in 1 second (FEV₁). The mean difference at 6 months was 3.97% (95% cofidence interval [CI] 1.74– 6.19). Patients on azithromycin were free from pulmonary exacerbation approximately twice as long as patients on placebo (odds ratio 1.96, 95% CI 1.15–3.33).^6,7

The Cystic Fibrosis Foundation recommends long-term azithromycin therapy to improve lung function and reduce exacerbations in patients age 6 or older who have persistent Pseudomonas aeruginosa airway cultures (level of evidence: fair).⁸

DIFFUSE PANBRONCHIOLITIS

Diffuse panbronchiolitis, or diffuse chronic inflammatory bronchiolitis and sinusitis, is seen mainly in patients of Asian descent.⁹ In the past, the mortality rate was greater than 90%, but between 1970 and 1979 the 10-year survival rate increased by more than 40% with chronic macrolide therapy, ie, with erythromycin.^10,11

Later retrospective studies of azithromycin 500 mg 3 times a week showed results comparable to those with erythromycin, with improvement in symptoms, lung function, arterial partial pressure of oxygen, and radiologic findings, as well as fewer adverse effects.¹² These benefits justify the current recommendation for azithromycin as the mainstay of therapy in diffuse panbronchiolitis.

BRONCHIOLITIS OBLITERANS SYNDROME

Bronchiolitis obliterans syndrome is an airflow limitation that arises without infection or imaging evidence of bronchiolitis in patients who received allogeneic hematopoietic stem cell or lung transplant. It occurs in 50% of lung transplant recipients as a form of chronic graft rejection and in 6% to 20% of allogeneic stem cell transplant recipients as a manifestation of chronic graft-vs-host disease.^13,14

Azithromycin has been used in its management. A meta-analysis of lung transplant recipients found a significant improvement in the survival rate and overall lung function after an average of 7 months of treatment with azithromycin, with a mean increase in FEV₁ of 8.8% (95% CI 5.1–12.47, P < .001).¹⁴ The evidence currently supports long-term azithromycin 250 mg 3 times a week after lung transplant to reduce any decline in lung function and to lower the mortality rate.^14,15

In allogeneic stem cell transplant recipients, the evidence for long-term azithromycin treatment is sparse. A recent prospective multicenter study evaluated the effect of an azithromycin-based regimen (fluticasone, azithromycin, and montelukast, plus a steroid pulse) in stem cell recipients with bronchiolitis obliterans syndrome during the first 3 months after diagnosis. In the treated group, 6% had a drop in FEV₁ of more than 10% at 3-month follow-up compared with 40% of historical controls (95% CI 1%–19%, P < .001). Also, treatment resulted in a 50% reduction in the dose of systemic steroids and a substantial improvement in functional status.¹⁶

Given the limited options in the management of these patients and until further studies are available, azithromycin 3 times weekly is suggested.

NON-CYSTIC FIBROSIS BRONCHIECTASIS

Non-cystic fibrosis bronchiectasis is a chronic inflammatory lung condition characterized by irreversible dilation of the bronchi and bronchioles due to a variety of causes including recurrent or old infection, immunodeficiency, autoimmune conditions, and connective tissue disease; it can also be idiopathic.¹⁷

Altenburg et al,¹⁸ in a randomized, double-blind, placebo-controlled trial, found that azithromycin 250 mg 3 times a week for 12 months reduced the number of exacerbations  from a median number of 2 per patient with placebo to 0 per patient with azithromycin (P < .001). At 3 months, the FEV₁ as a percent of predicted had increased by 1.03% in the azithromycin group and decreased by 0.10% in the placebo group (P = .047). The number needed to treat with azithromycin to maintain clinical stability was 3.0.

Wong et al¹⁹ randomized patients to receive azithromycin 500 mg 3 times a week or placebo for 6 months. The rate of exacerbations was 0.59 per patient in the azithromycin group and 1.57 per patient in the placebo group (P < .0001). The FEV₁ remained unchanged from baseline in the azithromycin group while decreasing in the placebo group, but the difference was not significant.

EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of death, poor quality of life, and healthcare expenditures.²⁰ Prevention is therefore of the utmost importance.

Several studies have shown that azithromycin prophylaxis can reduce acute exacerbations of COPD. A recent meta-analysis showed that long-term macrolide prophylaxis significantly reduced exacerbations compared with rates in controls (risk ratio = 0.70, 95% CI 0.56–0.87, P < .01) and increased the median time to first COPD exacerbation by more than 90 days (P < .01).²¹ Long-term azithromycin therapy may be considered in selected patients who have frequent exacerbations despite optimal maintenance inhaler therapy.

PROPHYLAXIS IN IMMUNODEFICIENCY

Disseminated Mycobacterium avium complex (MAC) is an opportunistic infection most commonly occurring in patients with acquired immunodeficiency syndrome with CD4 counts below 50 cells/µL.^22,23

In a double-blinded, randomized trial, patients who received azithromycin had a 47% reduction in the incidence of MAC infection.

Given the long half-life of azithromycin, it is effective with once-weekly dosing of 1,200 mg.²³ Ideally, patients are placed on a prophylactic agent for disseminated MAC infection until the CD4 count reaches 100 cells/µL and remains at or above this level for 3 consecutive months.²⁴

ADVERSE EFFECTS AND PRECAUTIONS

Long-term azithromycin therapy may produce bacterial resistance; the risk has been estimated at 2.7 times greater in patients who are on long-term azithromycin treatment.²⁵ Also, patients at risk for MAC infection, such as those with cystic fibrosis, should be screened for it before starting treatment in order to prevent resistance to azithromycin.

The US Food and Drug Administration warns that azithromycin can lead to a prolonged corrected QT interval and potential fatal arrhythmias such as torsades de pointes. Major reviews have largely agreed that arrhythmias are more pronounced in patients with a coexisting cardiac risk factor such as existing QT-interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or arrhythmias, or who are on class IA and III antiarrhythmic drugs.^26–28

Other potential adverse effects of long-term azithromycin treatment are gastrointestinal symptoms and hearing impairment.^29,30 A review of potential drug interactions is advised when patients are placed on long-term azithromycin therapy.

Although azithromycin is generally well tolerated, long-term treatment should be individualized and the benefits weighed against the risks. Patients should be monitored during treatment for any of the above adverse effects.

We routinely use low-volume (2-L) polyethylene glycol electrolyte preparations such as Moviprep and Miralax in split-dose regimens, in which patients drink half of the preparation the day before the procedure and the other half the day of the procedure. In our experience, these are well tolerated by patients with a history of bariatric surgery and provide adequate colon cleansing before colonoscopy.

RATIONALE

Adequate bowel preparation by the ingestion of a cleansing agent is extremely important before colonoscopy: the quality of colon preparation affects the diagnostic accuracy and safety of the procedure, as inadequate bowel preparation has been associated with failure to detect polyps and with a higher rate of adverse events during the procedure.^1–3

The most commonly used bowel preparations can be divided into high-volume (which require drinking at least 4 L of a cathartic solution) and low-volume (which require drinking about 2 L).⁴ Polyethylene glycol electrolyte solutions are among the most commonly used and are available in both high-volume (eg, Golytely, Nulytely) and low-volume (eg, Moviprep, Miralax) forms.

Other low-volume preparations include sodium picosulfate (Prepopik), magnesium citrate, and sodium phosphate tablets. However, these should be avoided in patients with renal insufficiency.⁴

Prices for bowel preparations vary. For example, the average reported wholesale price of Golytely is $24.56, Moviprep $81.17, and Miralax $10.08.⁴ However, the final cost depends on the patient’s insurance coverage. Generic formulations are available for some preparations.

After bariatric surgery, patients have a smaller stomach

After bariatric surgery, patients have significantly reduced stomach volume, due either to resection of a part of the stomach (such as in partial gastrectomy) or to diversion of the gastrointestinal (GI) tract to bypass most of the stomach (such as in Roux-en-Y gastric bypass). This causes early satiety with smaller amounts of food and leads to weight loss. However, this restriction in stomach volume also makes it more difficult for the patient to tolerate the intake of large volumes of fluids for bowel cleansing before colonoscopy.

Bariatric surgery patients may require colonoscopy for indications such as colorectal cancer screening, chronic diarrhea, or GI bleeding, all of which are commonly encountered during routine clinical practice.

Guidelines are available

Currently, there are no published data available to support the use of one preparation over another in patients with a history of bariatric surgery. However, for patients who have had bariatric surgery, guidelines from the US Multi-Society Task Force on Colorectal Cancer—endorsed by the three major American gastroenterology societies, ie, the American Gastroenterological Association, the American College of Gastroenterology, and the American Society for Gastrointestinal Endoscopy—recommend either a low-volume solution or, if a high-volume solution is used, extending the duration over which the preparation is consumed.⁵ In addition, it is recommended that patients consume sugar-free drinks and liquids to avoid dumping syndrome from high sugar content.⁶

The use of split-dose regimens is also strongly recommended for elective colonoscopy by the US Multi-Society Task Force on Colorectal Cancer.⁵

Our clinical experience has been in line with the above recommendations.

We routinely use low-volume (2-L) polyethylene glycol electrolyte preparations such as Moviprep and Miralax in split-dose regimens, in which patients drink half of the preparation the day before the procedure and the other half the day of the procedure. In our experience, these are well tolerated by patients with a history of bariatric surgery and provide adequate colon cleansing before colonoscopy.

RATIONALE

Adequate bowel preparation by the ingestion of a cleansing agent is extremely important before colonoscopy: the quality of colon preparation affects the diagnostic accuracy and safety of the procedure, as inadequate bowel preparation has been associated with failure to detect polyps and with a higher rate of adverse events during the procedure.^1–3

The most commonly used bowel preparations can be divided into high-volume (which require drinking at least 4 L of a cathartic solution) and low-volume (which require drinking about 2 L).⁴ Polyethylene glycol electrolyte solutions are among the most commonly used and are available in both high-volume (eg, Golytely, Nulytely) and low-volume (eg, Moviprep, Miralax) forms.

Other low-volume preparations include sodium picosulfate (Prepopik), magnesium citrate, and sodium phosphate tablets. However, these should be avoided in patients with renal insufficiency.⁴

Prices for bowel preparations vary. For example, the average reported wholesale price of Golytely is $24.56, Moviprep $81.17, and Miralax $10.08.⁴ However, the final cost depends on the patient’s insurance coverage. Generic formulations are available for some preparations.

After bariatric surgery, patients have a smaller stomach

After bariatric surgery, patients have significantly reduced stomach volume, due either to resection of a part of the stomach (such as in partial gastrectomy) or to diversion of the gastrointestinal (GI) tract to bypass most of the stomach (such as in Roux-en-Y gastric bypass). This causes early satiety with smaller amounts of food and leads to weight loss. However, this restriction in stomach volume also makes it more difficult for the patient to tolerate the intake of large volumes of fluids for bowel cleansing before colonoscopy.

Bariatric surgery patients may require colonoscopy for indications such as colorectal cancer screening, chronic diarrhea, or GI bleeding, all of which are commonly encountered during routine clinical practice.

Guidelines are available

Currently, there are no published data available to support the use of one preparation over another in patients with a history of bariatric surgery. However, for patients who have had bariatric surgery, guidelines from the US Multi-Society Task Force on Colorectal Cancer—endorsed by the three major American gastroenterology societies, ie, the American Gastroenterological Association, the American College of Gastroenterology, and the American Society for Gastrointestinal Endoscopy—recommend either a low-volume solution or, if a high-volume solution is used, extending the duration over which the preparation is consumed.⁵ In addition, it is recommended that patients consume sugar-free drinks and liquids to avoid dumping syndrome from high sugar content.⁶

The use of split-dose regimens is also strongly recommended for elective colonoscopy by the US Multi-Society Task Force on Colorectal Cancer.⁵

Our clinical experience has been in line with the above recommendations.

We routinely use low-volume (2-L) polyethylene glycol electrolyte preparations such as Moviprep and Miralax in split-dose regimens, in which patients drink half of the preparation the day before the procedure and the other half the day of the procedure. In our experience, these are well tolerated by patients with a history of bariatric surgery and provide adequate colon cleansing before colonoscopy.

RATIONALE

Adequate bowel preparation by the ingestion of a cleansing agent is extremely important before colonoscopy: the quality of colon preparation affects the diagnostic accuracy and safety of the procedure, as inadequate bowel preparation has been associated with failure to detect polyps and with a higher rate of adverse events during the procedure.^1–3

The most commonly used bowel preparations can be divided into high-volume (which require drinking at least 4 L of a cathartic solution) and low-volume (which require drinking about 2 L).⁴ Polyethylene glycol electrolyte solutions are among the most commonly used and are available in both high-volume (eg, Golytely, Nulytely) and low-volume (eg, Moviprep, Miralax) forms.

Other low-volume preparations include sodium picosulfate (Prepopik), magnesium citrate, and sodium phosphate tablets. However, these should be avoided in patients with renal insufficiency.⁴

Prices for bowel preparations vary. For example, the average reported wholesale price of Golytely is $24.56, Moviprep $81.17, and Miralax $10.08.⁴ However, the final cost depends on the patient’s insurance coverage. Generic formulations are available for some preparations.

After bariatric surgery, patients have a smaller stomach

After bariatric surgery, patients have significantly reduced stomach volume, due either to resection of a part of the stomach (such as in partial gastrectomy) or to diversion of the gastrointestinal (GI) tract to bypass most of the stomach (such as in Roux-en-Y gastric bypass). This causes early satiety with smaller amounts of food and leads to weight loss. However, this restriction in stomach volume also makes it more difficult for the patient to tolerate the intake of large volumes of fluids for bowel cleansing before colonoscopy.

Bariatric surgery patients may require colonoscopy for indications such as colorectal cancer screening, chronic diarrhea, or GI bleeding, all of which are commonly encountered during routine clinical practice.

Guidelines are available

Currently, there are no published data available to support the use of one preparation over another in patients with a history of bariatric surgery. However, for patients who have had bariatric surgery, guidelines from the US Multi-Society Task Force on Colorectal Cancer—endorsed by the three major American gastroenterology societies, ie, the American Gastroenterological Association, the American College of Gastroenterology, and the American Society for Gastrointestinal Endoscopy—recommend either a low-volume solution or, if a high-volume solution is used, extending the duration over which the preparation is consumed.⁵ In addition, it is recommended that patients consume sugar-free drinks and liquids to avoid dumping syndrome from high sugar content.⁶

The use of split-dose regimens is also strongly recommended for elective colonoscopy by the US Multi-Society Task Force on Colorectal Cancer.⁵

Our clinical experience has been in line with the above recommendations.

Patients should undergo biopsy to guide management and prognosis if suspected of having steatohepatitis or fibrosis.

WHAT IS NAFLD?

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the United States and is the second most common reason for liver transplant.¹ It is thought to be the hepatic consequence of systemic insulin resistance and the metabolic syndrome characterized by obesity, dyslipidemia, and type 2 diabetes mellitus.

WHAT IS THE RELATIONSHIP BETWEEN NAFLD AND NASH?

NAFLD is defined by the accumulation of hepatic fat as evidenced by imaging or histologic study and without a coexisting cause of chronic liver disease or a secondary cause of hepatic steatosis, including significant alcohol use, medications, or an inherited or acquired metabolic state.

NAFLD has two subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL is characterized by steatosis, including inflammation, in at least 5% of hepatocytes. NASH is defined by a constellation of features that include steatosis, lobular and portal inflammation, and liver cell injury in the form of hepatocyte ballooning.²

Clinically, it is especially important to distinguish patients with the NASH subtype, as most NAFLD patients have steatosis without necroinflammation or fibrosis and do not require medical therapy.

CLINICAL SIGNIFICANCE OF NAFLD: NASH IS WORSE THAN NAFL

NAFL carries an excellent prognosis in terms of histologic progression of liver disease, whereas NASH can histologically progress to fibrosis and, in up to 15% of patients, to cirrhosis.³

Progression of fibrosis poses secondary risks, including complications associated with portal hypertension (ascites, variceal hemorrhage, hepatic encephalopathy), end-stage liver disease, and hepatocellular carcinoma. In Western countries, 4% to 22% of cases of hepatocellular carcinoma are attributed to NAFLD.⁴

In a 2015 meta-analysis, patients with NAFL and stage 0 fibrosis at baseline progressed 1 stage of fibrosis over 14.3 years, whereas patients with NASH and stage 0 fibrosis experienced an accelerated rate of progression, advancing 1 stage of fibrosis over 7.1 years.⁵ A systematic review of patients with NASH identified age and inflammation on initial liver biopsy as independent predictors of progression to advanced fibrosis.⁶

Patients with NAFLD have a higher all-cause mortality rate than patients of the same age and sex without NAFLD.⁷

HOW SHOULD PATIENTS WITH NAFLD BE EVALUATED?

Initial evaluation of a patient with suspected NAFLD should include a thorough serologic evaluation to exclude coexisting causes of chronic liver disease. Tests include:

• A viral hepatitis panel
• Antinuclear antibody (ANA)
• Antismooth muscle antibody (ASMA)
• Antimitochondrial antibody (AMA)
• Iron studies
• Alpha-1 antitrypsin level
• Ceruloplasmin level.

Aminotransferase levels and imaging studies (ultrasonography, computed tomography, and magnetic resonance imaging) do not reliably convey the degree of NASH and fibrosis.

Biopsy. Whereas sensitive serologic tests have been introduced to detect and diagnose many causes of liver disease, liver biopsy (trans­jugular or percutaneous) with histologic examination remains the only way to accurately assess the degree of steatosis and, thus, to distinguish NAFL from NASH.²

The Pathology Committee of the NASH Clinical Research Network designed and validated a NAFLD scoring system,^8,9 with points allocated for degrees of:

• Steatosis (0–3)
• Lobular inflammation (0–2)
• Hepatocellular ballooning (0–2)
• Fibrosis (0–4).

A NAFLD Activity Score of less than 3 is consistent with “not NASH,” a score of 3 or 4 with borderline NASH, and a score of 5 or more with NASH.⁸ However, the diagnosis of NASH is not based on the NAFLD scoring system, but rather on the pathologist’s overall evaluation of the liver biopsy.⁹

The metabolic syndrome is an established risk factor for steatohepatitis in patients with NAFLD, and its presence in patients with persistently elevated liver biochemical tests may help identify those who would benefit from further diagnostic and prognostic evaluation, including liver biopsy.^2,10 In addition, a 2008 study that used a decision-tree modeling system demonstrated that early liver biopsy could provide a survival benefit.¹¹

Since liver biopsy is associated with procedure-related morbidity, mortality, and cost, researchers have been developing noninvasive markers of steatohepatitis and fibrosis.¹²

The NAFLD fibrosis score—based on patient age, body mass index, hyperglycemia, platelet count, albumin, and ratio of aspartate aminotransferase to alanine aminotransferase—has been shown to have an area under the receiver operating curve of 0.85 for predicting advanced fibrosis, with a negative predictive value of 88% to 93% and a positive predictive value of 82% to 90%.¹³ The NAFLD fibrosis score can be used to identify patients who may have fibrosis or cirrhosis and can help direct the use of liver biopsy in patients who would benefit from prognostication and potential treatment.

Of note, the NAFLD fibrosis score is only slightly less accurate than the imaging techniques of magnetic resonance elastography and transient elastography, particularly when the relative costs are considered.¹⁴

INDICATIONS FOR LIVER BIOPSY

There are two clear indications for liver biopsy in NAFLD.

Before starting any pharmacologic therapy for NAFLD. Most NAFLD patients have steatosis without NASH or fibrosis and do not require medical therapy. Importantly, the available treatments have significant adverse effects—prostate cancer with vitamin E, bladder cancer and weight gain with pioglitazone, and nausea with pentoxifylline.

Diagnosis. Up to 30% of patients have elevated serum ferritin and autoantibodies, including ANA, ASMA, and AMA. Liver biopsy is often needed to exclude hemochromatosis or autoimmune hepatitis.¹⁵ Occasionally, a possible confounding drug-induced liver injury may necessitate a liver biopsy.

LIFESTYLE MODIFICATION

The first step in managing patients who have NAFLD is to treat components of the metabolic syndrome, including obesity, dyslipidemia, and type 2 diabetes.

In a randomized controlled trial in 31 obese patients with biopsy-proven NASH,¹⁶ intensive lifestyle modification (consisting of diet, behavior modification, and 200 minutes of exercise weekly for 48 weeks) was shown to improve histologic NAFLD Activity Scores, including degrees of steatosis, necrosis, and inflammation. As a result, weight loss of 7% to 9% is generally recommended for patients with NAFLD.

DRUG THERAPIES

Much research has been directed toward identifying risk factors for progression of fibrosis and toward developing new therapies for patients with NAFLD. A 2015 meta-analysis concluded that pentoxifylline and obeticholic acid improve fibrosis, while vitamin E, thiazolidinediones, and obeticholic acid improve necroinflammation associated with NASH.¹⁷

Long-term studies are needed to determine the impact of these drugs on NASH-related morbidity, mortality, and need for liver transplant.

TAKE-AWAY POINTS

• NAFLD is the leading cause of chronic liver disease in the United States and is increasing as a reason for liver transplant.
• NASH is associated with the metabolic syndrome and can progress to fibrosis, cirrhosis, and end-stage liver disease. Noninvasive markers such as the NAFLD Activity Score can be useful in identifying patients who may have advanced fibrosis and can select patients who should be directed to liver biopsy for definitive diagnosis.^8,9
• Liver biopsy is the gold standard for diagnosing steatohepatitis and fibrosis and is the only diagnostic tool used in clinical trials to direct pharmacotherapy for NASH.
• Liver biopsy should be reserved for patients suspected of having NASH or fibrosis and who might benefit from therapy.
• Liver biopsy is also indicated for those NAFLD patients who have confounding laboratory findings such as an elevated ferritin level and autoantibodies including ANA, ASMA, and AMA.

Patients should undergo biopsy to guide management and prognosis if suspected of having steatohepatitis or fibrosis.

WHAT IS NAFLD?

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the United States and is the second most common reason for liver transplant.¹ It is thought to be the hepatic consequence of systemic insulin resistance and the metabolic syndrome characterized by obesity, dyslipidemia, and type 2 diabetes mellitus.

WHAT IS THE RELATIONSHIP BETWEEN NAFLD AND NASH?

NAFLD is defined by the accumulation of hepatic fat as evidenced by imaging or histologic study and without a coexisting cause of chronic liver disease or a secondary cause of hepatic steatosis, including significant alcohol use, medications, or an inherited or acquired metabolic state.

NAFLD has two subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL is characterized by steatosis, including inflammation, in at least 5% of hepatocytes. NASH is defined by a constellation of features that include steatosis, lobular and portal inflammation, and liver cell injury in the form of hepatocyte ballooning.²

Clinically, it is especially important to distinguish patients with the NASH subtype, as most NAFLD patients have steatosis without necroinflammation or fibrosis and do not require medical therapy.

CLINICAL SIGNIFICANCE OF NAFLD: NASH IS WORSE THAN NAFL

NAFL carries an excellent prognosis in terms of histologic progression of liver disease, whereas NASH can histologically progress to fibrosis and, in up to 15% of patients, to cirrhosis.³

Progression of fibrosis poses secondary risks, including complications associated with portal hypertension (ascites, variceal hemorrhage, hepatic encephalopathy), end-stage liver disease, and hepatocellular carcinoma. In Western countries, 4% to 22% of cases of hepatocellular carcinoma are attributed to NAFLD.⁴

In a 2015 meta-analysis, patients with NAFL and stage 0 fibrosis at baseline progressed 1 stage of fibrosis over 14.3 years, whereas patients with NASH and stage 0 fibrosis experienced an accelerated rate of progression, advancing 1 stage of fibrosis over 7.1 years.⁵ A systematic review of patients with NASH identified age and inflammation on initial liver biopsy as independent predictors of progression to advanced fibrosis.⁶

Patients with NAFLD have a higher all-cause mortality rate than patients of the same age and sex without NAFLD.⁷

HOW SHOULD PATIENTS WITH NAFLD BE EVALUATED?

Initial evaluation of a patient with suspected NAFLD should include a thorough serologic evaluation to exclude coexisting causes of chronic liver disease. Tests include:

• A viral hepatitis panel
• Antinuclear antibody (ANA)
• Antismooth muscle antibody (ASMA)
• Antimitochondrial antibody (AMA)
• Iron studies
• Alpha-1 antitrypsin level
• Ceruloplasmin level.

Aminotransferase levels and imaging studies (ultrasonography, computed tomography, and magnetic resonance imaging) do not reliably convey the degree of NASH and fibrosis.

Biopsy. Whereas sensitive serologic tests have been introduced to detect and diagnose many causes of liver disease, liver biopsy (trans­jugular or percutaneous) with histologic examination remains the only way to accurately assess the degree of steatosis and, thus, to distinguish NAFL from NASH.²

The Pathology Committee of the NASH Clinical Research Network designed and validated a NAFLD scoring system,^8,9 with points allocated for degrees of:

• Steatosis (0–3)
• Lobular inflammation (0–2)
• Hepatocellular ballooning (0–2)
• Fibrosis (0–4).

A NAFLD Activity Score of less than 3 is consistent with “not NASH,” a score of 3 or 4 with borderline NASH, and a score of 5 or more with NASH.⁸ However, the diagnosis of NASH is not based on the NAFLD scoring system, but rather on the pathologist’s overall evaluation of the liver biopsy.⁹

The metabolic syndrome is an established risk factor for steatohepatitis in patients with NAFLD, and its presence in patients with persistently elevated liver biochemical tests may help identify those who would benefit from further diagnostic and prognostic evaluation, including liver biopsy.^2,10 In addition, a 2008 study that used a decision-tree modeling system demonstrated that early liver biopsy could provide a survival benefit.¹¹

Since liver biopsy is associated with procedure-related morbidity, mortality, and cost, researchers have been developing noninvasive markers of steatohepatitis and fibrosis.¹²

The NAFLD fibrosis score—based on patient age, body mass index, hyperglycemia, platelet count, albumin, and ratio of aspartate aminotransferase to alanine aminotransferase—has been shown to have an area under the receiver operating curve of 0.85 for predicting advanced fibrosis, with a negative predictive value of 88% to 93% and a positive predictive value of 82% to 90%.¹³ The NAFLD fibrosis score can be used to identify patients who may have fibrosis or cirrhosis and can help direct the use of liver biopsy in patients who would benefit from prognostication and potential treatment.

Of note, the NAFLD fibrosis score is only slightly less accurate than the imaging techniques of magnetic resonance elastography and transient elastography, particularly when the relative costs are considered.¹⁴

INDICATIONS FOR LIVER BIOPSY

There are two clear indications for liver biopsy in NAFLD.

Before starting any pharmacologic therapy for NAFLD. Most NAFLD patients have steatosis without NASH or fibrosis and do not require medical therapy. Importantly, the available treatments have significant adverse effects—prostate cancer with vitamin E, bladder cancer and weight gain with pioglitazone, and nausea with pentoxifylline.

Diagnosis. Up to 30% of patients have elevated serum ferritin and autoantibodies, including ANA, ASMA, and AMA. Liver biopsy is often needed to exclude hemochromatosis or autoimmune hepatitis.¹⁵ Occasionally, a possible confounding drug-induced liver injury may necessitate a liver biopsy.

LIFESTYLE MODIFICATION

The first step in managing patients who have NAFLD is to treat components of the metabolic syndrome, including obesity, dyslipidemia, and type 2 diabetes.

In a randomized controlled trial in 31 obese patients with biopsy-proven NASH,¹⁶ intensive lifestyle modification (consisting of diet, behavior modification, and 200 minutes of exercise weekly for 48 weeks) was shown to improve histologic NAFLD Activity Scores, including degrees of steatosis, necrosis, and inflammation. As a result, weight loss of 7% to 9% is generally recommended for patients with NAFLD.

DRUG THERAPIES

Much research has been directed toward identifying risk factors for progression of fibrosis and toward developing new therapies for patients with NAFLD. A 2015 meta-analysis concluded that pentoxifylline and obeticholic acid improve fibrosis, while vitamin E, thiazolidinediones, and obeticholic acid improve necroinflammation associated with NASH.¹⁷

Long-term studies are needed to determine the impact of these drugs on NASH-related morbidity, mortality, and need for liver transplant.

TAKE-AWAY POINTS

• NAFLD is the leading cause of chronic liver disease in the United States and is increasing as a reason for liver transplant.
• NASH is associated with the metabolic syndrome and can progress to fibrosis, cirrhosis, and end-stage liver disease. Noninvasive markers such as the NAFLD Activity Score can be useful in identifying patients who may have advanced fibrosis and can select patients who should be directed to liver biopsy for definitive diagnosis.^8,9
• Liver biopsy is the gold standard for diagnosing steatohepatitis and fibrosis and is the only diagnostic tool used in clinical trials to direct pharmacotherapy for NASH.
• Liver biopsy should be reserved for patients suspected of having NASH or fibrosis and who might benefit from therapy.
• Liver biopsy is also indicated for those NAFLD patients who have confounding laboratory findings such as an elevated ferritin level and autoantibodies including ANA, ASMA, and AMA.

Patients should undergo biopsy to guide management and prognosis if suspected of having steatohepatitis or fibrosis.

WHAT IS NAFLD?

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the United States and is the second most common reason for liver transplant.¹ It is thought to be the hepatic consequence of systemic insulin resistance and the metabolic syndrome characterized by obesity, dyslipidemia, and type 2 diabetes mellitus.

WHAT IS THE RELATIONSHIP BETWEEN NAFLD AND NASH?

NAFLD is defined by the accumulation of hepatic fat as evidenced by imaging or histologic study and without a coexisting cause of chronic liver disease or a secondary cause of hepatic steatosis, including significant alcohol use, medications, or an inherited or acquired metabolic state.

NAFLD has two subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL is characterized by steatosis, including inflammation, in at least 5% of hepatocytes. NASH is defined by a constellation of features that include steatosis, lobular and portal inflammation, and liver cell injury in the form of hepatocyte ballooning.²

Clinically, it is especially important to distinguish patients with the NASH subtype, as most NAFLD patients have steatosis without necroinflammation or fibrosis and do not require medical therapy.

CLINICAL SIGNIFICANCE OF NAFLD: NASH IS WORSE THAN NAFL

NAFL carries an excellent prognosis in terms of histologic progression of liver disease, whereas NASH can histologically progress to fibrosis and, in up to 15% of patients, to cirrhosis.³

Progression of fibrosis poses secondary risks, including complications associated with portal hypertension (ascites, variceal hemorrhage, hepatic encephalopathy), end-stage liver disease, and hepatocellular carcinoma. In Western countries, 4% to 22% of cases of hepatocellular carcinoma are attributed to NAFLD.⁴

In a 2015 meta-analysis, patients with NAFL and stage 0 fibrosis at baseline progressed 1 stage of fibrosis over 14.3 years, whereas patients with NASH and stage 0 fibrosis experienced an accelerated rate of progression, advancing 1 stage of fibrosis over 7.1 years.⁵ A systematic review of patients with NASH identified age and inflammation on initial liver biopsy as independent predictors of progression to advanced fibrosis.⁶

Patients with NAFLD have a higher all-cause mortality rate than patients of the same age and sex without NAFLD.⁷

HOW SHOULD PATIENTS WITH NAFLD BE EVALUATED?

Initial evaluation of a patient with suspected NAFLD should include a thorough serologic evaluation to exclude coexisting causes of chronic liver disease. Tests include:

• A viral hepatitis panel
• Antinuclear antibody (ANA)
• Antismooth muscle antibody (ASMA)
• Antimitochondrial antibody (AMA)
• Iron studies
• Alpha-1 antitrypsin level
• Ceruloplasmin level.

Aminotransferase levels and imaging studies (ultrasonography, computed tomography, and magnetic resonance imaging) do not reliably convey the degree of NASH and fibrosis.

Biopsy. Whereas sensitive serologic tests have been introduced to detect and diagnose many causes of liver disease, liver biopsy (trans­jugular or percutaneous) with histologic examination remains the only way to accurately assess the degree of steatosis and, thus, to distinguish NAFL from NASH.²

The Pathology Committee of the NASH Clinical Research Network designed and validated a NAFLD scoring system,^8,9 with points allocated for degrees of:

• Steatosis (0–3)
• Lobular inflammation (0–2)
• Hepatocellular ballooning (0–2)
• Fibrosis (0–4).

A NAFLD Activity Score of less than 3 is consistent with “not NASH,” a score of 3 or 4 with borderline NASH, and a score of 5 or more with NASH.⁸ However, the diagnosis of NASH is not based on the NAFLD scoring system, but rather on the pathologist’s overall evaluation of the liver biopsy.⁹

The metabolic syndrome is an established risk factor for steatohepatitis in patients with NAFLD, and its presence in patients with persistently elevated liver biochemical tests may help identify those who would benefit from further diagnostic and prognostic evaluation, including liver biopsy.^2,10 In addition, a 2008 study that used a decision-tree modeling system demonstrated that early liver biopsy could provide a survival benefit.¹¹

Since liver biopsy is associated with procedure-related morbidity, mortality, and cost, researchers have been developing noninvasive markers of steatohepatitis and fibrosis.¹²

The NAFLD fibrosis score—based on patient age, body mass index, hyperglycemia, platelet count, albumin, and ratio of aspartate aminotransferase to alanine aminotransferase—has been shown to have an area under the receiver operating curve of 0.85 for predicting advanced fibrosis, with a negative predictive value of 88% to 93% and a positive predictive value of 82% to 90%.¹³ The NAFLD fibrosis score can be used to identify patients who may have fibrosis or cirrhosis and can help direct the use of liver biopsy in patients who would benefit from prognostication and potential treatment.

Of note, the NAFLD fibrosis score is only slightly less accurate than the imaging techniques of magnetic resonance elastography and transient elastography, particularly when the relative costs are considered.¹⁴

INDICATIONS FOR LIVER BIOPSY

There are two clear indications for liver biopsy in NAFLD.

Before starting any pharmacologic therapy for NAFLD. Most NAFLD patients have steatosis without NASH or fibrosis and do not require medical therapy. Importantly, the available treatments have significant adverse effects—prostate cancer with vitamin E, bladder cancer and weight gain with pioglitazone, and nausea with pentoxifylline.

Diagnosis. Up to 30% of patients have elevated serum ferritin and autoantibodies, including ANA, ASMA, and AMA. Liver biopsy is often needed to exclude hemochromatosis or autoimmune hepatitis.¹⁵ Occasionally, a possible confounding drug-induced liver injury may necessitate a liver biopsy.

LIFESTYLE MODIFICATION

The first step in managing patients who have NAFLD is to treat components of the metabolic syndrome, including obesity, dyslipidemia, and type 2 diabetes.

In a randomized controlled trial in 31 obese patients with biopsy-proven NASH,¹⁶ intensive lifestyle modification (consisting of diet, behavior modification, and 200 minutes of exercise weekly for 48 weeks) was shown to improve histologic NAFLD Activity Scores, including degrees of steatosis, necrosis, and inflammation. As a result, weight loss of 7% to 9% is generally recommended for patients with NAFLD.

DRUG THERAPIES

Much research has been directed toward identifying risk factors for progression of fibrosis and toward developing new therapies for patients with NAFLD. A 2015 meta-analysis concluded that pentoxifylline and obeticholic acid improve fibrosis, while vitamin E, thiazolidinediones, and obeticholic acid improve necroinflammation associated with NASH.¹⁷

Long-term studies are needed to determine the impact of these drugs on NASH-related morbidity, mortality, and need for liver transplant.

TAKE-AWAY POINTS

• NAFLD is the leading cause of chronic liver disease in the United States and is increasing as a reason for liver transplant.
• NASH is associated with the metabolic syndrome and can progress to fibrosis, cirrhosis, and end-stage liver disease. Noninvasive markers such as the NAFLD Activity Score can be useful in identifying patients who may have advanced fibrosis and can select patients who should be directed to liver biopsy for definitive diagnosis.^8,9
• Liver biopsy is the gold standard for diagnosing steatohepatitis and fibrosis and is the only diagnostic tool used in clinical trials to direct pharmacotherapy for NASH.
• Liver biopsy should be reserved for patients suspected of having NASH or fibrosis and who might benefit from therapy.
• Liver biopsy is also indicated for those NAFLD patients who have confounding laboratory findings such as an elevated ferritin level and autoantibodies including ANA, ASMA, and AMA.