The Journal of Family Practice

ILLUSTRATIVE CASE

A 70-year-old White woman with a history of type 2 diabetes and a normal body mass index (BMI) presents to your office for a preventive care exam. She is otherwise doing well, without concerns. Her first dual-energy x-ray absorptiometry (DXA) scan, completed at age 67, demonstrated normal bone density. Should you recommend a repeat DXA scan today?

As many as 1 in 2 postmenopausal women are at risk for an ­osteoporosis-related fracture.² Each year, about 2 million fragility fractures occur in the United States.^2,3 The US Preventive Services Task Force (USPSTF) recommends bone mineral density (BMD) measurement in all women ages 65 years and older, as well as in younger postmenopausal women with certain clinical risk factors.⁴ The USPSTF does not make a recommendation regarding the interval for follow-up BMD testing.

Two prospective cohort studies determined that repeat BMD testing 4 to 8 years after baseline screening did not improve fracture risk prediction.^5,6 Limitations of these studies included no analysis of high-risk subgroups, as well as failure to include many younger postmenopausal women in the studies.^5,6 An additional longitudinal study that followed postmenopausal women for up to 15 years estimated that the interval for at least 10% of women to develop osteoporosis after initial screening was more than 15 years for women with normal BMD and about 5 years for those with moderate osteopenia.⁷

STUDY SUMMARY

No added predictive benefit found in 3-year repeat scan

The current study examined data from the Women’s Health Initiative Extension 1 Study, a large prospective cohort that included a broader range of postmenopausal women (N = 7419) than the previous studies. The purpose of this study was to determine if a second BMD measurement, about 3 years after the baseline BMD screening, would be useful in predicting risk for major osteoporotic fracture (MOF), compared with baseline BMD measurement alone. It analyzed data from prespecified subgroups defined by age, BMI, race/ethnicity, presence or absence of diabetes, and baseline BMD T score.¹

Study participants averaged 66 years of age, with a mean BMI of 29, and 23% were non-White. In addition, 97% had either normal BMD or osteopenia (T score ≥ −2.4). Participants were excluded from the study if they had been treated with bone-active medications other than vitamin D and calcium, reported a history of MOF (fracture of the hip, spine, radius, ulna, wrist, upper arm, or shoulder) at baseline or between BMD tests, missed follow-up visits after the Year 3 BMD scan, or had missing covariate data. Participants self-reported fractures on annual patient questionnaires, and hip fractures were confirmed through medical records.

During the mean follow-up period of 9 years after the second BMD test, 139 women (1.9%) had 1 or more hip fractures, and 732 women (9.9%) had 1 or more MOFs.

Area under the receiver operating characteristic curve (AU-ROC) values for baseline BMD screening and baseline plus 3-year BMD measurement were similar in their ability to discriminate between women who had a hip fracture or MOF and women who did not. AU-ROC values communicate the usefulness of a diagnostic or screening test. An AU-ROC value of 1 would be considered perfect (100% sensitive and 100% specific), whereas an AU-ROC of 0.5 suggests a test with no ability to discriminate at all. Values between 0.7 and 0.8 would be considered acceptable, and those between 0.8 and 0.9, excellent.

Continue to: The AU-ROCs in this study...

The AU-ROCs in this study were 0.71 (95% CI, 0.67-0.75) for baseline total hip BMD, 0.61 (95% CI, 0.56-0.65) for change in total hip BMD between baseline and 3-year BMD scan, and 0.73 (95% CI, 0.69-0.77) for the combined baseline total hip BMD and change in total hip BMD. For femoral neck and lumbar spine BMD, AU-ROC values demonstrated comparable discrimination of hip fracture and MOF as those for total hip BMD. The AU-ROC values among age subgroups (< 65 years, 65-74 years, and ≥ 75 years) were also similar. Associations between change in bone density and fracture risk did not change when adjusted for factors such as BMI, race/ethnicity, diabetes, or baseline BMD.

WHAT’S NEW

Results can be applied to a wider range of patients

This study found that for postmenopausal women, a repeat BMD measurement obtained 3 years after the initial assessment did not improve risk discrimination for hip fracture or MOF beyond the baseline BMD value and should not be routinely performed. Additionally, evidence from this study allows this recommendation to apply to younger postmenopausal women and a variety of high-risk subgroups.

CAVEATS

Possible bias due to self-reporting of fractures

This study suggests that for women without a diagnosis of osteoporosis at initial screening, repeat testing is unlikely to affect future risk stratification. Repeat BMD testing should still be considered when the results are likely to influence clinical management.

However, an important consideration is that fractures were self-reported in this study, introducing a possible source of bias. Additionally, although this study supports foregoing repeat screening at a 3-year interval, there is still no agreed-upon determination of when (or if) to repeat BMD screening in women without osteoporosis.

A large subset of the study population was younger than 65 (44%), the age when family physicians typically recommend screening for osteoporosis. However, the age-adjusted AU-ROC values for fracture risk prediction were the same, and this should not invalidate the conclusions for the study population at large.

CHALLENGES TO IMPLEMENTATION

No challenges seen

We see no challenges in implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 70-year-old White woman with a history of type 2 diabetes and a normal body mass index (BMI) presents to your office for a preventive care exam. She is otherwise doing well, without concerns. Her first dual-energy x-ray absorptiometry (DXA) scan, completed at age 67, demonstrated normal bone density. Should you recommend a repeat DXA scan today?

As many as 1 in 2 postmenopausal women are at risk for an ­osteoporosis-related fracture.² Each year, about 2 million fragility fractures occur in the United States.^2,3 The US Preventive Services Task Force (USPSTF) recommends bone mineral density (BMD) measurement in all women ages 65 years and older, as well as in younger postmenopausal women with certain clinical risk factors.⁴ The USPSTF does not make a recommendation regarding the interval for follow-up BMD testing.

Two prospective cohort studies determined that repeat BMD testing 4 to 8 years after baseline screening did not improve fracture risk prediction.^5,6 Limitations of these studies included no analysis of high-risk subgroups, as well as failure to include many younger postmenopausal women in the studies.^5,6 An additional longitudinal study that followed postmenopausal women for up to 15 years estimated that the interval for at least 10% of women to develop osteoporosis after initial screening was more than 15 years for women with normal BMD and about 5 years for those with moderate osteopenia.⁷

STUDY SUMMARY

No added predictive benefit found in 3-year repeat scan

The current study examined data from the Women’s Health Initiative Extension 1 Study, a large prospective cohort that included a broader range of postmenopausal women (N = 7419) than the previous studies. The purpose of this study was to determine if a second BMD measurement, about 3 years after the baseline BMD screening, would be useful in predicting risk for major osteoporotic fracture (MOF), compared with baseline BMD measurement alone. It analyzed data from prespecified subgroups defined by age, BMI, race/ethnicity, presence or absence of diabetes, and baseline BMD T score.¹

Study participants averaged 66 years of age, with a mean BMI of 29, and 23% were non-White. In addition, 97% had either normal BMD or osteopenia (T score ≥ −2.4). Participants were excluded from the study if they had been treated with bone-active medications other than vitamin D and calcium, reported a history of MOF (fracture of the hip, spine, radius, ulna, wrist, upper arm, or shoulder) at baseline or between BMD tests, missed follow-up visits after the Year 3 BMD scan, or had missing covariate data. Participants self-reported fractures on annual patient questionnaires, and hip fractures were confirmed through medical records.

During the mean follow-up period of 9 years after the second BMD test, 139 women (1.9%) had 1 or more hip fractures, and 732 women (9.9%) had 1 or more MOFs.

Area under the receiver operating characteristic curve (AU-ROC) values for baseline BMD screening and baseline plus 3-year BMD measurement were similar in their ability to discriminate between women who had a hip fracture or MOF and women who did not. AU-ROC values communicate the usefulness of a diagnostic or screening test. An AU-ROC value of 1 would be considered perfect (100% sensitive and 100% specific), whereas an AU-ROC of 0.5 suggests a test with no ability to discriminate at all. Values between 0.7 and 0.8 would be considered acceptable, and those between 0.8 and 0.9, excellent.

Continue to: The AU-ROCs in this study...

The AU-ROCs in this study were 0.71 (95% CI, 0.67-0.75) for baseline total hip BMD, 0.61 (95% CI, 0.56-0.65) for change in total hip BMD between baseline and 3-year BMD scan, and 0.73 (95% CI, 0.69-0.77) for the combined baseline total hip BMD and change in total hip BMD. For femoral neck and lumbar spine BMD, AU-ROC values demonstrated comparable discrimination of hip fracture and MOF as those for total hip BMD. The AU-ROC values among age subgroups (< 65 years, 65-74 years, and ≥ 75 years) were also similar. Associations between change in bone density and fracture risk did not change when adjusted for factors such as BMI, race/ethnicity, diabetes, or baseline BMD.

WHAT’S NEW

Results can be applied to a wider range of patients

This study found that for postmenopausal women, a repeat BMD measurement obtained 3 years after the initial assessment did not improve risk discrimination for hip fracture or MOF beyond the baseline BMD value and should not be routinely performed. Additionally, evidence from this study allows this recommendation to apply to younger postmenopausal women and a variety of high-risk subgroups.

CAVEATS

Possible bias due to self-reporting of fractures

This study suggests that for women without a diagnosis of osteoporosis at initial screening, repeat testing is unlikely to affect future risk stratification. Repeat BMD testing should still be considered when the results are likely to influence clinical management.

However, an important consideration is that fractures were self-reported in this study, introducing a possible source of bias. Additionally, although this study supports foregoing repeat screening at a 3-year interval, there is still no agreed-upon determination of when (or if) to repeat BMD screening in women without osteoporosis.

A large subset of the study population was younger than 65 (44%), the age when family physicians typically recommend screening for osteoporosis. However, the age-adjusted AU-ROC values for fracture risk prediction were the same, and this should not invalidate the conclusions for the study population at large.

CHALLENGES TO IMPLEMENTATION

No challenges seen

We see no challenges in implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 70-year-old White woman with a history of type 2 diabetes and a normal body mass index (BMI) presents to your office for a preventive care exam. She is otherwise doing well, without concerns. Her first dual-energy x-ray absorptiometry (DXA) scan, completed at age 67, demonstrated normal bone density. Should you recommend a repeat DXA scan today?

As many as 1 in 2 postmenopausal women are at risk for an ­osteoporosis-related fracture.² Each year, about 2 million fragility fractures occur in the United States.^2,3 The US Preventive Services Task Force (USPSTF) recommends bone mineral density (BMD) measurement in all women ages 65 years and older, as well as in younger postmenopausal women with certain clinical risk factors.⁴ The USPSTF does not make a recommendation regarding the interval for follow-up BMD testing.

Two prospective cohort studies determined that repeat BMD testing 4 to 8 years after baseline screening did not improve fracture risk prediction.^5,6 Limitations of these studies included no analysis of high-risk subgroups, as well as failure to include many younger postmenopausal women in the studies.^5,6 An additional longitudinal study that followed postmenopausal women for up to 15 years estimated that the interval for at least 10% of women to develop osteoporosis after initial screening was more than 15 years for women with normal BMD and about 5 years for those with moderate osteopenia.⁷

STUDY SUMMARY

No added predictive benefit found in 3-year repeat scan

The current study examined data from the Women’s Health Initiative Extension 1 Study, a large prospective cohort that included a broader range of postmenopausal women (N = 7419) than the previous studies. The purpose of this study was to determine if a second BMD measurement, about 3 years after the baseline BMD screening, would be useful in predicting risk for major osteoporotic fracture (MOF), compared with baseline BMD measurement alone. It analyzed data from prespecified subgroups defined by age, BMI, race/ethnicity, presence or absence of diabetes, and baseline BMD T score.¹

Study participants averaged 66 years of age, with a mean BMI of 29, and 23% were non-White. In addition, 97% had either normal BMD or osteopenia (T score ≥ −2.4). Participants were excluded from the study if they had been treated with bone-active medications other than vitamin D and calcium, reported a history of MOF (fracture of the hip, spine, radius, ulna, wrist, upper arm, or shoulder) at baseline or between BMD tests, missed follow-up visits after the Year 3 BMD scan, or had missing covariate data. Participants self-reported fractures on annual patient questionnaires, and hip fractures were confirmed through medical records.

During the mean follow-up period of 9 years after the second BMD test, 139 women (1.9%) had 1 or more hip fractures, and 732 women (9.9%) had 1 or more MOFs.

Area under the receiver operating characteristic curve (AU-ROC) values for baseline BMD screening and baseline plus 3-year BMD measurement were similar in their ability to discriminate between women who had a hip fracture or MOF and women who did not. AU-ROC values communicate the usefulness of a diagnostic or screening test. An AU-ROC value of 1 would be considered perfect (100% sensitive and 100% specific), whereas an AU-ROC of 0.5 suggests a test with no ability to discriminate at all. Values between 0.7 and 0.8 would be considered acceptable, and those between 0.8 and 0.9, excellent.

Continue to: The AU-ROCs in this study...

The AU-ROCs in this study were 0.71 (95% CI, 0.67-0.75) for baseline total hip BMD, 0.61 (95% CI, 0.56-0.65) for change in total hip BMD between baseline and 3-year BMD scan, and 0.73 (95% CI, 0.69-0.77) for the combined baseline total hip BMD and change in total hip BMD. For femoral neck and lumbar spine BMD, AU-ROC values demonstrated comparable discrimination of hip fracture and MOF as those for total hip BMD. The AU-ROC values among age subgroups (< 65 years, 65-74 years, and ≥ 75 years) were also similar. Associations between change in bone density and fracture risk did not change when adjusted for factors such as BMI, race/ethnicity, diabetes, or baseline BMD.

WHAT’S NEW

Results can be applied to a wider range of patients

This study found that for postmenopausal women, a repeat BMD measurement obtained 3 years after the initial assessment did not improve risk discrimination for hip fracture or MOF beyond the baseline BMD value and should not be routinely performed. Additionally, evidence from this study allows this recommendation to apply to younger postmenopausal women and a variety of high-risk subgroups.

CAVEATS

Possible bias due to self-reporting of fractures

This study suggests that for women without a diagnosis of osteoporosis at initial screening, repeat testing is unlikely to affect future risk stratification. Repeat BMD testing should still be considered when the results are likely to influence clinical management.

However, an important consideration is that fractures were self-reported in this study, introducing a possible source of bias. Additionally, although this study supports foregoing repeat screening at a 3-year interval, there is still no agreed-upon determination of when (or if) to repeat BMD screening in women without osteoporosis.

A large subset of the study population was younger than 65 (44%), the age when family physicians typically recommend screening for osteoporosis. However, the age-adjusted AU-ROC values for fracture risk prediction were the same, and this should not invalidate the conclusions for the study population at large.

CHALLENGES TO IMPLEMENTATION

No challenges seen

We see no challenges in implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

In July 2021, the Centers for Disease Control and Prevention (CDC) published its updated guidelines on the diagnosis, treatment, and prevention of sexually transmitted infections (STIs).¹ These guidelines were last published in 2015.² Family physicians should be familiar with these guidelines as they are considered the standard of care for the treatment and prevention of STIs.

To revise the guidelines, the CDC convened a large panel that included CDC staff and subject matter experts from around the country. Using methodology borrowed from the US Preventive Services Task Force (USPSTF),³ the panel developed key questions and completed systematic reviews using a standard approach. The evidence behind key recommendations was ranked as high, medium, or low. However, the specific recommendations presented in the published guidelines appear without strength-of-recommendation descriptions or rankings of the levels of evidence supporting them.

The CDC approach to STI control involves 5 strategies (TABLE 1),¹ which family physicians can implement as follows:

• Elicit an accurate sexual history.
• Discuss with patients and advise them on preventive interventions including barrier methods, microbicides, vaccines, and HIV pre-exposure prophylaxis.
• Order recommended screening tests for specific STIs from all sites of potential infection.
• Recognize the signs and symptoms of STIs and order recommended tests for confirmation.
• Treat confirmed infections using current recommended medications.
• Seek to advise, evaluate, and treat sex partners of those with documented STIs, and offer expedited partner therapy if allowed by state law.
• Perform recommended follow-up services for treated individuals.

Details on each of these strategies can be found in the new guidelines and are described for each specific pathogen and for specific demographic groups. Recommendations on screening for asymptomatic STIs can be found on the USPSTF website.⁴

The first step leading to targeted prevention strategies such as behavioral counseling, vaccination, and screening involves taking an accurate and complete sexual history. The CDC offers a 5-step process it calls the “5 Ps approach” to gathering needed information (TABLE 2).¹

Major updates on the treatment of specific infections

Gonorrhea

The current recommendation for treating uncomplicated gonococcal infections of the cervix, urethra, pharynx, and rectum in adults and adolescents weighing < 150 kg is ceftriaxone 500 mg intramuscularly (IM) as a single dose; give 1 g for those weighing ≥ 150 kg.¹ If co-infection with chlamydia has not been ruled out, co-treatment with doxycycline 100 mg po twice a day for 7 days is also recommended.¹

This differs from the first-line treatment recommended in the previous guideline, which was dual therapy with ceftriaxone 250 mg IM and azithromycin 1 g po as a single dose, regardless of testing results for chlamydia.² The higher dose for ceftriaxone now recommended is due to a gradual decrease in gonorrhea susceptibility to cephalosporins in recent years, although complete resistance remains rare. The move away from universal dual therapy reflects a concern about antibiotic stewardship and the potential effects of antibiotics on the microbiome. The elimination of azithromycin from recommended first-line therapies is due to a 10-fold increase in the proportion of bacterium isolates demonstrating reduced susceptibility, as measured by minimal inhibitory concentrations in the past few years.

Continue to: If ceftriaxone...

If ceftriaxone is unavailable, there are 2 alternative regimens: gentamicin 240 mg IM in a single dose, plus azithromycin 2 g po in a single dose; or cefixime 800 mg po in a single dose.¹ However, these alternatives are not recommended for gonococcal infection of the pharynx, for which ceftriaxone should be used.

Counsel those treated for gonorrhea to avoid sexual activity for 7 days after treatment and until all sex partners have been treated. Because of the high rates of asymptomatic infections, tell patients to refer those with whom they have had sexual contact during the previous 60 days for evaluation, testing, and presumptive treatment.

Following treatment with the recommended dose of ceftriaxone, performing a test of cure is not recommended, with 1 exception: those with confirmed pharyngeal infection should be tested to confirm treatment success 7 to 14 days after being treated. However, all those treated for gonorrhea should be seen again in 3 months and retested to rule out reinfection, regardless of whether they think their sex partners have been adequately treated.

Chlamydia

The recommended first-line therapy for chlamydia is now doxycycline 100 mg twice a day for 7 days, which has proven to be superior to azithromycin (which was recommended as first-line therapy in 2015) for urogenital chlamydia in men and anal chlamydia in both men and women.^1,2 Alternatives to doxycycline include azithromycin 1 g po as a single dose or levofloxacin 500 mg po once a day for 7 days.¹ No test of cure is recommended; but as with gonorrhea, retesting at 3 months is recommended because of the risk for re-infection.

No test of cure is needed following gonococcal infection treated with a recommended dose of ceftriaxone, except in those with confirmed pharyngeal infection.

Instruct patients treated for chlamydia to avoid sexual intercourse for 7 days after therapy is initiated or until symptoms, if present, have resolved. To reduce the chances of reinfection, advise treated individuals to abstain from sexual intercourse until all of their sex partners have been treated.

Continue to: Sex partners...

Sex partners in the 60 days prior to the patient’s onset of symptoms or diagnosis should be advised to seek evaluation, testing, and presumptive treatment.

Trichomonas

The recommended first-line treatment for trichomonas now differs for men and women: metronidazole 2 g po as a single dose for men, and metronidazole 500 mg po twice a day for 7 days for women.¹ Tinidazole 2 g po as a single dose is an alternative for both men and women. Previously, the single metronidazole dose was recommended for men and women,² but there is now evidence that the 7-day course is markedly superior in achieving a cure in women.

No test of cure is recommended, but women should be retested at 3 months because of a high rate of re-infection. Current sex partners should be treated presumptively, and treated patients and their partners should avoid sex until all current sex partners have been treated. Consider expedited partner therapy if allowed by state law.

Bacterial vaginosis

First-line treatment recommendations for bacterial vaginosis (BV) have not changed: metronidazole 500 mg po twice a day for 7 days, or metronidazole gel 0.75% intravaginally daily for 5 days, or clindamycin cream 2% intravaginally at bedtime for 7 days. Advise women to avoid sexual activity or to use condoms for the duration of the treatment regimen.

A test of cure is not recommended if symptoms resolve, and no treatment or evaluation of sex partners is recommended. The guidelines describe several treatment options for women who have frequent, recurrent BV. To help prevent recurrences, they additionally suggest treating male partners with metronidazole 400 mg po twice a day and with 2% clindamycin cream applied to the penis twice a day, both for 7 days.

Continue to: Pelvic inflammatory disease

Recommended regimens for treating pelvic inflammatory disease (PID) have changed (TABLES 3 and 4).¹ Women with mild or moderate PID can be treated with intramuscular or oral regimens, as outcomes with these regimens are equivalent to those seen with intravenous treatments. The nonintravenous options all include 3 antibiotics: a cephalosporin, doxycycline, and metronidazole.

To minimize disease transmission, instruct women to avoid sex until therapy is complete, their symptoms have resolved, and sex partners have been treated. Sex partners of those with PID in the 60 days prior to the onset of symptoms should be evaluated, tested, and presumptively treated for chlamydia and gonorrhea.

Follow through on public health procedures

STIs are an important set of diseases from a public health perspective. Family physicians have the opportunity to assist with the prevention and control of these infections through screening, making accurate diagnoses, and applying recommended treatments. When you suspect that a patient has an STI, test for the most common ones: gonorrhea, chlamydia, HIV, and syphilis. Report all confirmed diagnoses to the local public health department and be prepared to refer patients’ sexual contacts to the local public health department or to provide contact evaluation and treatment.

Vaccines against STIs include hepatitis B vaccine, human papillomavirus vaccine, and hepatitis A vaccine. Offer these vaccines to all previously unvaccinated adolescents and young adults as per recommendations from the Advisory Committee on Immunization Practices.⁵

In July 2021, the Centers for Disease Control and Prevention (CDC) published its updated guidelines on the diagnosis, treatment, and prevention of sexually transmitted infections (STIs).¹ These guidelines were last published in 2015.² Family physicians should be familiar with these guidelines as they are considered the standard of care for the treatment and prevention of STIs.

To revise the guidelines, the CDC convened a large panel that included CDC staff and subject matter experts from around the country. Using methodology borrowed from the US Preventive Services Task Force (USPSTF),³ the panel developed key questions and completed systematic reviews using a standard approach. The evidence behind key recommendations was ranked as high, medium, or low. However, the specific recommendations presented in the published guidelines appear without strength-of-recommendation descriptions or rankings of the levels of evidence supporting them.

The CDC approach to STI control involves 5 strategies (TABLE 1),¹ which family physicians can implement as follows:

• Elicit an accurate sexual history.
• Discuss with patients and advise them on preventive interventions including barrier methods, microbicides, vaccines, and HIV pre-exposure prophylaxis.
• Order recommended screening tests for specific STIs from all sites of potential infection.
• Recognize the signs and symptoms of STIs and order recommended tests for confirmation.
• Treat confirmed infections using current recommended medications.
• Seek to advise, evaluate, and treat sex partners of those with documented STIs, and offer expedited partner therapy if allowed by state law.
• Perform recommended follow-up services for treated individuals.

Details on each of these strategies can be found in the new guidelines and are described for each specific pathogen and for specific demographic groups. Recommendations on screening for asymptomatic STIs can be found on the USPSTF website.⁴

The first step leading to targeted prevention strategies such as behavioral counseling, vaccination, and screening involves taking an accurate and complete sexual history. The CDC offers a 5-step process it calls the “5 Ps approach” to gathering needed information (TABLE 2).¹

Major updates on the treatment of specific infections

Gonorrhea

The current recommendation for treating uncomplicated gonococcal infections of the cervix, urethra, pharynx, and rectum in adults and adolescents weighing < 150 kg is ceftriaxone 500 mg intramuscularly (IM) as a single dose; give 1 g for those weighing ≥ 150 kg.¹ If co-infection with chlamydia has not been ruled out, co-treatment with doxycycline 100 mg po twice a day for 7 days is also recommended.¹

This differs from the first-line treatment recommended in the previous guideline, which was dual therapy with ceftriaxone 250 mg IM and azithromycin 1 g po as a single dose, regardless of testing results for chlamydia.² The higher dose for ceftriaxone now recommended is due to a gradual decrease in gonorrhea susceptibility to cephalosporins in recent years, although complete resistance remains rare. The move away from universal dual therapy reflects a concern about antibiotic stewardship and the potential effects of antibiotics on the microbiome. The elimination of azithromycin from recommended first-line therapies is due to a 10-fold increase in the proportion of bacterium isolates demonstrating reduced susceptibility, as measured by minimal inhibitory concentrations in the past few years.

Continue to: If ceftriaxone...

If ceftriaxone is unavailable, there are 2 alternative regimens: gentamicin 240 mg IM in a single dose, plus azithromycin 2 g po in a single dose; or cefixime 800 mg po in a single dose.¹ However, these alternatives are not recommended for gonococcal infection of the pharynx, for which ceftriaxone should be used.

Counsel those treated for gonorrhea to avoid sexual activity for 7 days after treatment and until all sex partners have been treated. Because of the high rates of asymptomatic infections, tell patients to refer those with whom they have had sexual contact during the previous 60 days for evaluation, testing, and presumptive treatment.

Following treatment with the recommended dose of ceftriaxone, performing a test of cure is not recommended, with 1 exception: those with confirmed pharyngeal infection should be tested to confirm treatment success 7 to 14 days after being treated. However, all those treated for gonorrhea should be seen again in 3 months and retested to rule out reinfection, regardless of whether they think their sex partners have been adequately treated.

Chlamydia

The recommended first-line therapy for chlamydia is now doxycycline 100 mg twice a day for 7 days, which has proven to be superior to azithromycin (which was recommended as first-line therapy in 2015) for urogenital chlamydia in men and anal chlamydia in both men and women.^1,2 Alternatives to doxycycline include azithromycin 1 g po as a single dose or levofloxacin 500 mg po once a day for 7 days.¹ No test of cure is recommended; but as with gonorrhea, retesting at 3 months is recommended because of the risk for re-infection.

No test of cure is needed following gonococcal infection treated with a recommended dose of ceftriaxone, except in those with confirmed pharyngeal infection.

Instruct patients treated for chlamydia to avoid sexual intercourse for 7 days after therapy is initiated or until symptoms, if present, have resolved. To reduce the chances of reinfection, advise treated individuals to abstain from sexual intercourse until all of their sex partners have been treated.

Continue to: Sex partners...

Sex partners in the 60 days prior to the patient’s onset of symptoms or diagnosis should be advised to seek evaluation, testing, and presumptive treatment.

Trichomonas

The recommended first-line treatment for trichomonas now differs for men and women: metronidazole 2 g po as a single dose for men, and metronidazole 500 mg po twice a day for 7 days for women.¹ Tinidazole 2 g po as a single dose is an alternative for both men and women. Previously, the single metronidazole dose was recommended for men and women,² but there is now evidence that the 7-day course is markedly superior in achieving a cure in women.

No test of cure is recommended, but women should be retested at 3 months because of a high rate of re-infection. Current sex partners should be treated presumptively, and treated patients and their partners should avoid sex until all current sex partners have been treated. Consider expedited partner therapy if allowed by state law.

Bacterial vaginosis

First-line treatment recommendations for bacterial vaginosis (BV) have not changed: metronidazole 500 mg po twice a day for 7 days, or metronidazole gel 0.75% intravaginally daily for 5 days, or clindamycin cream 2% intravaginally at bedtime for 7 days. Advise women to avoid sexual activity or to use condoms for the duration of the treatment regimen.

A test of cure is not recommended if symptoms resolve, and no treatment or evaluation of sex partners is recommended. The guidelines describe several treatment options for women who have frequent, recurrent BV. To help prevent recurrences, they additionally suggest treating male partners with metronidazole 400 mg po twice a day and with 2% clindamycin cream applied to the penis twice a day, both for 7 days.

Continue to: Pelvic inflammatory disease

Recommended regimens for treating pelvic inflammatory disease (PID) have changed (TABLES 3 and 4).¹ Women with mild or moderate PID can be treated with intramuscular or oral regimens, as outcomes with these regimens are equivalent to those seen with intravenous treatments. The nonintravenous options all include 3 antibiotics: a cephalosporin, doxycycline, and metronidazole.

To minimize disease transmission, instruct women to avoid sex until therapy is complete, their symptoms have resolved, and sex partners have been treated. Sex partners of those with PID in the 60 days prior to the onset of symptoms should be evaluated, tested, and presumptively treated for chlamydia and gonorrhea.

Follow through on public health procedures

STIs are an important set of diseases from a public health perspective. Family physicians have the opportunity to assist with the prevention and control of these infections through screening, making accurate diagnoses, and applying recommended treatments. When you suspect that a patient has an STI, test for the most common ones: gonorrhea, chlamydia, HIV, and syphilis. Report all confirmed diagnoses to the local public health department and be prepared to refer patients’ sexual contacts to the local public health department or to provide contact evaluation and treatment.

Vaccines against STIs include hepatitis B vaccine, human papillomavirus vaccine, and hepatitis A vaccine. Offer these vaccines to all previously unvaccinated adolescents and young adults as per recommendations from the Advisory Committee on Immunization Practices.⁵

In July 2021, the Centers for Disease Control and Prevention (CDC) published its updated guidelines on the diagnosis, treatment, and prevention of sexually transmitted infections (STIs).¹ These guidelines were last published in 2015.² Family physicians should be familiar with these guidelines as they are considered the standard of care for the treatment and prevention of STIs.

To revise the guidelines, the CDC convened a large panel that included CDC staff and subject matter experts from around the country. Using methodology borrowed from the US Preventive Services Task Force (USPSTF),³ the panel developed key questions and completed systematic reviews using a standard approach. The evidence behind key recommendations was ranked as high, medium, or low. However, the specific recommendations presented in the published guidelines appear without strength-of-recommendation descriptions or rankings of the levels of evidence supporting them.

The CDC approach to STI control involves 5 strategies (TABLE 1),¹ which family physicians can implement as follows:

• Elicit an accurate sexual history.
• Discuss with patients and advise them on preventive interventions including barrier methods, microbicides, vaccines, and HIV pre-exposure prophylaxis.
• Order recommended screening tests for specific STIs from all sites of potential infection.
• Recognize the signs and symptoms of STIs and order recommended tests for confirmation.
• Treat confirmed infections using current recommended medications.
• Seek to advise, evaluate, and treat sex partners of those with documented STIs, and offer expedited partner therapy if allowed by state law.
• Perform recommended follow-up services for treated individuals.

Details on each of these strategies can be found in the new guidelines and are described for each specific pathogen and for specific demographic groups. Recommendations on screening for asymptomatic STIs can be found on the USPSTF website.⁴

The first step leading to targeted prevention strategies such as behavioral counseling, vaccination, and screening involves taking an accurate and complete sexual history. The CDC offers a 5-step process it calls the “5 Ps approach” to gathering needed information (TABLE 2).¹

Major updates on the treatment of specific infections

Gonorrhea

The current recommendation for treating uncomplicated gonococcal infections of the cervix, urethra, pharynx, and rectum in adults and adolescents weighing < 150 kg is ceftriaxone 500 mg intramuscularly (IM) as a single dose; give 1 g for those weighing ≥ 150 kg.¹ If co-infection with chlamydia has not been ruled out, co-treatment with doxycycline 100 mg po twice a day for 7 days is also recommended.¹

This differs from the first-line treatment recommended in the previous guideline, which was dual therapy with ceftriaxone 250 mg IM and azithromycin 1 g po as a single dose, regardless of testing results for chlamydia.² The higher dose for ceftriaxone now recommended is due to a gradual decrease in gonorrhea susceptibility to cephalosporins in recent years, although complete resistance remains rare. The move away from universal dual therapy reflects a concern about antibiotic stewardship and the potential effects of antibiotics on the microbiome. The elimination of azithromycin from recommended first-line therapies is due to a 10-fold increase in the proportion of bacterium isolates demonstrating reduced susceptibility, as measured by minimal inhibitory concentrations in the past few years.

Continue to: If ceftriaxone...

If ceftriaxone is unavailable, there are 2 alternative regimens: gentamicin 240 mg IM in a single dose, plus azithromycin 2 g po in a single dose; or cefixime 800 mg po in a single dose.¹ However, these alternatives are not recommended for gonococcal infection of the pharynx, for which ceftriaxone should be used.

Counsel those treated for gonorrhea to avoid sexual activity for 7 days after treatment and until all sex partners have been treated. Because of the high rates of asymptomatic infections, tell patients to refer those with whom they have had sexual contact during the previous 60 days for evaluation, testing, and presumptive treatment.

Following treatment with the recommended dose of ceftriaxone, performing a test of cure is not recommended, with 1 exception: those with confirmed pharyngeal infection should be tested to confirm treatment success 7 to 14 days after being treated. However, all those treated for gonorrhea should be seen again in 3 months and retested to rule out reinfection, regardless of whether they think their sex partners have been adequately treated.

Chlamydia

The recommended first-line therapy for chlamydia is now doxycycline 100 mg twice a day for 7 days, which has proven to be superior to azithromycin (which was recommended as first-line therapy in 2015) for urogenital chlamydia in men and anal chlamydia in both men and women.^1,2 Alternatives to doxycycline include azithromycin 1 g po as a single dose or levofloxacin 500 mg po once a day for 7 days.¹ No test of cure is recommended; but as with gonorrhea, retesting at 3 months is recommended because of the risk for re-infection.

No test of cure is needed following gonococcal infection treated with a recommended dose of ceftriaxone, except in those with confirmed pharyngeal infection.

Instruct patients treated for chlamydia to avoid sexual intercourse for 7 days after therapy is initiated or until symptoms, if present, have resolved. To reduce the chances of reinfection, advise treated individuals to abstain from sexual intercourse until all of their sex partners have been treated.

Continue to: Sex partners...

Sex partners in the 60 days prior to the patient’s onset of symptoms or diagnosis should be advised to seek evaluation, testing, and presumptive treatment.

Trichomonas

The recommended first-line treatment for trichomonas now differs for men and women: metronidazole 2 g po as a single dose for men, and metronidazole 500 mg po twice a day for 7 days for women.¹ Tinidazole 2 g po as a single dose is an alternative for both men and women. Previously, the single metronidazole dose was recommended for men and women,² but there is now evidence that the 7-day course is markedly superior in achieving a cure in women.

No test of cure is recommended, but women should be retested at 3 months because of a high rate of re-infection. Current sex partners should be treated presumptively, and treated patients and their partners should avoid sex until all current sex partners have been treated. Consider expedited partner therapy if allowed by state law.

Bacterial vaginosis

First-line treatment recommendations for bacterial vaginosis (BV) have not changed: metronidazole 500 mg po twice a day for 7 days, or metronidazole gel 0.75% intravaginally daily for 5 days, or clindamycin cream 2% intravaginally at bedtime for 7 days. Advise women to avoid sexual activity or to use condoms for the duration of the treatment regimen.

A test of cure is not recommended if symptoms resolve, and no treatment or evaluation of sex partners is recommended. The guidelines describe several treatment options for women who have frequent, recurrent BV. To help prevent recurrences, they additionally suggest treating male partners with metronidazole 400 mg po twice a day and with 2% clindamycin cream applied to the penis twice a day, both for 7 days.

Continue to: Pelvic inflammatory disease

Recommended regimens for treating pelvic inflammatory disease (PID) have changed (TABLES 3 and 4).¹ Women with mild or moderate PID can be treated with intramuscular or oral regimens, as outcomes with these regimens are equivalent to those seen with intravenous treatments. The nonintravenous options all include 3 antibiotics: a cephalosporin, doxycycline, and metronidazole.

To minimize disease transmission, instruct women to avoid sex until therapy is complete, their symptoms have resolved, and sex partners have been treated. Sex partners of those with PID in the 60 days prior to the onset of symptoms should be evaluated, tested, and presumptively treated for chlamydia and gonorrhea.

Follow through on public health procedures

STIs are an important set of diseases from a public health perspective. Family physicians have the opportunity to assist with the prevention and control of these infections through screening, making accurate diagnoses, and applying recommended treatments. When you suspect that a patient has an STI, test for the most common ones: gonorrhea, chlamydia, HIV, and syphilis. Report all confirmed diagnoses to the local public health department and be prepared to refer patients’ sexual contacts to the local public health department or to provide contact evaluation and treatment.

Vaccines against STIs include hepatitis B vaccine, human papillomavirus vaccine, and hepatitis A vaccine. Offer these vaccines to all previously unvaccinated adolescents and young adults as per recommendations from the Advisory Committee on Immunization Practices.⁵

CASE A 34-year-old woman presents with fatigue. She appears defensive when asked about her alcohol use. She answers No to all questions on the CAGE (cut down, annoyed, guilty, eye-opener) screening tool, but acknowledges drinking excessively on rare occasions. Her physician has a high suspicion for alcohol use disorder (AUD) and recommends further testing. The patient agrees but denies having used alcohol over the past several days. Which of the following is most likely to help support the suspicion of a heavy drinking pattern?

1. Routine lab tests (liver panel and complete blood count).
2. Blood or urine alcohol level.
3. Phosphatidylethanol (PEth) level in the blood.
4. Ethyl glucuronide (EtG) in the urine.
5. Carbohydrate-deficient transferrin (CDT) in the blood.

(See "Case answer.").

About 1 in 12 Americans have AUD,¹ and 1 in 10 children live in a home with a parent who has a drinking problem.² While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) succinctly defines AUD with specific criteria,¹ the term generally refers to an inability to control or stop drinking despite adverse social or health consequences. AUD is regarded as > 4 drinks per day for men and > 3 drinks per day for women.³ A “standard drink” would be a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz of distilled spirits. Effects of chronic alcohol use are vast and include malnutrition, alcohol withdrawal syndrome, alcoholic liver disease, pancreatitis/pancreatic cancer, cardiomyopathy, and stroke.^4-6 Alcohol use by a pregnant woman can lead to fetal alcohol syndrome in her child.⁷

AUD may be more prevalent in the wake of COVID-19. Primary care practitioners tend to miss a large fraction of patients with AUD in their practice, especially younger patients and those without somatic comorbidities.⁸ Systematic screening for AUD can identify many of these people.⁸ Particularly as the COVID-19 pandemic continues to unfold and increases stress for everyone, risk of worsening drinking increases both in individuals with current AUD and for those in remission.⁹ Contrary to common belief, patients visiting primary care favor screening for at-risk drinking.¹⁰ Thus, awareness of the prevalence of AUD and patient acceptance of screening should encourage wider testing.

Screening tools. The 2014 guidelines published by the Centers for Disease Control and Prevention recommend using quick screening tools—ie, single question or ­AUDIT 1-3 (TABLE 1^11-18)—as an objective means of determining whether patients’ drinking creates a risk for themselves or others.¹¹ Excessive drinking identified using alcohol questionnaires can help reduce medical complications and health care costs.¹⁹ The questionnaires we review do not provide a diagnosis but help identify individuals who might benefit from more thorough assessment.²⁰ Following up, as needed, by testing for alcohol biomarkers can provide quantitative insight into problematic alcohol use.²

Primary care practitioners tend to miss a large fraction of patients with alcohol use disorder in their practice. Systematic screening for AUD can identify many of these patients.

But before we discuss the utility of biomarkers, it’s important to quickly review how alcohol is eliminated from the body.

Alcohol elimination

The stomach and small intestine are the primary sites for alcohol absorption. Alcohol elimination from the body occurs through 3 pathways. The first involves oxidative metabolism, which eliminates most ethanol (95%) through the actions of alcohol dehydrogenase, cytochrome P4502E1, or catalase. A lesser amount of alcohol (2%-5%) is eliminated, unchanged, via the second pathway, which includes urine, sweat, and breath. Nonoxidative metabolism makes up the third pathway. Nonoxidative metabolism removes a very small amount (0.1%) of alcohol and involves the direct ethanol biomarkers PEth, EtG, ethyl sulfate (EtS), and fatty acid ethyl esters (FAEEs).²¹ Our emphasis in this article is on assays of direct metabolites of alcohol—particularly PEth.

Continue to: To understand the utility...

To understand the utility of these direct biomarkers, it is helpful to look at the indirect biomarkers first.

Indirect biomarkers have limited sensitivity and specificity

When alcohol is consumed in large enough quantities over time, indirect biomarkers of alcohol can become abnormal.²² The major indirect biomarkers are the liver enzymes aspartate and alanine aminotransferase (AST and ALT), gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV) of red blood cells, and carbohydrate-deficient transferrin (CDT). Indirect biomarkers have limited sensitivity and specificity for AUD. (For specifics on sensitivity and specificity of indirect and direct biomarkers, see TABLE 2.^23-31)

Liver enzymes. AST and ALT are also present in the heart, muscle, and kidneys. Elevated levels usually imply injury to hepatocytes, with ALT being more reflective of liver involvement than AST. Both AST and ALT are elevated in other common liver conditions including hepatitis C virus infection and fatty liver disease. In alcoholic liver disease (ALD), AST is elevated more than ALT; an AST-to-ALT ratio > 3 suggests ALD. An elevated GGT often indicates hepatic injury and is used to confirm that elevated alkaline phosphatase is of hepatic origin.³²

MCV is the average volume of erythrocytes,³³ and an elevated MCV is a potential indicator of excessive alcohol intake. Macrocytosis requires sustained alcohol use, and the test has low sensitivity. Other diseases such as vitamin B12 or folic acid deficiency, hypothyroidism, hematologic diseases (eg, cold agglutinin disease, multiple myeloma, amyloidosis), and certain medications can also increase MCV.³⁴ Moreover, MCV responds slowly to alcohol use, abstinence, and relapse because red cells have a life span of 120 days.³⁵

CDT. Transferrin is a glycoprotein produced in the liver. The level of transferrin with sialic acid chains increases with alcohol consumption as well as in the carbohydrate deficient glycoprotein syndrome, leading to so-called carbohydrate deficient transferrin.³⁶ It is a sensitive marker for detecting alcohol relapse and monitoring sobriety. Moderate-to-heavy alcohol use, averaging ≥ 40 g of alcohol per day for 2 weeks,³⁶ can decrease the amount of carbohydrate attached to transferrin. Two weeks after complete alcohol cessation, CDT levels will return to normal.³⁷

Continue to: CDT is approved...

CDT is approved by the FDA as an assay for alcohol consumption.³⁷ While CDT is felt to be one of the better indirect markers of AUD and can extend the window of detection, there are still issues with its sensitivity and specificity.³⁸ This biomarker can be elevated with other liver diseases and can be affected by the patient’s age, body mass index, gender, and tobacco use.^39,40 Testing for CDT has never achieved widespread clinical use and has been largely supplanted by the more accurate PEth test (described in a bit).

Direct biomarkers offer insight into recent alcohol use

Other than ethanol itself, direct biomarkers of alcohol use are minor ethanol metabolites created through biochemical reactions when ethanol is coupled to endogenous compounds. Hence, the presence of these metabolites is usually directly related to ethanol consumption.⁴¹ Direct alcohol biomarkers are EtG, EtS, FAEEs, and PEth (TABLE 2^23-31). They reflect alcohol consumption over a period of several days, making them useful when paired with questionnaire data, especially for identifying young adults who engage in binge drinking.⁴²

Ethanol can be measured in blood, urine, and breath and is detectable a bit longer in urine than in blood. However, alcohol is detectable in the blood only for 6 to 12 hours after drinking. After alcohol consumption, concentrations peak in the blood within 2 hours. The window for detecting ethanol in the blood depends on the amount of alcohol consumed and the elimination rate of alcohol, which is about 12 mg/dL/h (or 0.012%)—approximately the same amount of alcohol contained in a standard drink (14 g).

EtG can be detected in urine for ≥ 24 hours after just 1 or 2 drinks, and for up to 4 days after heavy consumption.

Checking the blood alcohol level might be helpful in the office if a patient appears intoxicated but denies alcohol use. A blood alcohol level > 300 mg/dL, or > 150 mg/dL without gross evidence of intoxication, or > 100 mg/dL upon routine examination indicates AUD with a high degree of reliability.^33,43 But the short half-life of ethanol in blood limits its use as a biomarker,³³ and it is not a good indicator of chronic drinking.⁴⁴

EtG and EtS. Less than 0.1% of ethanol is secreted as the metabolites EtG and EtS, which are generated, respectively, by the enzymes uridine diphosphate glucuronosyltransferase and sulfotransferase.⁴⁵ They have value in the diagnosis of AUD because of the length of time in which they can be detected. Urinary EtG and EtS have been especially important biomarkers for monitoring relapse in outpatients treated for alcohol-­related problems.⁴⁶ Generally, EtG and EtS can be detected in urine for 13 to 20 hours after a single drink (0.1 g/kg), and for up to 4 to 5 days following ingestion of large amounts of alcohol.⁴⁷

Continue to: EtG has been detectable...

EtG has been detectable in urine for ≥ 24 hours following only 1 or 2 drinks, and for up to 4 days following heavy consumption.⁴⁸ Shortly after alcohol intake, even in small amounts, EtG is detectable. Analysis of EtG in urine is helpful in monitoring alcohol consumption during withdrawal treatment, for workplace testing, and to check for abstinence in legal matters. The EtG urine test is useful in detecting alcohol consumption in a person who claims to be abstinent but who drank 2 or 3 days before the evaluation. Although accurate, EtG’s window for detection is narrower than that of the PEth assay.

EtS is a good marker of acute short-term alcohol use, up to 12 hours in the blood (or longer in heavier drinkers) and up to 5 days in urine.⁴⁹ Its sensitivity is highest in heavy drinkers. Post-sampling formation and degradation of EtS have not been known to occur in urine samples. Testing for this second metabolite of ethanol can slightly improve the sensitivity and specificity of the EtG test. A urine test for EtS has a wider detection window. But it has little practical advantage compared with EtG.⁵⁰

For better clinical specificity, a combination of both EtG and EtS testing has been recommended. However, the EtS assay is more cumbersome and provides little advantage over EtG. EtG values do not correlate precisely with the amount or frequency of ethanol use, but the magnitude of the EtG finding roughly corresponds to the amount of alcohol recently consumed.

False-positive and false-negative results for EtG and EtS are uncommon in practice. However, false-positive results are possible with the EtG test in certain circumstances: presence of Escherichia coli in the specimen, use of ethanol-based hand sanitizers (> 20 times a day) or mouthwashes, and the consumption of substances like pralines, nonalcoholic beer, pharmaceutical products, and fruit juice. Similarly, false-negative results of EtG can occur from degradation if the samples are contaminated with other bacteria, transported without cooling, or stored improperly.⁵¹ In practice, this is uncommon, and the test is believed to be specific with few false-positive results. Commercially available EtG colorimetric test strips permit on-site analysis of urine samples.

FAEEs are a combination of different esters and products of alcohol metabolism through a nonoxidative pathway. They are formed by esterification of endogenous free fatty acids and ethanol in blood and several tissues.²⁹ These are sensitive and specific markers of alcohol ingestion and can differentiate chronic alcohol consumption from binge drinking.²⁹ It is elevated for up to 99 hours in heavy alcohol drinkers.³⁰ It can be detected in hair for a longer period than in blood.⁵² Detection of FAEEs in meconium can help establish fetal alcohol exposure.⁵³

Continue to: PEth

PEth. Use of the PEth assay has increased in recent years and its accuracy has had a transformative effect on the diagnosis of AUD.⁵⁴ PEth is a phospholipid found in erythrocyte membranes, formed by an interaction between ethanol and phosphatidylcholine, catalyzed by phospholipase D.^55,56 Major advantages of PEth include an unusually long half-life and specificity. Red cells lack enzymes to degrade PEth, therefore PEth accumulates in red cells and has a half-life of 4 to 10 days^57,58 allowing for detection of significant ethanol consumption extending back 3 to 4 weeks.⁵⁹ There is no evidence that PEth is formed in the absence of ethanol, making the test essentially 100% specific, particularly at higher cutoff values of ≥ 150 ng/mL.^31,60

PEth is known to be formed only in the presence of ethanol, making the test virtually 100% specific.

PEth levels are not affected by age, gender, or underlying liver or renal disease.⁶¹ PEth can differentiate between heavy alcohol use and social drinking and can therefore identify chronic excessive use.⁶² With chronic excessive alcohol consumption, PEth is detectable in blood up to 28 days after sobriety.⁶³ A correlation exists between PEth concentrations in blood and the amount of consumed ethanol. PEth has increased specificity and sensitivity for the detection of latent ethanol use compared with other direct biomarkers.²¹ It can identify recent heavy drinking earlier than indirect biomarkers, as it does not rely on hepatic injury.

Using a cutoff level of 20 ng/mL, PEth assays have a sensitivity of 73% for any alcohol use in the past month; at 80 ng/mL, the sensitivity is 91% for > 4 drinks/d.⁶¹ PEth is considered semi-quantitative. The World Health Organization defines acceptable social alcohol use at a PEth value < 40 ng/dL for men and < 20 ng/dL for women. Chronic excessive use is defined by a level > 60 ng/dL.⁵⁵ The cutoff levels tend to be arbitrary and vary with different guidelines.

PEth may be a useful marker in difficult-toassess settings, or in confirming or invalidating self-reported alcohol consumption.

Although false-positive PEth test results may be possible, most experts believe that dishonesty in self-reporting by test subjects is more likely. That said, the true specificity of PEth remains unknown; a lower value detected should not be regarded as absolute proof of relapse or chronic alcoholism.

Studies have shown a positive correlation between the AUDIT-C score and PEth values combined with self-reported alcohol consumption, indicating that PEth may be a useful marker in difficult-to-assess settings, or in confirming or invalidating self-reported alcohol consumption.^61,64,65 The PEth test is now widely available and, in the authors’ experience, usually costs $100 to $200. Analysis typically costs $40 to $100,⁶⁶ and costs could decrease as the test becomes more widely used. Turnaround time for PEth is 5 to 10 days. It is now the recommended assay by transplant hepatologists for detecting alcohol use.⁶⁷TABLE 3^22,68 explains the currently accepted ranges for various PEth results.

Continue to: CASE ANSWER

CASE ANSWER While every test mentioned can aid in detecting alcohol consumption, the PEth assay in this scenario would be the most clinically useful.

CORRESPONDENCE
Frederick Nunes, MD, Pennsylvania Hospital of University of Pennsylvania, 230 West Washington Square, 4th Floor, Philadelphia, PA 19104; frederick.nunes@pennmedicine.upenn.edu

CASE A 34-year-old woman presents with fatigue. She appears defensive when asked about her alcohol use. She answers No to all questions on the CAGE (cut down, annoyed, guilty, eye-opener) screening tool, but acknowledges drinking excessively on rare occasions. Her physician has a high suspicion for alcohol use disorder (AUD) and recommends further testing. The patient agrees but denies having used alcohol over the past several days. Which of the following is most likely to help support the suspicion of a heavy drinking pattern?

1. Routine lab tests (liver panel and complete blood count).
2. Blood or urine alcohol level.
3. Phosphatidylethanol (PEth) level in the blood.
4. Ethyl glucuronide (EtG) in the urine.
5. Carbohydrate-deficient transferrin (CDT) in the blood.

(See "Case answer.").

About 1 in 12 Americans have AUD,¹ and 1 in 10 children live in a home with a parent who has a drinking problem.² While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) succinctly defines AUD with specific criteria,¹ the term generally refers to an inability to control or stop drinking despite adverse social or health consequences. AUD is regarded as > 4 drinks per day for men and > 3 drinks per day for women.³ A “standard drink” would be a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz of distilled spirits. Effects of chronic alcohol use are vast and include malnutrition, alcohol withdrawal syndrome, alcoholic liver disease, pancreatitis/pancreatic cancer, cardiomyopathy, and stroke.^4-6 Alcohol use by a pregnant woman can lead to fetal alcohol syndrome in her child.⁷

AUD may be more prevalent in the wake of COVID-19. Primary care practitioners tend to miss a large fraction of patients with AUD in their practice, especially younger patients and those without somatic comorbidities.⁸ Systematic screening for AUD can identify many of these people.⁸ Particularly as the COVID-19 pandemic continues to unfold and increases stress for everyone, risk of worsening drinking increases both in individuals with current AUD and for those in remission.⁹ Contrary to common belief, patients visiting primary care favor screening for at-risk drinking.¹⁰ Thus, awareness of the prevalence of AUD and patient acceptance of screening should encourage wider testing.

Screening tools. The 2014 guidelines published by the Centers for Disease Control and Prevention recommend using quick screening tools—ie, single question or ­AUDIT 1-3 (TABLE 1^11-18)—as an objective means of determining whether patients’ drinking creates a risk for themselves or others.¹¹ Excessive drinking identified using alcohol questionnaires can help reduce medical complications and health care costs.¹⁹ The questionnaires we review do not provide a diagnosis but help identify individuals who might benefit from more thorough assessment.²⁰ Following up, as needed, by testing for alcohol biomarkers can provide quantitative insight into problematic alcohol use.²

Primary care practitioners tend to miss a large fraction of patients with alcohol use disorder in their practice. Systematic screening for AUD can identify many of these patients.

But before we discuss the utility of biomarkers, it’s important to quickly review how alcohol is eliminated from the body.

Alcohol elimination

The stomach and small intestine are the primary sites for alcohol absorption. Alcohol elimination from the body occurs through 3 pathways. The first involves oxidative metabolism, which eliminates most ethanol (95%) through the actions of alcohol dehydrogenase, cytochrome P4502E1, or catalase. A lesser amount of alcohol (2%-5%) is eliminated, unchanged, via the second pathway, which includes urine, sweat, and breath. Nonoxidative metabolism makes up the third pathway. Nonoxidative metabolism removes a very small amount (0.1%) of alcohol and involves the direct ethanol biomarkers PEth, EtG, ethyl sulfate (EtS), and fatty acid ethyl esters (FAEEs).²¹ Our emphasis in this article is on assays of direct metabolites of alcohol—particularly PEth.

Continue to: To understand the utility...

To understand the utility of these direct biomarkers, it is helpful to look at the indirect biomarkers first.

Indirect biomarkers have limited sensitivity and specificity

When alcohol is consumed in large enough quantities over time, indirect biomarkers of alcohol can become abnormal.²² The major indirect biomarkers are the liver enzymes aspartate and alanine aminotransferase (AST and ALT), gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV) of red blood cells, and carbohydrate-deficient transferrin (CDT). Indirect biomarkers have limited sensitivity and specificity for AUD. (For specifics on sensitivity and specificity of indirect and direct biomarkers, see TABLE 2.^23-31)

Liver enzymes. AST and ALT are also present in the heart, muscle, and kidneys. Elevated levels usually imply injury to hepatocytes, with ALT being more reflective of liver involvement than AST. Both AST and ALT are elevated in other common liver conditions including hepatitis C virus infection and fatty liver disease. In alcoholic liver disease (ALD), AST is elevated more than ALT; an AST-to-ALT ratio > 3 suggests ALD. An elevated GGT often indicates hepatic injury and is used to confirm that elevated alkaline phosphatase is of hepatic origin.³²

MCV is the average volume of erythrocytes,³³ and an elevated MCV is a potential indicator of excessive alcohol intake. Macrocytosis requires sustained alcohol use, and the test has low sensitivity. Other diseases such as vitamin B12 or folic acid deficiency, hypothyroidism, hematologic diseases (eg, cold agglutinin disease, multiple myeloma, amyloidosis), and certain medications can also increase MCV.³⁴ Moreover, MCV responds slowly to alcohol use, abstinence, and relapse because red cells have a life span of 120 days.³⁵

CDT. Transferrin is a glycoprotein produced in the liver. The level of transferrin with sialic acid chains increases with alcohol consumption as well as in the carbohydrate deficient glycoprotein syndrome, leading to so-called carbohydrate deficient transferrin.³⁶ It is a sensitive marker for detecting alcohol relapse and monitoring sobriety. Moderate-to-heavy alcohol use, averaging ≥ 40 g of alcohol per day for 2 weeks,³⁶ can decrease the amount of carbohydrate attached to transferrin. Two weeks after complete alcohol cessation, CDT levels will return to normal.³⁷

Continue to: CDT is approved...

CDT is approved by the FDA as an assay for alcohol consumption.³⁷ While CDT is felt to be one of the better indirect markers of AUD and can extend the window of detection, there are still issues with its sensitivity and specificity.³⁸ This biomarker can be elevated with other liver diseases and can be affected by the patient’s age, body mass index, gender, and tobacco use.^39,40 Testing for CDT has never achieved widespread clinical use and has been largely supplanted by the more accurate PEth test (described in a bit).

Direct biomarkers offer insight into recent alcohol use

Other than ethanol itself, direct biomarkers of alcohol use are minor ethanol metabolites created through biochemical reactions when ethanol is coupled to endogenous compounds. Hence, the presence of these metabolites is usually directly related to ethanol consumption.⁴¹ Direct alcohol biomarkers are EtG, EtS, FAEEs, and PEth (TABLE 2^23-31). They reflect alcohol consumption over a period of several days, making them useful when paired with questionnaire data, especially for identifying young adults who engage in binge drinking.⁴²

Ethanol can be measured in blood, urine, and breath and is detectable a bit longer in urine than in blood. However, alcohol is detectable in the blood only for 6 to 12 hours after drinking. After alcohol consumption, concentrations peak in the blood within 2 hours. The window for detecting ethanol in the blood depends on the amount of alcohol consumed and the elimination rate of alcohol, which is about 12 mg/dL/h (or 0.012%)—approximately the same amount of alcohol contained in a standard drink (14 g).

EtG can be detected in urine for ≥ 24 hours after just 1 or 2 drinks, and for up to 4 days after heavy consumption.

Checking the blood alcohol level might be helpful in the office if a patient appears intoxicated but denies alcohol use. A blood alcohol level > 300 mg/dL, or > 150 mg/dL without gross evidence of intoxication, or > 100 mg/dL upon routine examination indicates AUD with a high degree of reliability.^33,43 But the short half-life of ethanol in blood limits its use as a biomarker,³³ and it is not a good indicator of chronic drinking.⁴⁴

EtG and EtS. Less than 0.1% of ethanol is secreted as the metabolites EtG and EtS, which are generated, respectively, by the enzymes uridine diphosphate glucuronosyltransferase and sulfotransferase.⁴⁵ They have value in the diagnosis of AUD because of the length of time in which they can be detected. Urinary EtG and EtS have been especially important biomarkers for monitoring relapse in outpatients treated for alcohol-­related problems.⁴⁶ Generally, EtG and EtS can be detected in urine for 13 to 20 hours after a single drink (0.1 g/kg), and for up to 4 to 5 days following ingestion of large amounts of alcohol.⁴⁷

Continue to: EtG has been detectable...

EtG has been detectable in urine for ≥ 24 hours following only 1 or 2 drinks, and for up to 4 days following heavy consumption.⁴⁸ Shortly after alcohol intake, even in small amounts, EtG is detectable. Analysis of EtG in urine is helpful in monitoring alcohol consumption during withdrawal treatment, for workplace testing, and to check for abstinence in legal matters. The EtG urine test is useful in detecting alcohol consumption in a person who claims to be abstinent but who drank 2 or 3 days before the evaluation. Although accurate, EtG’s window for detection is narrower than that of the PEth assay.

EtS is a good marker of acute short-term alcohol use, up to 12 hours in the blood (or longer in heavier drinkers) and up to 5 days in urine.⁴⁹ Its sensitivity is highest in heavy drinkers. Post-sampling formation and degradation of EtS have not been known to occur in urine samples. Testing for this second metabolite of ethanol can slightly improve the sensitivity and specificity of the EtG test. A urine test for EtS has a wider detection window. But it has little practical advantage compared with EtG.⁵⁰

For better clinical specificity, a combination of both EtG and EtS testing has been recommended. However, the EtS assay is more cumbersome and provides little advantage over EtG. EtG values do not correlate precisely with the amount or frequency of ethanol use, but the magnitude of the EtG finding roughly corresponds to the amount of alcohol recently consumed.

False-positive and false-negative results for EtG and EtS are uncommon in practice. However, false-positive results are possible with the EtG test in certain circumstances: presence of Escherichia coli in the specimen, use of ethanol-based hand sanitizers (> 20 times a day) or mouthwashes, and the consumption of substances like pralines, nonalcoholic beer, pharmaceutical products, and fruit juice. Similarly, false-negative results of EtG can occur from degradation if the samples are contaminated with other bacteria, transported without cooling, or stored improperly.⁵¹ In practice, this is uncommon, and the test is believed to be specific with few false-positive results. Commercially available EtG colorimetric test strips permit on-site analysis of urine samples.

FAEEs are a combination of different esters and products of alcohol metabolism through a nonoxidative pathway. They are formed by esterification of endogenous free fatty acids and ethanol in blood and several tissues.²⁹ These are sensitive and specific markers of alcohol ingestion and can differentiate chronic alcohol consumption from binge drinking.²⁹ It is elevated for up to 99 hours in heavy alcohol drinkers.³⁰ It can be detected in hair for a longer period than in blood.⁵² Detection of FAEEs in meconium can help establish fetal alcohol exposure.⁵³

Continue to: PEth

PEth. Use of the PEth assay has increased in recent years and its accuracy has had a transformative effect on the diagnosis of AUD.⁵⁴ PEth is a phospholipid found in erythrocyte membranes, formed by an interaction between ethanol and phosphatidylcholine, catalyzed by phospholipase D.^55,56 Major advantages of PEth include an unusually long half-life and specificity. Red cells lack enzymes to degrade PEth, therefore PEth accumulates in red cells and has a half-life of 4 to 10 days^57,58 allowing for detection of significant ethanol consumption extending back 3 to 4 weeks.⁵⁹ There is no evidence that PEth is formed in the absence of ethanol, making the test essentially 100% specific, particularly at higher cutoff values of ≥ 150 ng/mL.^31,60

PEth is known to be formed only in the presence of ethanol, making the test virtually 100% specific.

PEth levels are not affected by age, gender, or underlying liver or renal disease.⁶¹ PEth can differentiate between heavy alcohol use and social drinking and can therefore identify chronic excessive use.⁶² With chronic excessive alcohol consumption, PEth is detectable in blood up to 28 days after sobriety.⁶³ A correlation exists between PEth concentrations in blood and the amount of consumed ethanol. PEth has increased specificity and sensitivity for the detection of latent ethanol use compared with other direct biomarkers.²¹ It can identify recent heavy drinking earlier than indirect biomarkers, as it does not rely on hepatic injury.

Using a cutoff level of 20 ng/mL, PEth assays have a sensitivity of 73% for any alcohol use in the past month; at 80 ng/mL, the sensitivity is 91% for > 4 drinks/d.⁶¹ PEth is considered semi-quantitative. The World Health Organization defines acceptable social alcohol use at a PEth value < 40 ng/dL for men and < 20 ng/dL for women. Chronic excessive use is defined by a level > 60 ng/dL.⁵⁵ The cutoff levels tend to be arbitrary and vary with different guidelines.

PEth may be a useful marker in difficult-toassess settings, or in confirming or invalidating self-reported alcohol consumption.

Although false-positive PEth test results may be possible, most experts believe that dishonesty in self-reporting by test subjects is more likely. That said, the true specificity of PEth remains unknown; a lower value detected should not be regarded as absolute proof of relapse or chronic alcoholism.

Studies have shown a positive correlation between the AUDIT-C score and PEth values combined with self-reported alcohol consumption, indicating that PEth may be a useful marker in difficult-to-assess settings, or in confirming or invalidating self-reported alcohol consumption.^61,64,65 The PEth test is now widely available and, in the authors’ experience, usually costs $100 to $200. Analysis typically costs $40 to $100,⁶⁶ and costs could decrease as the test becomes more widely used. Turnaround time for PEth is 5 to 10 days. It is now the recommended assay by transplant hepatologists for detecting alcohol use.⁶⁷TABLE 3^22,68 explains the currently accepted ranges for various PEth results.

Continue to: CASE ANSWER

CASE ANSWER While every test mentioned can aid in detecting alcohol consumption, the PEth assay in this scenario would be the most clinically useful.

CORRESPONDENCE
Frederick Nunes, MD, Pennsylvania Hospital of University of Pennsylvania, 230 West Washington Square, 4th Floor, Philadelphia, PA 19104; frederick.nunes@pennmedicine.upenn.edu

CASE A 34-year-old woman presents with fatigue. She appears defensive when asked about her alcohol use. She answers No to all questions on the CAGE (cut down, annoyed, guilty, eye-opener) screening tool, but acknowledges drinking excessively on rare occasions. Her physician has a high suspicion for alcohol use disorder (AUD) and recommends further testing. The patient agrees but denies having used alcohol over the past several days. Which of the following is most likely to help support the suspicion of a heavy drinking pattern?

1. Routine lab tests (liver panel and complete blood count).
2. Blood or urine alcohol level.
3. Phosphatidylethanol (PEth) level in the blood.
4. Ethyl glucuronide (EtG) in the urine.
5. Carbohydrate-deficient transferrin (CDT) in the blood.

(See "Case answer.").

About 1 in 12 Americans have AUD,¹ and 1 in 10 children live in a home with a parent who has a drinking problem.² While the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) succinctly defines AUD with specific criteria,¹ the term generally refers to an inability to control or stop drinking despite adverse social or health consequences. AUD is regarded as > 4 drinks per day for men and > 3 drinks per day for women.³ A “standard drink” would be a 12-oz bottle of beer, a 5-oz glass of wine, or 1.5 oz of distilled spirits. Effects of chronic alcohol use are vast and include malnutrition, alcohol withdrawal syndrome, alcoholic liver disease, pancreatitis/pancreatic cancer, cardiomyopathy, and stroke.^4-6 Alcohol use by a pregnant woman can lead to fetal alcohol syndrome in her child.⁷

AUD may be more prevalent in the wake of COVID-19. Primary care practitioners tend to miss a large fraction of patients with AUD in their practice, especially younger patients and those without somatic comorbidities.⁸ Systematic screening for AUD can identify many of these people.⁸ Particularly as the COVID-19 pandemic continues to unfold and increases stress for everyone, risk of worsening drinking increases both in individuals with current AUD and for those in remission.⁹ Contrary to common belief, patients visiting primary care favor screening for at-risk drinking.¹⁰ Thus, awareness of the prevalence of AUD and patient acceptance of screening should encourage wider testing.

Screening tools. The 2014 guidelines published by the Centers for Disease Control and Prevention recommend using quick screening tools—ie, single question or ­AUDIT 1-3 (TABLE 1^11-18)—as an objective means of determining whether patients’ drinking creates a risk for themselves or others.¹¹ Excessive drinking identified using alcohol questionnaires can help reduce medical complications and health care costs.¹⁹ The questionnaires we review do not provide a diagnosis but help identify individuals who might benefit from more thorough assessment.²⁰ Following up, as needed, by testing for alcohol biomarkers can provide quantitative insight into problematic alcohol use.²

Primary care practitioners tend to miss a large fraction of patients with alcohol use disorder in their practice. Systematic screening for AUD can identify many of these patients.

But before we discuss the utility of biomarkers, it’s important to quickly review how alcohol is eliminated from the body.

Alcohol elimination

The stomach and small intestine are the primary sites for alcohol absorption. Alcohol elimination from the body occurs through 3 pathways. The first involves oxidative metabolism, which eliminates most ethanol (95%) through the actions of alcohol dehydrogenase, cytochrome P4502E1, or catalase. A lesser amount of alcohol (2%-5%) is eliminated, unchanged, via the second pathway, which includes urine, sweat, and breath. Nonoxidative metabolism makes up the third pathway. Nonoxidative metabolism removes a very small amount (0.1%) of alcohol and involves the direct ethanol biomarkers PEth, EtG, ethyl sulfate (EtS), and fatty acid ethyl esters (FAEEs).²¹ Our emphasis in this article is on assays of direct metabolites of alcohol—particularly PEth.

Continue to: To understand the utility...

To understand the utility of these direct biomarkers, it is helpful to look at the indirect biomarkers first.

Indirect biomarkers have limited sensitivity and specificity

When alcohol is consumed in large enough quantities over time, indirect biomarkers of alcohol can become abnormal.²² The major indirect biomarkers are the liver enzymes aspartate and alanine aminotransferase (AST and ALT), gamma-glutamyl transferase (GGT), mean corpuscular volume (MCV) of red blood cells, and carbohydrate-deficient transferrin (CDT). Indirect biomarkers have limited sensitivity and specificity for AUD. (For specifics on sensitivity and specificity of indirect and direct biomarkers, see TABLE 2.^23-31)

Liver enzymes. AST and ALT are also present in the heart, muscle, and kidneys. Elevated levels usually imply injury to hepatocytes, with ALT being more reflective of liver involvement than AST. Both AST and ALT are elevated in other common liver conditions including hepatitis C virus infection and fatty liver disease. In alcoholic liver disease (ALD), AST is elevated more than ALT; an AST-to-ALT ratio > 3 suggests ALD. An elevated GGT often indicates hepatic injury and is used to confirm that elevated alkaline phosphatase is of hepatic origin.³²

MCV is the average volume of erythrocytes,³³ and an elevated MCV is a potential indicator of excessive alcohol intake. Macrocytosis requires sustained alcohol use, and the test has low sensitivity. Other diseases such as vitamin B12 or folic acid deficiency, hypothyroidism, hematologic diseases (eg, cold agglutinin disease, multiple myeloma, amyloidosis), and certain medications can also increase MCV.³⁴ Moreover, MCV responds slowly to alcohol use, abstinence, and relapse because red cells have a life span of 120 days.³⁵

CDT. Transferrin is a glycoprotein produced in the liver. The level of transferrin with sialic acid chains increases with alcohol consumption as well as in the carbohydrate deficient glycoprotein syndrome, leading to so-called carbohydrate deficient transferrin.³⁶ It is a sensitive marker for detecting alcohol relapse and monitoring sobriety. Moderate-to-heavy alcohol use, averaging ≥ 40 g of alcohol per day for 2 weeks,³⁶ can decrease the amount of carbohydrate attached to transferrin. Two weeks after complete alcohol cessation, CDT levels will return to normal.³⁷

Continue to: CDT is approved...

CDT is approved by the FDA as an assay for alcohol consumption.³⁷ While CDT is felt to be one of the better indirect markers of AUD and can extend the window of detection, there are still issues with its sensitivity and specificity.³⁸ This biomarker can be elevated with other liver diseases and can be affected by the patient’s age, body mass index, gender, and tobacco use.^39,40 Testing for CDT has never achieved widespread clinical use and has been largely supplanted by the more accurate PEth test (described in a bit).

Direct biomarkers offer insight into recent alcohol use

Other than ethanol itself, direct biomarkers of alcohol use are minor ethanol metabolites created through biochemical reactions when ethanol is coupled to endogenous compounds. Hence, the presence of these metabolites is usually directly related to ethanol consumption.⁴¹ Direct alcohol biomarkers are EtG, EtS, FAEEs, and PEth (TABLE 2^23-31). They reflect alcohol consumption over a period of several days, making them useful when paired with questionnaire data, especially for identifying young adults who engage in binge drinking.⁴²

Ethanol can be measured in blood, urine, and breath and is detectable a bit longer in urine than in blood. However, alcohol is detectable in the blood only for 6 to 12 hours after drinking. After alcohol consumption, concentrations peak in the blood within 2 hours. The window for detecting ethanol in the blood depends on the amount of alcohol consumed and the elimination rate of alcohol, which is about 12 mg/dL/h (or 0.012%)—approximately the same amount of alcohol contained in a standard drink (14 g).

EtG can be detected in urine for ≥ 24 hours after just 1 or 2 drinks, and for up to 4 days after heavy consumption.

Checking the blood alcohol level might be helpful in the office if a patient appears intoxicated but denies alcohol use. A blood alcohol level > 300 mg/dL, or > 150 mg/dL without gross evidence of intoxication, or > 100 mg/dL upon routine examination indicates AUD with a high degree of reliability.^33,43 But the short half-life of ethanol in blood limits its use as a biomarker,³³ and it is not a good indicator of chronic drinking.⁴⁴

EtG and EtS. Less than 0.1% of ethanol is secreted as the metabolites EtG and EtS, which are generated, respectively, by the enzymes uridine diphosphate glucuronosyltransferase and sulfotransferase.⁴⁵ They have value in the diagnosis of AUD because of the length of time in which they can be detected. Urinary EtG and EtS have been especially important biomarkers for monitoring relapse in outpatients treated for alcohol-­related problems.⁴⁶ Generally, EtG and EtS can be detected in urine for 13 to 20 hours after a single drink (0.1 g/kg), and for up to 4 to 5 days following ingestion of large amounts of alcohol.⁴⁷

Continue to: EtG has been detectable...

EtG has been detectable in urine for ≥ 24 hours following only 1 or 2 drinks, and for up to 4 days following heavy consumption.⁴⁸ Shortly after alcohol intake, even in small amounts, EtG is detectable. Analysis of EtG in urine is helpful in monitoring alcohol consumption during withdrawal treatment, for workplace testing, and to check for abstinence in legal matters. The EtG urine test is useful in detecting alcohol consumption in a person who claims to be abstinent but who drank 2 or 3 days before the evaluation. Although accurate, EtG’s window for detection is narrower than that of the PEth assay.

EtS is a good marker of acute short-term alcohol use, up to 12 hours in the blood (or longer in heavier drinkers) and up to 5 days in urine.⁴⁹ Its sensitivity is highest in heavy drinkers. Post-sampling formation and degradation of EtS have not been known to occur in urine samples. Testing for this second metabolite of ethanol can slightly improve the sensitivity and specificity of the EtG test. A urine test for EtS has a wider detection window. But it has little practical advantage compared with EtG.⁵⁰

For better clinical specificity, a combination of both EtG and EtS testing has been recommended. However, the EtS assay is more cumbersome and provides little advantage over EtG. EtG values do not correlate precisely with the amount or frequency of ethanol use, but the magnitude of the EtG finding roughly corresponds to the amount of alcohol recently consumed.

False-positive and false-negative results for EtG and EtS are uncommon in practice. However, false-positive results are possible with the EtG test in certain circumstances: presence of Escherichia coli in the specimen, use of ethanol-based hand sanitizers (> 20 times a day) or mouthwashes, and the consumption of substances like pralines, nonalcoholic beer, pharmaceutical products, and fruit juice. Similarly, false-negative results of EtG can occur from degradation if the samples are contaminated with other bacteria, transported without cooling, or stored improperly.⁵¹ In practice, this is uncommon, and the test is believed to be specific with few false-positive results. Commercially available EtG colorimetric test strips permit on-site analysis of urine samples.

FAEEs are a combination of different esters and products of alcohol metabolism through a nonoxidative pathway. They are formed by esterification of endogenous free fatty acids and ethanol in blood and several tissues.²⁹ These are sensitive and specific markers of alcohol ingestion and can differentiate chronic alcohol consumption from binge drinking.²⁹ It is elevated for up to 99 hours in heavy alcohol drinkers.³⁰ It can be detected in hair for a longer period than in blood.⁵² Detection of FAEEs in meconium can help establish fetal alcohol exposure.⁵³

Continue to: PEth

PEth. Use of the PEth assay has increased in recent years and its accuracy has had a transformative effect on the diagnosis of AUD.⁵⁴ PEth is a phospholipid found in erythrocyte membranes, formed by an interaction between ethanol and phosphatidylcholine, catalyzed by phospholipase D.^55,56 Major advantages of PEth include an unusually long half-life and specificity. Red cells lack enzymes to degrade PEth, therefore PEth accumulates in red cells and has a half-life of 4 to 10 days^57,58 allowing for detection of significant ethanol consumption extending back 3 to 4 weeks.⁵⁹ There is no evidence that PEth is formed in the absence of ethanol, making the test essentially 100% specific, particularly at higher cutoff values of ≥ 150 ng/mL.^31,60

PEth is known to be formed only in the presence of ethanol, making the test virtually 100% specific.

PEth levels are not affected by age, gender, or underlying liver or renal disease.⁶¹ PEth can differentiate between heavy alcohol use and social drinking and can therefore identify chronic excessive use.⁶² With chronic excessive alcohol consumption, PEth is detectable in blood up to 28 days after sobriety.⁶³ A correlation exists between PEth concentrations in blood and the amount of consumed ethanol. PEth has increased specificity and sensitivity for the detection of latent ethanol use compared with other direct biomarkers.²¹ It can identify recent heavy drinking earlier than indirect biomarkers, as it does not rely on hepatic injury.

Using a cutoff level of 20 ng/mL, PEth assays have a sensitivity of 73% for any alcohol use in the past month; at 80 ng/mL, the sensitivity is 91% for > 4 drinks/d.⁶¹ PEth is considered semi-quantitative. The World Health Organization defines acceptable social alcohol use at a PEth value < 40 ng/dL for men and < 20 ng/dL for women. Chronic excessive use is defined by a level > 60 ng/dL.⁵⁵ The cutoff levels tend to be arbitrary and vary with different guidelines.

PEth may be a useful marker in difficult-toassess settings, or in confirming or invalidating self-reported alcohol consumption.

Although false-positive PEth test results may be possible, most experts believe that dishonesty in self-reporting by test subjects is more likely. That said, the true specificity of PEth remains unknown; a lower value detected should not be regarded as absolute proof of relapse or chronic alcoholism.

Studies have shown a positive correlation between the AUDIT-C score and PEth values combined with self-reported alcohol consumption, indicating that PEth may be a useful marker in difficult-to-assess settings, or in confirming or invalidating self-reported alcohol consumption.^61,64,65 The PEth test is now widely available and, in the authors’ experience, usually costs $100 to $200. Analysis typically costs $40 to $100,⁶⁶ and costs could decrease as the test becomes more widely used. Turnaround time for PEth is 5 to 10 days. It is now the recommended assay by transplant hepatologists for detecting alcohol use.⁶⁷TABLE 3^22,68 explains the currently accepted ranges for various PEth results.

Continue to: CASE ANSWER

CASE ANSWER While every test mentioned can aid in detecting alcohol consumption, the PEth assay in this scenario would be the most clinically useful.

CORRESPONDENCE
Frederick Nunes, MD, Pennsylvania Hospital of University of Pennsylvania, 230 West Washington Square, 4th Floor, Philadelphia, PA 19104; frederick.nunes@pennmedicine.upenn.edu

Evidence summary

Multiple analyses suggest short sleep increases obesity risk

Three recent, large systematic reviews of prospective cohort studies with meta-analyses in infants, children, and adolescents all found associations between short sleep at intake and later excessive weight.

The largest meta-analysis included 42 prospective studies with 75,499 patients ranging in age from infancy to adolescence and with follow-up ranging from 1 to 27 years. In a pooled analysis, short sleep—variously defined across trials and mostly assessed by parental report—was associated with an increased risk of obesity or overweight (relative risk [RR] = 1.58; 95% CI, 1.35-1.85; I²= 92%), compared to normal and long sleep. When the authors adjusted for suspected publication bias using a “trim and fill” method, short sleep remained associated with later overweight or obesity (RR = 1.42; 95% CI, 1.12-1.81). Short sleep was associated with later unhealthy weight status in all age groups: 0 to < 3 years (RR = 1.4; 95% CI, 1.19-1.65); 3 to < 9 years (RR = 1.57; 95% CI, 1.4-1.76);9 to < 12 years (RR = 2.23; 95% CI, 2.18-2.27); and 12 to 18 years (RR = 1.3; 95% CI, 1.11-1.53). In addition to high heterogeneity, limitations of the review included variability in the definition of short sleep, use of parent- or self-reported sleep duration, and variability in classification of overweight and obesity in primary studies.¹

A second systematic review and meta-analysis included 25 longitudinal studies (20 of which overlapped with the previously discussed meta-analysis) of children and adolescents (N = 56,584). Patients ranged in age from infancy to 16 years, and follow-up ranged from 6 months to 10 years (mean, 3.4 years). Children and adolescents with the shortest sleep duration were more likely to be overweight or obese at follow-up (pooled odds ratio [OR] = 1.76; 95% CI, 1.39-2.23; I² = 70.5%) than those with the longest sleep duration. Due to the overlap in studies, the limitations of this analysis were similar to those already mentioned. Lack of a linear association between sleep duration and weight was cited as evidence of possible publication bias; the authors did not attempt to correct for it.²

Three large systematic reviews all found associations between short sleep at intake and later excessive weight.

The third systematic review and meta-analysis included 22 longitudinal studies (18 overlapped with first meta-analysis and 17 with the second) of children and adolescents (N = 24,821) ages 6 months to 18 years. Follow-up ranged from 1 to 27 years. This meta-analysis standardized the categories of sleep duration using recommendations from the Sleep Health Foundation. Patients with short sleep duration had an increased risk of overweight or obesity compared with patients sleeping “normal” or “longer than normal” durations (pooled OR = 2.15; 95% CI, 1.64-2.81; I² = 67%). The authors indicated that their analysis could have been more robust if information about daytime sleep (ie, napping) had been available, but it was not collected in many of the included studies.³

Accelerometer data quantify the sleep/obesity association

A subsequent cohort study (N = 202) sought to better examine the association between sleep characteristics and adiposity by measuring sleep duration using accelerometers. Toddlers (ages 12 to 26 months) without previous medical history were recruited from early childhood education centers. Patients wore accelerometers for 7 consecutive days and then returned to the clinic after 12 months for collection of biometric information. Researchers measured body morphology with the BMI z-score (ie, the number of standard deviations from the mean). Every additional hour of total sleep time was associated with a 0.12-unit lower BMI z-score (95% CI, –0.23 to –0.01) at 1 year. However, every hour increase in nap duration was associated with a 0.41-unit higher BMI z-score (95% CI, 0.14-0.68).⁴

Recommendations from others

In 2016, the American Academy of Sleep Medicine (AASM) recommended the following sleep durations (per 24 hours): infants ages 4 to 12 months, 12-16 hours; children 1 to 2 years, 11-14 hours; children 3 to 5 years, 10-13 hours; children 6 to 12 years, 9-12 hours; and teenagers 13 to 18 years, 8-10 hours. The AASM further stated that sleeping the recommended number of hours was associated with better health outcomes, and that sleeping too few hours increased the risk of various health conditions, including obesity.⁵ In 2015, the American Academy of Pediatrics Committee on Nutrition acknowledged the association between obesity and short sleep duration and recommended that health care professionals counsel parents about age-appropriate sleep guidelines.⁶

Editor’s takeaway

Studies demonstrate that short sleep duration in pediatric patients is associated with later weight gain. However, associations do not prove a causal link, and other factors may contribute to both weight gain and poor sleep.

Evidence summary

Multiple analyses suggest short sleep increases obesity risk

Three recent, large systematic reviews of prospective cohort studies with meta-analyses in infants, children, and adolescents all found associations between short sleep at intake and later excessive weight.

The largest meta-analysis included 42 prospective studies with 75,499 patients ranging in age from infancy to adolescence and with follow-up ranging from 1 to 27 years. In a pooled analysis, short sleep—variously defined across trials and mostly assessed by parental report—was associated with an increased risk of obesity or overweight (relative risk [RR] = 1.58; 95% CI, 1.35-1.85; I²= 92%), compared to normal and long sleep. When the authors adjusted for suspected publication bias using a “trim and fill” method, short sleep remained associated with later overweight or obesity (RR = 1.42; 95% CI, 1.12-1.81). Short sleep was associated with later unhealthy weight status in all age groups: 0 to < 3 years (RR = 1.4; 95% CI, 1.19-1.65); 3 to < 9 years (RR = 1.57; 95% CI, 1.4-1.76);9 to < 12 years (RR = 2.23; 95% CI, 2.18-2.27); and 12 to 18 years (RR = 1.3; 95% CI, 1.11-1.53). In addition to high heterogeneity, limitations of the review included variability in the definition of short sleep, use of parent- or self-reported sleep duration, and variability in classification of overweight and obesity in primary studies.¹

A second systematic review and meta-analysis included 25 longitudinal studies (20 of which overlapped with the previously discussed meta-analysis) of children and adolescents (N = 56,584). Patients ranged in age from infancy to 16 years, and follow-up ranged from 6 months to 10 years (mean, 3.4 years). Children and adolescents with the shortest sleep duration were more likely to be overweight or obese at follow-up (pooled odds ratio [OR] = 1.76; 95% CI, 1.39-2.23; I² = 70.5%) than those with the longest sleep duration. Due to the overlap in studies, the limitations of this analysis were similar to those already mentioned. Lack of a linear association between sleep duration and weight was cited as evidence of possible publication bias; the authors did not attempt to correct for it.²

Three large systematic reviews all found associations between short sleep at intake and later excessive weight.

The third systematic review and meta-analysis included 22 longitudinal studies (18 overlapped with first meta-analysis and 17 with the second) of children and adolescents (N = 24,821) ages 6 months to 18 years. Follow-up ranged from 1 to 27 years. This meta-analysis standardized the categories of sleep duration using recommendations from the Sleep Health Foundation. Patients with short sleep duration had an increased risk of overweight or obesity compared with patients sleeping “normal” or “longer than normal” durations (pooled OR = 2.15; 95% CI, 1.64-2.81; I² = 67%). The authors indicated that their analysis could have been more robust if information about daytime sleep (ie, napping) had been available, but it was not collected in many of the included studies.³

Accelerometer data quantify the sleep/obesity association

A subsequent cohort study (N = 202) sought to better examine the association between sleep characteristics and adiposity by measuring sleep duration using accelerometers. Toddlers (ages 12 to 26 months) without previous medical history were recruited from early childhood education centers. Patients wore accelerometers for 7 consecutive days and then returned to the clinic after 12 months for collection of biometric information. Researchers measured body morphology with the BMI z-score (ie, the number of standard deviations from the mean). Every additional hour of total sleep time was associated with a 0.12-unit lower BMI z-score (95% CI, –0.23 to –0.01) at 1 year. However, every hour increase in nap duration was associated with a 0.41-unit higher BMI z-score (95% CI, 0.14-0.68).⁴

Recommendations from others

In 2016, the American Academy of Sleep Medicine (AASM) recommended the following sleep durations (per 24 hours): infants ages 4 to 12 months, 12-16 hours; children 1 to 2 years, 11-14 hours; children 3 to 5 years, 10-13 hours; children 6 to 12 years, 9-12 hours; and teenagers 13 to 18 years, 8-10 hours. The AASM further stated that sleeping the recommended number of hours was associated with better health outcomes, and that sleeping too few hours increased the risk of various health conditions, including obesity.⁵ In 2015, the American Academy of Pediatrics Committee on Nutrition acknowledged the association between obesity and short sleep duration and recommended that health care professionals counsel parents about age-appropriate sleep guidelines.⁶

Editor’s takeaway

Studies demonstrate that short sleep duration in pediatric patients is associated with later weight gain. However, associations do not prove a causal link, and other factors may contribute to both weight gain and poor sleep.

Evidence summary

Multiple analyses suggest short sleep increases obesity risk

Three recent, large systematic reviews of prospective cohort studies with meta-analyses in infants, children, and adolescents all found associations between short sleep at intake and later excessive weight.

The largest meta-analysis included 42 prospective studies with 75,499 patients ranging in age from infancy to adolescence and with follow-up ranging from 1 to 27 years. In a pooled analysis, short sleep—variously defined across trials and mostly assessed by parental report—was associated with an increased risk of obesity or overweight (relative risk [RR] = 1.58; 95% CI, 1.35-1.85; I²= 92%), compared to normal and long sleep. When the authors adjusted for suspected publication bias using a “trim and fill” method, short sleep remained associated with later overweight or obesity (RR = 1.42; 95% CI, 1.12-1.81). Short sleep was associated with later unhealthy weight status in all age groups: 0 to < 3 years (RR = 1.4; 95% CI, 1.19-1.65); 3 to < 9 years (RR = 1.57; 95% CI, 1.4-1.76);9 to < 12 years (RR = 2.23; 95% CI, 2.18-2.27); and 12 to 18 years (RR = 1.3; 95% CI, 1.11-1.53). In addition to high heterogeneity, limitations of the review included variability in the definition of short sleep, use of parent- or self-reported sleep duration, and variability in classification of overweight and obesity in primary studies.¹

A second systematic review and meta-analysis included 25 longitudinal studies (20 of which overlapped with the previously discussed meta-analysis) of children and adolescents (N = 56,584). Patients ranged in age from infancy to 16 years, and follow-up ranged from 6 months to 10 years (mean, 3.4 years). Children and adolescents with the shortest sleep duration were more likely to be overweight or obese at follow-up (pooled odds ratio [OR] = 1.76; 95% CI, 1.39-2.23; I² = 70.5%) than those with the longest sleep duration. Due to the overlap in studies, the limitations of this analysis were similar to those already mentioned. Lack of a linear association between sleep duration and weight was cited as evidence of possible publication bias; the authors did not attempt to correct for it.²

Three large systematic reviews all found associations between short sleep at intake and later excessive weight.

The third systematic review and meta-analysis included 22 longitudinal studies (18 overlapped with first meta-analysis and 17 with the second) of children and adolescents (N = 24,821) ages 6 months to 18 years. Follow-up ranged from 1 to 27 years. This meta-analysis standardized the categories of sleep duration using recommendations from the Sleep Health Foundation. Patients with short sleep duration had an increased risk of overweight or obesity compared with patients sleeping “normal” or “longer than normal” durations (pooled OR = 2.15; 95% CI, 1.64-2.81; I² = 67%). The authors indicated that their analysis could have been more robust if information about daytime sleep (ie, napping) had been available, but it was not collected in many of the included studies.³

Accelerometer data quantify the sleep/obesity association

A subsequent cohort study (N = 202) sought to better examine the association between sleep characteristics and adiposity by measuring sleep duration using accelerometers. Toddlers (ages 12 to 26 months) without previous medical history were recruited from early childhood education centers. Patients wore accelerometers for 7 consecutive days and then returned to the clinic after 12 months for collection of biometric information. Researchers measured body morphology with the BMI z-score (ie, the number of standard deviations from the mean). Every additional hour of total sleep time was associated with a 0.12-unit lower BMI z-score (95% CI, –0.23 to –0.01) at 1 year. However, every hour increase in nap duration was associated with a 0.41-unit higher BMI z-score (95% CI, 0.14-0.68).⁴

Recommendations from others

In 2016, the American Academy of Sleep Medicine (AASM) recommended the following sleep durations (per 24 hours): infants ages 4 to 12 months, 12-16 hours; children 1 to 2 years, 11-14 hours; children 3 to 5 years, 10-13 hours; children 6 to 12 years, 9-12 hours; and teenagers 13 to 18 years, 8-10 hours. The AASM further stated that sleeping the recommended number of hours was associated with better health outcomes, and that sleeping too few hours increased the risk of various health conditions, including obesity.⁵ In 2015, the American Academy of Pediatrics Committee on Nutrition acknowledged the association between obesity and short sleep duration and recommended that health care professionals counsel parents about age-appropriate sleep guidelines.⁶

Editor’s takeaway

Studies demonstrate that short sleep duration in pediatric patients is associated with later weight gain. However, associations do not prove a causal link, and other factors may contribute to both weight gain and poor sleep.

A biopsy was performed and sent for immunofluorescence; the results were negative. This, along with the patient’s history of diabetes, led us to the diagnosis of bullosis diabeticorum (BD). This condition, also known as bullous disease of diabetes, is characterized by abrupt development of noninflammatory bullae on acral areas in patients with diabetes.

The etiology of BD is unknown. The acral location suggests that trauma may be a contributing factor. Although electron microscopy has suggested an abnormality in anchoring fibrils, this cellular change does not fully explain the development of multiple blisters at varying sites.

A diagnosis of BD can be made when biopsy with immunofluorescence excludes other histologically similar diagnoses such as epidermolysis bullosa, noninflammatory bullous pemphigoid, and porphyria cutanea tarda. And, while immunofluorescence findings are typically negative, elevated levels of immunoglobulin M and C3 have, on occasion, been reported.^1,2 Cultures are warranted only if a secondary infection is suspected.

The distribution of lesions and the presence—or absence—of systemic symptoms go a long way toward narrowing the differential of blistering diseases. The presence of generalized blistering and systemic symptoms would suggest conditions related to medication exposure, such as Stevens-Johnson syndrome or toxic epidermal necrolysis; infectious etiologies (eg, staphylococcal scalded skin syndrome); autoimmune causes; or underlying malignancy.³ Generalized blistering in the absence of systemic symptoms would support diagnoses such as bullous impetigo and pemphigoid.³

The blisters associated with BD spontaneously resolve over several weeks without treatment but tend to recur. The lesions typically heal without significant scarring, although they may have a darker pigmentation after the first occurrence. Treatment may be warranted if a patient develops a secondary infection. For this patient, the bullae resolved within 2 weeks without treatment, although mild hyperpigmentation remained.

‌

This case was adapted from: Mims L, Savage A, Chessman A. Blisters on an elderly woman’s toes. J Fam Pract. 2014;63:273-274.

A biopsy was performed and sent for immunofluorescence; the results were negative. This, along with the patient’s history of diabetes, led us to the diagnosis of bullosis diabeticorum (BD). This condition, also known as bullous disease of diabetes, is characterized by abrupt development of noninflammatory bullae on acral areas in patients with diabetes.

The etiology of BD is unknown. The acral location suggests that trauma may be a contributing factor. Although electron microscopy has suggested an abnormality in anchoring fibrils, this cellular change does not fully explain the development of multiple blisters at varying sites.

A diagnosis of BD can be made when biopsy with immunofluorescence excludes other histologically similar diagnoses such as epidermolysis bullosa, noninflammatory bullous pemphigoid, and porphyria cutanea tarda. And, while immunofluorescence findings are typically negative, elevated levels of immunoglobulin M and C3 have, on occasion, been reported.^1,2 Cultures are warranted only if a secondary infection is suspected.

The distribution of lesions and the presence—or absence—of systemic symptoms go a long way toward narrowing the differential of blistering diseases. The presence of generalized blistering and systemic symptoms would suggest conditions related to medication exposure, such as Stevens-Johnson syndrome or toxic epidermal necrolysis; infectious etiologies (eg, staphylococcal scalded skin syndrome); autoimmune causes; or underlying malignancy.³ Generalized blistering in the absence of systemic symptoms would support diagnoses such as bullous impetigo and pemphigoid.³

The blisters associated with BD spontaneously resolve over several weeks without treatment but tend to recur. The lesions typically heal without significant scarring, although they may have a darker pigmentation after the first occurrence. Treatment may be warranted if a patient develops a secondary infection. For this patient, the bullae resolved within 2 weeks without treatment, although mild hyperpigmentation remained.

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This case was adapted from: Mims L, Savage A, Chessman A. Blisters on an elderly woman’s toes. J Fam Pract. 2014;63:273-274.

A biopsy was performed and sent for immunofluorescence; the results were negative. This, along with the patient’s history of diabetes, led us to the diagnosis of bullosis diabeticorum (BD). This condition, also known as bullous disease of diabetes, is characterized by abrupt development of noninflammatory bullae on acral areas in patients with diabetes.

The etiology of BD is unknown. The acral location suggests that trauma may be a contributing factor. Although electron microscopy has suggested an abnormality in anchoring fibrils, this cellular change does not fully explain the development of multiple blisters at varying sites.

A diagnosis of BD can be made when biopsy with immunofluorescence excludes other histologically similar diagnoses such as epidermolysis bullosa, noninflammatory bullous pemphigoid, and porphyria cutanea tarda. And, while immunofluorescence findings are typically negative, elevated levels of immunoglobulin M and C3 have, on occasion, been reported.^1,2 Cultures are warranted only if a secondary infection is suspected.

The distribution of lesions and the presence—or absence—of systemic symptoms go a long way toward narrowing the differential of blistering diseases. The presence of generalized blistering and systemic symptoms would suggest conditions related to medication exposure, such as Stevens-Johnson syndrome or toxic epidermal necrolysis; infectious etiologies (eg, staphylococcal scalded skin syndrome); autoimmune causes; or underlying malignancy.³ Generalized blistering in the absence of systemic symptoms would support diagnoses such as bullous impetigo and pemphigoid.³

The blisters associated with BD spontaneously resolve over several weeks without treatment but tend to recur. The lesions typically heal without significant scarring, although they may have a darker pigmentation after the first occurrence. Treatment may be warranted if a patient develops a secondary infection. For this patient, the bullae resolved within 2 weeks without treatment, although mild hyperpigmentation remained.

‌

This case was adapted from: Mims L, Savage A, Chessman A. Blisters on an elderly woman’s toes. J Fam Pract. 2014;63:273-274.