Sexuality is a central aspect of being human. It encompasses sex, gender identities and roles, sexual orientation, pleasure, eroticism, and intimacy, and is a major contributor to an individual’s quality of life and sense of wellbeing.^1,2 Positive sexual relationships and behaviors are integral to maintaining good health and general well-being later in life, as well.^2,3 Cynthia Graber, a reporter with Scientific American, reported that sex is a key reason retirees have a happy life.⁴

While there is a decline in sexual activity with age, a great number of men and women continue to engage in vaginal or anal intercourse, oral sex, and masturbation into the eighth and ninth decades of life.^2,5 In a survey conducted among married men and women, about 90% of respondents between the ages of 60 and 64 and almost 30% of those older than age 80 said they were still sexually active.2 Another study reported that 62% of men and 30% of women 80 to 102 years of age were still sexually active.⁶ However, sexuality is rarely discussed with the elderly, and most physicians are unsure about how to handle such conversations.⁷

The baby boomer population is aging in the United States and elsewhere. By 2030, 20% of the US population will be ≥65 years old, and 4% (3 million) will be lesbian, gay, bisexual, transgender, and queer (LGBTQ) elderly adults.^3,8 Given the impact of sex on maintaining quality of life, it is important for health care providers to be comfortable discussing sexuality with the elderly.⁹

Barriers to discussing sexuality

Physician barriers

Primary care physicians typically are the first point of contact for elderly adults experiencing health problems, including sexual dysfunction. According to the American Psychological Association, sex is not discussed enough with the elderly. Most physicians do not address sexual health proactively, and rarely do they include a sexual history as part of general health screening in the elderly.^2,10,11 Inadequate training of physicians in sexual health is likely a contributing factor.5 Physicians also often feel discomfort when discussing such matters with patients of the opposite sex.¹² (For a suggested approach to these conversations, see “Discussing sexuality with elderly patients: Getting beyond ‘don’t ask, don’t tell,” below.) With the increasing number of LGBTQ elderly adults, physicians should not assume their patients have any particular sexual behavior or orientation. This will help elderly LGBTQ patients feel more comfortable discussing their sexual health needs.⁸

In a study of married men and women, almost 30% of those older than age 80 said they were still sexually active.The PLISSIT model, developed in 1976 by clinical psychologist Dr. Jack Annon, can facilitate a discussion of sexuality with elderly patients.^11,13 First, the healthcare provider seeks permission (P) to discuss sexuality with the patient. After permission is given, the provider can share limited information (LI) about sexual issues that affect the older adult. Next, the provider may offer specific suggestions (SS) to improve sexual health or resolve problems. Finally, referral for intensive therapy (IT) may be needed for someone whose sexual dysfunction goes beyond the scope of the health care provider’s expertise. In 2000, open-ended questions were added to the PLISSIT model to more effectively guide an assessment of sexuality in older adults^13,14:
• Can you tell me how you express your sexuality?
• What concerns or questions do you have about fulfilling your continuing sexual needs?
• In what ways has your sexual relationship with your partner changed as you have aged?

Many physicians have only a vague understanding of the sexual needs of the elderly, and some may even consider sexuality among elderly people a taboo.⁵ The reality is that elderly adults need to be touched, held, and feel loved, and this does not diminish with age.^15-17 Unfortunately, many healthcare professionals have a mindset of, “I don’t want to think about my parents having sex, let alone my grandparents.” It is critical that physicians address intimacy needs as part of a medical assessment of the elderly.

Loss of physical and emotional intimacy is profound and often ignored as a source of suffering for the elderly. Most elderly patients want to discuss sexual issues with their physician, according to the Global Study of Sexual Attitudes among men and women ages 40 to 80 years.¹⁸ Surprisingly, even geriatricians often fail to take a sexual history of their patients. In one study, only 57% of 120 geriatricians surveyed routinely took a sexual history, even though 97% of them believed that patients with sexual problems should be managed further.¹

Patient barriers

Even given a desire to discuss sexual concerns with their health care provider, elderly patients can be reluctant due to embarrassment or a fear of sexuality. Others may hesitate because their caregiver is younger than they or is of the opposite sex.^19,20 The attitude of a medical professional has a powerful impact on the sexual attitudes and behaviors of elderly patients, and on their level of comfort in discussing sexual issues.²¹ Elderly patients do not usually complain to their physicians about sexual dysfunctions; 92% of men and 96% of women who reported at least one sexual problem in a survey had not sought help at all.¹⁸

Addressing issues in sexual dysfunction

Though sexual desires and needs may not decline with age, sexual function might, for any number of reasons.^1,2,7 Many chronic diseases are known to interfere with sexual function (TABLE).² Polypharmacy can lead to physical challenges, cognitive changes, and impaired sexual arousal, especially in men.³ However, the reason cited most often for absence of sexual activity is lack of a partner or a willing partner.² Unfortunately as one ages, the chance of finding a partner diminishes. Hence the need to discuss alternative expressions of sexuality that may not require a partner.³ Many elderly individuals enjoy masturbation as a form of sexual expression.

Men and women have different sexual problems, but they are all treatable. For instance, with normal aging, levels of testosterone in men and estrogen in women decrease.^5,15 Despite the number of sexual health dysfunctions, only 14% of men and 1% of women use medications to treat them.^2,5 With men who have erectile dysfunction, discuss possible testosterone replacement or medication. For women with postmenopausal (atrophic) vaginitis, estrogen therapy or a lubricant (for those with contraindication to estrogen therapy) can improve sexual function. Anorgasmia and low libido are other concerns for postmenopausal women, and may warrant gynecologic referral.

Loss of physical and emotional intimacy is profound and often ignored as a source of suffering for the elderly.For elderly adults moving into assisted living or a nursing home, the transition can signal the end of a sexual life.^16,22 There is limited opportunity for men and women in residential settings to engage in sexual activity, in part due to a lack of privacy.²³ The nursing home is still a home, and facility staff should provide opportunities for privacy and intimacy. In a study conducted in a residential setting, more than 25% of those ages 65 to 85 reported an active sex life, while 90% of those surveyed had sexual thoughts and fantasies.²² Of course, many elderly adults enter residential settings without a partner. They should be allowed to engage in sexual activities if they can understand, consent to, and form a relationship. Sexual needs remain even in those with dementia. But cognitive impairment frequently manifests as inappropriate sexual behavior. A study of cognitively impaired older adults revealed that 1.8% had displayed sexually inappropriate verbal or physical behavior.²⁴ In these situations, a behavior medicine specialist can be of great help.

Health risks of sexual activity in the elderly

In 2011, the Centers for Disease Control and Prevention reported that 5% of new human immunodeficiency virus (HIV) cases occurred in those ≥55 years, and almost 2% of new diagnoses were in the those ≥65 years.²⁵ Sexually active elderly individuals are at risk for acquiring HIV, in part because they do not consider themselves to be at risk for sexually transmitted diseases (STDs).²⁶ They also might not have received education about the importance of condom use.^11,26 In addition, prescribing erectile dysfunction medications for men and hormone replacement therapy for women might have played a part in increasing STDs among the elderly, particularly Chlamydia and HIV.²⁷ The long-term effects of STDs left untreated can easily be mistaken for other symptoms or diseases of aging, which further underscores the importance of discussing sexuality with elderly patients.

CORRESPONDENCE
Folashade Omole, MD, FAAFP, 1513 East Cleveland Avenue, Building 100, Suite 300-A, East Point, GA 30344; [email protected]

Sexuality is a central aspect of being human. It encompasses sex, gender identities and roles, sexual orientation, pleasure, eroticism, and intimacy, and is a major contributor to an individual’s quality of life and sense of wellbeing.^1,2 Positive sexual relationships and behaviors are integral to maintaining good health and general well-being later in life, as well.^2,3 Cynthia Graber, a reporter with Scientific American, reported that sex is a key reason retirees have a happy life.⁴

While there is a decline in sexual activity with age, a great number of men and women continue to engage in vaginal or anal intercourse, oral sex, and masturbation into the eighth and ninth decades of life.^2,5 In a survey conducted among married men and women, about 90% of respondents between the ages of 60 and 64 and almost 30% of those older than age 80 said they were still sexually active.2 Another study reported that 62% of men and 30% of women 80 to 102 years of age were still sexually active.⁶ However, sexuality is rarely discussed with the elderly, and most physicians are unsure about how to handle such conversations.⁷

The baby boomer population is aging in the United States and elsewhere. By 2030, 20% of the US population will be ≥65 years old, and 4% (3 million) will be lesbian, gay, bisexual, transgender, and queer (LGBTQ) elderly adults.^3,8 Given the impact of sex on maintaining quality of life, it is important for health care providers to be comfortable discussing sexuality with the elderly.⁹

Barriers to discussing sexuality

Physician barriers

Primary care physicians typically are the first point of contact for elderly adults experiencing health problems, including sexual dysfunction. According to the American Psychological Association, sex is not discussed enough with the elderly. Most physicians do not address sexual health proactively, and rarely do they include a sexual history as part of general health screening in the elderly.^2,10,11 Inadequate training of physicians in sexual health is likely a contributing factor.5 Physicians also often feel discomfort when discussing such matters with patients of the opposite sex.¹² (For a suggested approach to these conversations, see “Discussing sexuality with elderly patients: Getting beyond ‘don’t ask, don’t tell,” below.) With the increasing number of LGBTQ elderly adults, physicians should not assume their patients have any particular sexual behavior or orientation. This will help elderly LGBTQ patients feel more comfortable discussing their sexual health needs.⁸

In a study of married men and women, almost 30% of those older than age 80 said they were still sexually active.The PLISSIT model, developed in 1976 by clinical psychologist Dr. Jack Annon, can facilitate a discussion of sexuality with elderly patients.^11,13 First, the healthcare provider seeks permission (P) to discuss sexuality with the patient. After permission is given, the provider can share limited information (LI) about sexual issues that affect the older adult. Next, the provider may offer specific suggestions (SS) to improve sexual health or resolve problems. Finally, referral for intensive therapy (IT) may be needed for someone whose sexual dysfunction goes beyond the scope of the health care provider’s expertise. In 2000, open-ended questions were added to the PLISSIT model to more effectively guide an assessment of sexuality in older adults^13,14:
• Can you tell me how you express your sexuality?
• What concerns or questions do you have about fulfilling your continuing sexual needs?
• In what ways has your sexual relationship with your partner changed as you have aged?

Many physicians have only a vague understanding of the sexual needs of the elderly, and some may even consider sexuality among elderly people a taboo.⁵ The reality is that elderly adults need to be touched, held, and feel loved, and this does not diminish with age.^15-17 Unfortunately, many healthcare professionals have a mindset of, “I don’t want to think about my parents having sex, let alone my grandparents.” It is critical that physicians address intimacy needs as part of a medical assessment of the elderly.

Loss of physical and emotional intimacy is profound and often ignored as a source of suffering for the elderly. Most elderly patients want to discuss sexual issues with their physician, according to the Global Study of Sexual Attitudes among men and women ages 40 to 80 years.¹⁸ Surprisingly, even geriatricians often fail to take a sexual history of their patients. In one study, only 57% of 120 geriatricians surveyed routinely took a sexual history, even though 97% of them believed that patients with sexual problems should be managed further.¹

Patient barriers

Even given a desire to discuss sexual concerns with their health care provider, elderly patients can be reluctant due to embarrassment or a fear of sexuality. Others may hesitate because their caregiver is younger than they or is of the opposite sex.^19,20 The attitude of a medical professional has a powerful impact on the sexual attitudes and behaviors of elderly patients, and on their level of comfort in discussing sexual issues.²¹ Elderly patients do not usually complain to their physicians about sexual dysfunctions; 92% of men and 96% of women who reported at least one sexual problem in a survey had not sought help at all.¹⁸

Addressing issues in sexual dysfunction

Though sexual desires and needs may not decline with age, sexual function might, for any number of reasons.^1,2,7 Many chronic diseases are known to interfere with sexual function (TABLE).² Polypharmacy can lead to physical challenges, cognitive changes, and impaired sexual arousal, especially in men.³ However, the reason cited most often for absence of sexual activity is lack of a partner or a willing partner.² Unfortunately as one ages, the chance of finding a partner diminishes. Hence the need to discuss alternative expressions of sexuality that may not require a partner.³ Many elderly individuals enjoy masturbation as a form of sexual expression.

Men and women have different sexual problems, but they are all treatable. For instance, with normal aging, levels of testosterone in men and estrogen in women decrease.^5,15 Despite the number of sexual health dysfunctions, only 14% of men and 1% of women use medications to treat them.^2,5 With men who have erectile dysfunction, discuss possible testosterone replacement or medication. For women with postmenopausal (atrophic) vaginitis, estrogen therapy or a lubricant (for those with contraindication to estrogen therapy) can improve sexual function. Anorgasmia and low libido are other concerns for postmenopausal women, and may warrant gynecologic referral.

Loss of physical and emotional intimacy is profound and often ignored as a source of suffering for the elderly.For elderly adults moving into assisted living or a nursing home, the transition can signal the end of a sexual life.^16,22 There is limited opportunity for men and women in residential settings to engage in sexual activity, in part due to a lack of privacy.²³ The nursing home is still a home, and facility staff should provide opportunities for privacy and intimacy. In a study conducted in a residential setting, more than 25% of those ages 65 to 85 reported an active sex life, while 90% of those surveyed had sexual thoughts and fantasies.²² Of course, many elderly adults enter residential settings without a partner. They should be allowed to engage in sexual activities if they can understand, consent to, and form a relationship. Sexual needs remain even in those with dementia. But cognitive impairment frequently manifests as inappropriate sexual behavior. A study of cognitively impaired older adults revealed that 1.8% had displayed sexually inappropriate verbal or physical behavior.²⁴ In these situations, a behavior medicine specialist can be of great help.

Health risks of sexual activity in the elderly

In 2011, the Centers for Disease Control and Prevention reported that 5% of new human immunodeficiency virus (HIV) cases occurred in those ≥55 years, and almost 2% of new diagnoses were in the those ≥65 years.²⁵ Sexually active elderly individuals are at risk for acquiring HIV, in part because they do not consider themselves to be at risk for sexually transmitted diseases (STDs).²⁶ They also might not have received education about the importance of condom use.^11,26 In addition, prescribing erectile dysfunction medications for men and hormone replacement therapy for women might have played a part in increasing STDs among the elderly, particularly Chlamydia and HIV.²⁷ The long-term effects of STDs left untreated can easily be mistaken for other symptoms or diseases of aging, which further underscores the importance of discussing sexuality with elderly patients.

CORRESPONDENCE
Folashade Omole, MD, FAAFP, 1513 East Cleveland Avenue, Building 100, Suite 300-A, East Point, GA 30344; [email protected]

Sexuality is a central aspect of being human. It encompasses sex, gender identities and roles, sexual orientation, pleasure, eroticism, and intimacy, and is a major contributor to an individual’s quality of life and sense of wellbeing.^1,2 Positive sexual relationships and behaviors are integral to maintaining good health and general well-being later in life, as well.^2,3 Cynthia Graber, a reporter with Scientific American, reported that sex is a key reason retirees have a happy life.⁴

While there is a decline in sexual activity with age, a great number of men and women continue to engage in vaginal or anal intercourse, oral sex, and masturbation into the eighth and ninth decades of life.^2,5 In a survey conducted among married men and women, about 90% of respondents between the ages of 60 and 64 and almost 30% of those older than age 80 said they were still sexually active.2 Another study reported that 62% of men and 30% of women 80 to 102 years of age were still sexually active.⁶ However, sexuality is rarely discussed with the elderly, and most physicians are unsure about how to handle such conversations.⁷

The baby boomer population is aging in the United States and elsewhere. By 2030, 20% of the US population will be ≥65 years old, and 4% (3 million) will be lesbian, gay, bisexual, transgender, and queer (LGBTQ) elderly adults.^3,8 Given the impact of sex on maintaining quality of life, it is important for health care providers to be comfortable discussing sexuality with the elderly.⁹

Barriers to discussing sexuality

Physician barriers

Primary care physicians typically are the first point of contact for elderly adults experiencing health problems, including sexual dysfunction. According to the American Psychological Association, sex is not discussed enough with the elderly. Most physicians do not address sexual health proactively, and rarely do they include a sexual history as part of general health screening in the elderly.^2,10,11 Inadequate training of physicians in sexual health is likely a contributing factor.5 Physicians also often feel discomfort when discussing such matters with patients of the opposite sex.¹² (For a suggested approach to these conversations, see “Discussing sexuality with elderly patients: Getting beyond ‘don’t ask, don’t tell,” below.) With the increasing number of LGBTQ elderly adults, physicians should not assume their patients have any particular sexual behavior or orientation. This will help elderly LGBTQ patients feel more comfortable discussing their sexual health needs.⁸

In a study of married men and women, almost 30% of those older than age 80 said they were still sexually active.The PLISSIT model, developed in 1976 by clinical psychologist Dr. Jack Annon, can facilitate a discussion of sexuality with elderly patients.^11,13 First, the healthcare provider seeks permission (P) to discuss sexuality with the patient. After permission is given, the provider can share limited information (LI) about sexual issues that affect the older adult. Next, the provider may offer specific suggestions (SS) to improve sexual health or resolve problems. Finally, referral for intensive therapy (IT) may be needed for someone whose sexual dysfunction goes beyond the scope of the health care provider’s expertise. In 2000, open-ended questions were added to the PLISSIT model to more effectively guide an assessment of sexuality in older adults^13,14:
• Can you tell me how you express your sexuality?
• What concerns or questions do you have about fulfilling your continuing sexual needs?
• In what ways has your sexual relationship with your partner changed as you have aged?

Many physicians have only a vague understanding of the sexual needs of the elderly, and some may even consider sexuality among elderly people a taboo.⁵ The reality is that elderly adults need to be touched, held, and feel loved, and this does not diminish with age.^15-17 Unfortunately, many healthcare professionals have a mindset of, “I don’t want to think about my parents having sex, let alone my grandparents.” It is critical that physicians address intimacy needs as part of a medical assessment of the elderly.

Loss of physical and emotional intimacy is profound and often ignored as a source of suffering for the elderly. Most elderly patients want to discuss sexual issues with their physician, according to the Global Study of Sexual Attitudes among men and women ages 40 to 80 years.¹⁸ Surprisingly, even geriatricians often fail to take a sexual history of their patients. In one study, only 57% of 120 geriatricians surveyed routinely took a sexual history, even though 97% of them believed that patients with sexual problems should be managed further.¹

Patient barriers

Even given a desire to discuss sexual concerns with their health care provider, elderly patients can be reluctant due to embarrassment or a fear of sexuality. Others may hesitate because their caregiver is younger than they or is of the opposite sex.^19,20 The attitude of a medical professional has a powerful impact on the sexual attitudes and behaviors of elderly patients, and on their level of comfort in discussing sexual issues.²¹ Elderly patients do not usually complain to their physicians about sexual dysfunctions; 92% of men and 96% of women who reported at least one sexual problem in a survey had not sought help at all.¹⁸

Addressing issues in sexual dysfunction

Though sexual desires and needs may not decline with age, sexual function might, for any number of reasons.^1,2,7 Many chronic diseases are known to interfere with sexual function (TABLE).² Polypharmacy can lead to physical challenges, cognitive changes, and impaired sexual arousal, especially in men.³ However, the reason cited most often for absence of sexual activity is lack of a partner or a willing partner.² Unfortunately as one ages, the chance of finding a partner diminishes. Hence the need to discuss alternative expressions of sexuality that may not require a partner.³ Many elderly individuals enjoy masturbation as a form of sexual expression.

Men and women have different sexual problems, but they are all treatable. For instance, with normal aging, levels of testosterone in men and estrogen in women decrease.^5,15 Despite the number of sexual health dysfunctions, only 14% of men and 1% of women use medications to treat them.^2,5 With men who have erectile dysfunction, discuss possible testosterone replacement or medication. For women with postmenopausal (atrophic) vaginitis, estrogen therapy or a lubricant (for those with contraindication to estrogen therapy) can improve sexual function. Anorgasmia and low libido are other concerns for postmenopausal women, and may warrant gynecologic referral.

Loss of physical and emotional intimacy is profound and often ignored as a source of suffering for the elderly.For elderly adults moving into assisted living or a nursing home, the transition can signal the end of a sexual life.^16,22 There is limited opportunity for men and women in residential settings to engage in sexual activity, in part due to a lack of privacy.²³ The nursing home is still a home, and facility staff should provide opportunities for privacy and intimacy. In a study conducted in a residential setting, more than 25% of those ages 65 to 85 reported an active sex life, while 90% of those surveyed had sexual thoughts and fantasies.²² Of course, many elderly adults enter residential settings without a partner. They should be allowed to engage in sexual activities if they can understand, consent to, and form a relationship. Sexual needs remain even in those with dementia. But cognitive impairment frequently manifests as inappropriate sexual behavior. A study of cognitively impaired older adults revealed that 1.8% had displayed sexually inappropriate verbal or physical behavior.²⁴ In these situations, a behavior medicine specialist can be of great help.

Health risks of sexual activity in the elderly

In 2011, the Centers for Disease Control and Prevention reported that 5% of new human immunodeficiency virus (HIV) cases occurred in those ≥55 years, and almost 2% of new diagnoses were in the those ≥65 years.²⁵ Sexually active elderly individuals are at risk for acquiring HIV, in part because they do not consider themselves to be at risk for sexually transmitted diseases (STDs).²⁶ They also might not have received education about the importance of condom use.^11,26 In addition, prescribing erectile dysfunction medications for men and hormone replacement therapy for women might have played a part in increasing STDs among the elderly, particularly Chlamydia and HIV.²⁷ The long-term effects of STDs left untreated can easily be mistaken for other symptoms or diseases of aging, which further underscores the importance of discussing sexuality with elderly patients.

CORRESPONDENCE
Folashade Omole, MD, FAAFP, 1513 East Cleveland Avenue, Building 100, Suite 300-A, East Point, GA 30344; [email protected]

EVIDENCE SUMMARY

A network meta-analysis—designed to compare 2 interventions that haven’t been studied head-to-head—examined 9 trials that evaluated cardiovascular outcomes in 18,000 patients taking HCTZ and 60,000 patients taking chlorthalidone against outcomes for placebo or other antihypertensive agents.¹ Daily doses ranged from 12.5 to 25 mg for HCTZ and 12.5 to 100 mg for chlorthalidone (although most patients taking chlorthalidone were on 12.5-25 mg).

In a drug-adjusted analysis using shared comparator medications, chlorthalidone proved superior to HCTZ in reducing the risk of both heart failure (relative risk [RR]=0.77; 95% confidence interval [CI], 0.61-0.98) and combined cardiovascular events—myocardial infarction (MI), stroke, a new diagnosis of coronary artery disease, and new-onset congestive heart failure (RR=0.79; 95% CI, 0.72-0.88).

After adjusting for achieved blood pressure, chlorthalidone was still associated with lower rates of cardiovascular events than HCTZ (RR=0.82; 95% CI, 0.70-0.97). Relative to HCTZ, the number needed to treat with chlorthalidone to prevent 1 additional cardiovascular event over 5 years was 27. Because network meta-analyses draw from a wider body of research than standard meta-analyses, they may be weakened by increased variability in study design and patient demographics.

But another study shows no significant difference in cardiovascular outcomes

A subsequent retrospective cohort study didn’t find a significant difference in cardiovascular outcomes between HCTZ and chlorthalidone. The study compared pooled cardiovascular outcomes (MI, heart failure, and stroke) in 10,400 patients recently started on chlorthalidone and 19,500 started on HCTZ.² Initial doses were typically either 25 mg chlorthalidone (70% of patients on chlorthalidone) or 12.5 mg HCTZ (67% of patients on HCTZ). The median follow-up was about a year, but lasted as long as 5 years in some cases.

The 2 groups showed no significant difference in cardiovascular events (3.2 events per 100 person-years for chlorthalidone compared with 3.4 for HCTZ; adjusted hazard ratio [aHR]=0.93; 95% CI, 0.81-1.06).

Serious hypokalemia and hyponatremia are risks

Patients taking chlorthalidone were more likely to be hospitalized for hypokalemia (0.69 per 100 person-years vs 0.27 for HCTZ; aHR=3.1; 95% CI, 2.0-4.6; number needed to harm [NNH]=238 in 1 year) or hyponatremia (0.69 per 100 person-years vs 0.49 for HCTZ; aHR=1.7; 95% CI, 1.2-2.3; NNH=434 in 1 year).² However, the all-cause hospitalization rates for the 2 drugs were the same (aHR=1.0; 95% CI, 0.93-1.07).

Chlorthalidone may reduce the risk of cardiovascular events in patients with hypertension more than HCTZ.

Lower systolic BP and serum potassium found with chlorthalidone

A smaller retrospective cohort analysis (6441 participants who received either chlorthalidone or HCTZ starting at 50 mg and stepped once to 100 mg) also assessed the difference in cardiovascular events between patients taking the 2 drugs.³ (Cardiovascular events were defined as pooled MIs, onset of angina or peripheral artery occlusive disease, or need for coronary artery bypass.) Although significant reductions in pooled events occurred in both groups over the 7-year study, these reductions were significantly lower in the chlorthalidone group than in the HCTZ group (aHR=0.79; 95% CI, 0.68-0.92).

Systolic blood pressures were statistically lower in the chlorthalidone group during Years 1 through 5 but not in Years 6 and 7 (difference 2-4 mm Hg). Serum potassium was also lower in patients taking chlorthalidone (3.8 mEq/L on chlorthalidone vs 4.0 mEq/L on HCTZ after 7 years; P<.05).

A retrospective cohort study investigated medication tolerance in veterans who had recently started either HCTZ (120,000 patients) or chlorthalidone (2200 patients) and were followed for a year.⁴ Most received doses between 12.5 and 25 mg of active drug.

One primary outcome was “nonpersistence,” defined as failure to refill the medication after double the number of days as the initial prescription. The other was “insufficient response,” defined as the need to start another antihypertensive medication. Chlorthalidone users were less likely than HCTZ users to have an insufficient response (odds ratio [OR]=0.71; 95% CI, 0.63-0.80) but more likely to exhibit nonpersistence (OR=1.6; 95% CI, 1.5-1.8).

RECOMMENDATIONS

For primary hypertension, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommends diuretic monotherapy in patients older than 55 years who are poor candidates for calcium channel blockers.⁵ If a diuretic is to be initiated or changed, NICE recommends chlorthalidone (12.5-25 mg daily) or indapamide (1.5-2.5 mg daily) in preference to HCTZ. The guideline set forth in the eighth annual report of the United States Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure makes no distinction between chlorthalidone and HCTZ; it refers only to “thiazidetype diuretics.” Thiazide-type diuretics are listed as one option (along with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) for initial monotherapy in nonblack patients.⁶

EVIDENCE SUMMARY

A network meta-analysis—designed to compare 2 interventions that haven’t been studied head-to-head—examined 9 trials that evaluated cardiovascular outcomes in 18,000 patients taking HCTZ and 60,000 patients taking chlorthalidone against outcomes for placebo or other antihypertensive agents.¹ Daily doses ranged from 12.5 to 25 mg for HCTZ and 12.5 to 100 mg for chlorthalidone (although most patients taking chlorthalidone were on 12.5-25 mg).

In a drug-adjusted analysis using shared comparator medications, chlorthalidone proved superior to HCTZ in reducing the risk of both heart failure (relative risk [RR]=0.77; 95% confidence interval [CI], 0.61-0.98) and combined cardiovascular events—myocardial infarction (MI), stroke, a new diagnosis of coronary artery disease, and new-onset congestive heart failure (RR=0.79; 95% CI, 0.72-0.88).

After adjusting for achieved blood pressure, chlorthalidone was still associated with lower rates of cardiovascular events than HCTZ (RR=0.82; 95% CI, 0.70-0.97). Relative to HCTZ, the number needed to treat with chlorthalidone to prevent 1 additional cardiovascular event over 5 years was 27. Because network meta-analyses draw from a wider body of research than standard meta-analyses, they may be weakened by increased variability in study design and patient demographics.

But another study shows no significant difference in cardiovascular outcomes

A subsequent retrospective cohort study didn’t find a significant difference in cardiovascular outcomes between HCTZ and chlorthalidone. The study compared pooled cardiovascular outcomes (MI, heart failure, and stroke) in 10,400 patients recently started on chlorthalidone and 19,500 started on HCTZ.² Initial doses were typically either 25 mg chlorthalidone (70% of patients on chlorthalidone) or 12.5 mg HCTZ (67% of patients on HCTZ). The median follow-up was about a year, but lasted as long as 5 years in some cases.

The 2 groups showed no significant difference in cardiovascular events (3.2 events per 100 person-years for chlorthalidone compared with 3.4 for HCTZ; adjusted hazard ratio [aHR]=0.93; 95% CI, 0.81-1.06).

Serious hypokalemia and hyponatremia are risks

Patients taking chlorthalidone were more likely to be hospitalized for hypokalemia (0.69 per 100 person-years vs 0.27 for HCTZ; aHR=3.1; 95% CI, 2.0-4.6; number needed to harm [NNH]=238 in 1 year) or hyponatremia (0.69 per 100 person-years vs 0.49 for HCTZ; aHR=1.7; 95% CI, 1.2-2.3; NNH=434 in 1 year).² However, the all-cause hospitalization rates for the 2 drugs were the same (aHR=1.0; 95% CI, 0.93-1.07).

Chlorthalidone may reduce the risk of cardiovascular events in patients with hypertension more than HCTZ.

Lower systolic BP and serum potassium found with chlorthalidone

A smaller retrospective cohort analysis (6441 participants who received either chlorthalidone or HCTZ starting at 50 mg and stepped once to 100 mg) also assessed the difference in cardiovascular events between patients taking the 2 drugs.³ (Cardiovascular events were defined as pooled MIs, onset of angina or peripheral artery occlusive disease, or need for coronary artery bypass.) Although significant reductions in pooled events occurred in both groups over the 7-year study, these reductions were significantly lower in the chlorthalidone group than in the HCTZ group (aHR=0.79; 95% CI, 0.68-0.92).

Systolic blood pressures were statistically lower in the chlorthalidone group during Years 1 through 5 but not in Years 6 and 7 (difference 2-4 mm Hg). Serum potassium was also lower in patients taking chlorthalidone (3.8 mEq/L on chlorthalidone vs 4.0 mEq/L on HCTZ after 7 years; P<.05).

A retrospective cohort study investigated medication tolerance in veterans who had recently started either HCTZ (120,000 patients) or chlorthalidone (2200 patients) and were followed for a year.⁴ Most received doses between 12.5 and 25 mg of active drug.

One primary outcome was “nonpersistence,” defined as failure to refill the medication after double the number of days as the initial prescription. The other was “insufficient response,” defined as the need to start another antihypertensive medication. Chlorthalidone users were less likely than HCTZ users to have an insufficient response (odds ratio [OR]=0.71; 95% CI, 0.63-0.80) but more likely to exhibit nonpersistence (OR=1.6; 95% CI, 1.5-1.8).

RECOMMENDATIONS

For primary hypertension, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommends diuretic monotherapy in patients older than 55 years who are poor candidates for calcium channel blockers.⁵ If a diuretic is to be initiated or changed, NICE recommends chlorthalidone (12.5-25 mg daily) or indapamide (1.5-2.5 mg daily) in preference to HCTZ. The guideline set forth in the eighth annual report of the United States Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure makes no distinction between chlorthalidone and HCTZ; it refers only to “thiazidetype diuretics.” Thiazide-type diuretics are listed as one option (along with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) for initial monotherapy in nonblack patients.⁶

EVIDENCE SUMMARY

A network meta-analysis—designed to compare 2 interventions that haven’t been studied head-to-head—examined 9 trials that evaluated cardiovascular outcomes in 18,000 patients taking HCTZ and 60,000 patients taking chlorthalidone against outcomes for placebo or other antihypertensive agents.¹ Daily doses ranged from 12.5 to 25 mg for HCTZ and 12.5 to 100 mg for chlorthalidone (although most patients taking chlorthalidone were on 12.5-25 mg).

In a drug-adjusted analysis using shared comparator medications, chlorthalidone proved superior to HCTZ in reducing the risk of both heart failure (relative risk [RR]=0.77; 95% confidence interval [CI], 0.61-0.98) and combined cardiovascular events—myocardial infarction (MI), stroke, a new diagnosis of coronary artery disease, and new-onset congestive heart failure (RR=0.79; 95% CI, 0.72-0.88).

After adjusting for achieved blood pressure, chlorthalidone was still associated with lower rates of cardiovascular events than HCTZ (RR=0.82; 95% CI, 0.70-0.97). Relative to HCTZ, the number needed to treat with chlorthalidone to prevent 1 additional cardiovascular event over 5 years was 27. Because network meta-analyses draw from a wider body of research than standard meta-analyses, they may be weakened by increased variability in study design and patient demographics.

But another study shows no significant difference in cardiovascular outcomes

A subsequent retrospective cohort study didn’t find a significant difference in cardiovascular outcomes between HCTZ and chlorthalidone. The study compared pooled cardiovascular outcomes (MI, heart failure, and stroke) in 10,400 patients recently started on chlorthalidone and 19,500 started on HCTZ.² Initial doses were typically either 25 mg chlorthalidone (70% of patients on chlorthalidone) or 12.5 mg HCTZ (67% of patients on HCTZ). The median follow-up was about a year, but lasted as long as 5 years in some cases.

The 2 groups showed no significant difference in cardiovascular events (3.2 events per 100 person-years for chlorthalidone compared with 3.4 for HCTZ; adjusted hazard ratio [aHR]=0.93; 95% CI, 0.81-1.06).

Serious hypokalemia and hyponatremia are risks

Patients taking chlorthalidone were more likely to be hospitalized for hypokalemia (0.69 per 100 person-years vs 0.27 for HCTZ; aHR=3.1; 95% CI, 2.0-4.6; number needed to harm [NNH]=238 in 1 year) or hyponatremia (0.69 per 100 person-years vs 0.49 for HCTZ; aHR=1.7; 95% CI, 1.2-2.3; NNH=434 in 1 year).² However, the all-cause hospitalization rates for the 2 drugs were the same (aHR=1.0; 95% CI, 0.93-1.07).

Chlorthalidone may reduce the risk of cardiovascular events in patients with hypertension more than HCTZ.

Lower systolic BP and serum potassium found with chlorthalidone

A smaller retrospective cohort analysis (6441 participants who received either chlorthalidone or HCTZ starting at 50 mg and stepped once to 100 mg) also assessed the difference in cardiovascular events between patients taking the 2 drugs.³ (Cardiovascular events were defined as pooled MIs, onset of angina or peripheral artery occlusive disease, or need for coronary artery bypass.) Although significant reductions in pooled events occurred in both groups over the 7-year study, these reductions were significantly lower in the chlorthalidone group than in the HCTZ group (aHR=0.79; 95% CI, 0.68-0.92).

Systolic blood pressures were statistically lower in the chlorthalidone group during Years 1 through 5 but not in Years 6 and 7 (difference 2-4 mm Hg). Serum potassium was also lower in patients taking chlorthalidone (3.8 mEq/L on chlorthalidone vs 4.0 mEq/L on HCTZ after 7 years; P<.05).

A retrospective cohort study investigated medication tolerance in veterans who had recently started either HCTZ (120,000 patients) or chlorthalidone (2200 patients) and were followed for a year.⁴ Most received doses between 12.5 and 25 mg of active drug.

One primary outcome was “nonpersistence,” defined as failure to refill the medication after double the number of days as the initial prescription. The other was “insufficient response,” defined as the need to start another antihypertensive medication. Chlorthalidone users were less likely than HCTZ users to have an insufficient response (odds ratio [OR]=0.71; 95% CI, 0.63-0.80) but more likely to exhibit nonpersistence (OR=1.6; 95% CI, 1.5-1.8).

RECOMMENDATIONS

For primary hypertension, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommends diuretic monotherapy in patients older than 55 years who are poor candidates for calcium channel blockers.⁵ If a diuretic is to be initiated or changed, NICE recommends chlorthalidone (12.5-25 mg daily) or indapamide (1.5-2.5 mg daily) in preference to HCTZ. The guideline set forth in the eighth annual report of the United States Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure makes no distinction between chlorthalidone and HCTZ; it refers only to “thiazidetype diuretics.” Thiazide-type diuretics are listed as one option (along with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) for initial monotherapy in nonblack patients.⁶

EVIDENCE SUMMARY

A 28-week RCT compared the effects of placebo, allopurinol (300 mg/d), and febuxostat (80 mg, 120 mg, and 240 mg) on serum uric acid levels (sUA) and gout attacks in 1067 patients with gout and hyperuricemia (94% male, 78% white, 18 to 85 years of age with mean age ranging from 51 to 54 years ± 12 years in each group).¹ Patients also received prophylaxis with either colchicine or naproxen during the first 8 weeks of the study.

During Weeks 1 through 8, investigators found no statistically significant differences in the percentage of patients requiring treatment for gout attacks between the febuxostat 80 mg, allopurinol, and placebo groups (28%, 23%, and 20%, respectively). During Weeks 8 through 28, no statistically significant differences in gout attack rates occurred between the allopurinol and febuxostat groups, although the study didn’t report specific attack rates for this period.

Both allopurinol and all doses of febuxostat reduced sUA to <6 mg/dL more effectively than placebo; more patients treated with febuxostat than allopurinol achieved a uric acid level of less than <6 mg/dL.

Another RCT of 762 mostly white, male patients (mean age 52 years) with gout and sUA >8 mg/dL—35% of whom had renal impairment, defined as creatinine clearance <80 mL/min/1.73m²—also concluded that febuxostat and allopurinol are equally effective in reducing gout attacks (incidence of gout flares during Weeks 9 to 52 was 64% with both febuxostat 80 mg and allopurinol 300 mg).² The percentage of patients with sUA <6 mg/dL at the last 3 monthly visits was 53% in the febuxostat 80 mg group compared with 21% in the allopurinol 300 mg group (P<.001; number needed to treat [NNT]=4]).

One significant limitation of both RCTs was the fixed dose of allopurinol (300 mg/d). US Food and Drug Administration-approved dosing for allopurinol allows for titration to a maximum of 800 mg/d to achieve serum uric acid <6 mg/dL.

Pegloticase is an intravenously administered, recombinant form of uricase, the natural enzyme that converts uric acid to more soluble allantoin. Two RCTs compared pegloticase with placebo in a total of 212 patients with gout (mean age 54 to 59 years; 70% to 90% male) intolerant or refractory to allopurinol (defined as baseline sUA of ≥8 mg/dL and at least one of the following: ≥3 self-reported gout flares during the previous 18 months, ≥1 tophi, or gouty arthropathy.

These trials found that treatment with 8 mg of pegloticase every 2 weeks for 6 months initially increased gout flares during Months 1 to 3 (75% with pegloticase, 53% with placebo; P=.02; number needed to harm [NNH]=5) but then decreased the incidence of acute gout attacks during Months 4 to 6 (41% with pegloticase, 67% with placebo; P=.007; NNT=4).3 In addition, pegloticase resulted in statistically significant improvements in QOL measured at the final visit using the Health Assessment Questionnaire (HAQ) pain scale, the HAQ-Disability Index, and the 36-item Short Form Health Survey.

Colchicine plus probenecid or allopurinol reduces gout attacks

One small, low-quality RCT (N=38) found that colchicine 0.5 mg administered 3 times daily effectively prevented gout attacks when administered concomitantly with probenecid initiated to lower urate (gout attacks per month in colchicine and placebo-treated patients, respectively, were 0.19±0.05 and 0.48±0.12; P<.05).⁴

Another RCT that compared allopurinol with and without colchicine showed that coadministration of colchicine 0.6 mg twice daily reduced gout attacks: 33% of patients treated with colchicine experienced a gout flare compared with 77% of placebo-treated patients (P=.008; NNT=3 over 6 months).⁵

We identified no RCTs that evaluated the uricosuric agent probenecid and no studies that assessed the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent recurrent gout attacks.

RECOMMENDATIONS

Eight weeks of treatment with either allopurinol or febuxostat reduces the frequency of gout attacks equally.The American College of Rheumatology (ACR) guidelines on managing gout recommend allopurinol or febuxostat as first-line pharmacologic urate-lowering therapy, with a goal of reducing sUA to <6 mg/dL. They recommend probenecid as an alternative if contraindications exist or the patient is intolerant to allopurinol and febuxostat.⁶ The guidelines note that allopurinol doses may exceed 300 mg/d, even in patients with chronic kidney disease.

The ACR recommends anti-inflammatory prophylaxis with colchicine or NSAIDs upon initiation of urate-lowering therapy. Anti-inflammatory prophylaxis should be continued as long as clinical evidence of continuing gout disease exists and until the sUA target has been acheived.7

EVIDENCE SUMMARY

A 28-week RCT compared the effects of placebo, allopurinol (300 mg/d), and febuxostat (80 mg, 120 mg, and 240 mg) on serum uric acid levels (sUA) and gout attacks in 1067 patients with gout and hyperuricemia (94% male, 78% white, 18 to 85 years of age with mean age ranging from 51 to 54 years ± 12 years in each group).¹ Patients also received prophylaxis with either colchicine or naproxen during the first 8 weeks of the study.

During Weeks 1 through 8, investigators found no statistically significant differences in the percentage of patients requiring treatment for gout attacks between the febuxostat 80 mg, allopurinol, and placebo groups (28%, 23%, and 20%, respectively). During Weeks 8 through 28, no statistically significant differences in gout attack rates occurred between the allopurinol and febuxostat groups, although the study didn’t report specific attack rates for this period.

Both allopurinol and all doses of febuxostat reduced sUA to <6 mg/dL more effectively than placebo; more patients treated with febuxostat than allopurinol achieved a uric acid level of less than <6 mg/dL.

Another RCT of 762 mostly white, male patients (mean age 52 years) with gout and sUA >8 mg/dL—35% of whom had renal impairment, defined as creatinine clearance <80 mL/min/1.73m²—also concluded that febuxostat and allopurinol are equally effective in reducing gout attacks (incidence of gout flares during Weeks 9 to 52 was 64% with both febuxostat 80 mg and allopurinol 300 mg).² The percentage of patients with sUA <6 mg/dL at the last 3 monthly visits was 53% in the febuxostat 80 mg group compared with 21% in the allopurinol 300 mg group (P<.001; number needed to treat [NNT]=4]).

One significant limitation of both RCTs was the fixed dose of allopurinol (300 mg/d). US Food and Drug Administration-approved dosing for allopurinol allows for titration to a maximum of 800 mg/d to achieve serum uric acid <6 mg/dL.

Pegloticase is an intravenously administered, recombinant form of uricase, the natural enzyme that converts uric acid to more soluble allantoin. Two RCTs compared pegloticase with placebo in a total of 212 patients with gout (mean age 54 to 59 years; 70% to 90% male) intolerant or refractory to allopurinol (defined as baseline sUA of ≥8 mg/dL and at least one of the following: ≥3 self-reported gout flares during the previous 18 months, ≥1 tophi, or gouty arthropathy.

These trials found that treatment with 8 mg of pegloticase every 2 weeks for 6 months initially increased gout flares during Months 1 to 3 (75% with pegloticase, 53% with placebo; P=.02; number needed to harm [NNH]=5) but then decreased the incidence of acute gout attacks during Months 4 to 6 (41% with pegloticase, 67% with placebo; P=.007; NNT=4).3 In addition, pegloticase resulted in statistically significant improvements in QOL measured at the final visit using the Health Assessment Questionnaire (HAQ) pain scale, the HAQ-Disability Index, and the 36-item Short Form Health Survey.

Colchicine plus probenecid or allopurinol reduces gout attacks

One small, low-quality RCT (N=38) found that colchicine 0.5 mg administered 3 times daily effectively prevented gout attacks when administered concomitantly with probenecid initiated to lower urate (gout attacks per month in colchicine and placebo-treated patients, respectively, were 0.19±0.05 and 0.48±0.12; P<.05).⁴

Another RCT that compared allopurinol with and without colchicine showed that coadministration of colchicine 0.6 mg twice daily reduced gout attacks: 33% of patients treated with colchicine experienced a gout flare compared with 77% of placebo-treated patients (P=.008; NNT=3 over 6 months).⁵

We identified no RCTs that evaluated the uricosuric agent probenecid and no studies that assessed the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent recurrent gout attacks.

RECOMMENDATIONS

Eight weeks of treatment with either allopurinol or febuxostat reduces the frequency of gout attacks equally.The American College of Rheumatology (ACR) guidelines on managing gout recommend allopurinol or febuxostat as first-line pharmacologic urate-lowering therapy, with a goal of reducing sUA to <6 mg/dL. They recommend probenecid as an alternative if contraindications exist or the patient is intolerant to allopurinol and febuxostat.⁶ The guidelines note that allopurinol doses may exceed 300 mg/d, even in patients with chronic kidney disease.

The ACR recommends anti-inflammatory prophylaxis with colchicine or NSAIDs upon initiation of urate-lowering therapy. Anti-inflammatory prophylaxis should be continued as long as clinical evidence of continuing gout disease exists and until the sUA target has been acheived.7

EVIDENCE SUMMARY

A 28-week RCT compared the effects of placebo, allopurinol (300 mg/d), and febuxostat (80 mg, 120 mg, and 240 mg) on serum uric acid levels (sUA) and gout attacks in 1067 patients with gout and hyperuricemia (94% male, 78% white, 18 to 85 years of age with mean age ranging from 51 to 54 years ± 12 years in each group).¹ Patients also received prophylaxis with either colchicine or naproxen during the first 8 weeks of the study.

During Weeks 1 through 8, investigators found no statistically significant differences in the percentage of patients requiring treatment for gout attacks between the febuxostat 80 mg, allopurinol, and placebo groups (28%, 23%, and 20%, respectively). During Weeks 8 through 28, no statistically significant differences in gout attack rates occurred between the allopurinol and febuxostat groups, although the study didn’t report specific attack rates for this period.

Both allopurinol and all doses of febuxostat reduced sUA to <6 mg/dL more effectively than placebo; more patients treated with febuxostat than allopurinol achieved a uric acid level of less than <6 mg/dL.

Another RCT of 762 mostly white, male patients (mean age 52 years) with gout and sUA >8 mg/dL—35% of whom had renal impairment, defined as creatinine clearance <80 mL/min/1.73m²—also concluded that febuxostat and allopurinol are equally effective in reducing gout attacks (incidence of gout flares during Weeks 9 to 52 was 64% with both febuxostat 80 mg and allopurinol 300 mg).² The percentage of patients with sUA <6 mg/dL at the last 3 monthly visits was 53% in the febuxostat 80 mg group compared with 21% in the allopurinol 300 mg group (P<.001; number needed to treat [NNT]=4]).

One significant limitation of both RCTs was the fixed dose of allopurinol (300 mg/d). US Food and Drug Administration-approved dosing for allopurinol allows for titration to a maximum of 800 mg/d to achieve serum uric acid <6 mg/dL.

Pegloticase is an intravenously administered, recombinant form of uricase, the natural enzyme that converts uric acid to more soluble allantoin. Two RCTs compared pegloticase with placebo in a total of 212 patients with gout (mean age 54 to 59 years; 70% to 90% male) intolerant or refractory to allopurinol (defined as baseline sUA of ≥8 mg/dL and at least one of the following: ≥3 self-reported gout flares during the previous 18 months, ≥1 tophi, or gouty arthropathy.

These trials found that treatment with 8 mg of pegloticase every 2 weeks for 6 months initially increased gout flares during Months 1 to 3 (75% with pegloticase, 53% with placebo; P=.02; number needed to harm [NNH]=5) but then decreased the incidence of acute gout attacks during Months 4 to 6 (41% with pegloticase, 67% with placebo; P=.007; NNT=4).3 In addition, pegloticase resulted in statistically significant improvements in QOL measured at the final visit using the Health Assessment Questionnaire (HAQ) pain scale, the HAQ-Disability Index, and the 36-item Short Form Health Survey.

Colchicine plus probenecid or allopurinol reduces gout attacks

One small, low-quality RCT (N=38) found that colchicine 0.5 mg administered 3 times daily effectively prevented gout attacks when administered concomitantly with probenecid initiated to lower urate (gout attacks per month in colchicine and placebo-treated patients, respectively, were 0.19±0.05 and 0.48±0.12; P<.05).⁴

Another RCT that compared allopurinol with and without colchicine showed that coadministration of colchicine 0.6 mg twice daily reduced gout attacks: 33% of patients treated with colchicine experienced a gout flare compared with 77% of placebo-treated patients (P=.008; NNT=3 over 6 months).⁵

We identified no RCTs that evaluated the uricosuric agent probenecid and no studies that assessed the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent recurrent gout attacks.

RECOMMENDATIONS

Eight weeks of treatment with either allopurinol or febuxostat reduces the frequency of gout attacks equally.The American College of Rheumatology (ACR) guidelines on managing gout recommend allopurinol or febuxostat as first-line pharmacologic urate-lowering therapy, with a goal of reducing sUA to <6 mg/dL. They recommend probenecid as an alternative if contraindications exist or the patient is intolerant to allopurinol and febuxostat.⁶ The guidelines note that allopurinol doses may exceed 300 mg/d, even in patients with chronic kidney disease.

The ACR recommends anti-inflammatory prophylaxis with colchicine or NSAIDs upon initiation of urate-lowering therapy. Anti-inflammatory prophylaxis should be continued as long as clinical evidence of continuing gout disease exists and until the sUA target has been acheived.7

Welcome to a new column designed to provide practical advice regarding issues related to child mental health. It will be a joint effort, featuring contributions from several child psychiatrists working at the University of Vermont and the Vermont Center for Children, Youth, and Families. While psychopharmacology will certainly be a part of many of the columns, all of us here feel strongly that medications should be only one part of a comprehensive family-oriented plan. We encourage you to submit questions that you would like us address in future issues to [email protected].
 

Case summary

A 10-year-old boy presents for a follow-up appointment. He was diagnosed by another pediatrician in the practice 2 months ago with attention-deficit/hyperactivity disorder (ADHD) and now returns to the office with continued symptoms and a complaint from the mother that medication "isn’t working." The boy was started on an extended-release preparation of methylphenidate at 18 mg to take each morning. The child is in the fifth grade and weighs 80 lb (36 kg). He lives with his mother and 8-year-old brother. The father is no longer involved in the patient’s life, which puts added stress on the mother. The diagnosis of ADHD was made by the pediatrician based upon the history, the child’s hyperactive and intrusive behavior in the office, and the results of a standardized rating scale that was completed by the mother, who now requests that the pediatrician "try something different."

Discussion

Many children and adolescents respond extremely well to ADHD medications. Some, however, do not, and the parental complaint that the "medication isn’t working" is a frequent expression heard in pediatrician offices across the country. It is also one of the primary reasons a family is referred to a child psychiatrist. In the course of performing hundreds of these consultations, I have found that there are several possibilities to consider before assuming the medication simply isn’t effective.

We will start with simpler problems and work our way toward more challenging reasons.

• The dose is too low. Methylphenidate often needs to be dosed over 1 mg/kg/day to be effective. If the patient reports minimal response to the medication while experiencing no side effects, an increase may certainly be reasonable.

• The medication is working but wearing off. Despite the advertisements of long-acting stimulants continuing their therapeutic effect for 10-12 hours, many children seem to lose the benefit of the medication much faster. Gathering some data from the school or asking the mother about weekend mornings compared with evenings can be useful. If indeed such a wear-off is found, adding a dose of an immediate-release stimulant in the early afternoon may help.

• Symptoms are being caused by something other than ADHD. Hyperactivity due to exposures such as lead may not change your management of the symptoms, but certainly could necessitate other types of intervention. Chronic sleep problems and inadequate nutrition, especially when it comes to breakfast, also should be queried and can lead to problems with concentration.

• There is psychiatric comorbidity. Unlike many differentials in other specialties, psychiatric differential diagnosis is often a matter of "and" rather than "or." Anxiety disorders, for example, can frequently masquerade as ADHD or be present in addition to ADHD. Oppositional behavior is also very commonly present with ADHD and suggests additional types of treatment.

• There is noncompliance. This problem can surface frequently in two ways. Older children may be responsible at home for taking their medications and forget or refuse to do so. I often ask, "Are you taking the medication every single day?" Diversion is also a potential problem from the parents or for an adolescent. Checking if the refills are occurring on time can provide a clue here, and some states have systems to check for duplicate prescriptions from multiple clinicians.

• Side effects are appearing as untreated ADHD. Sometimes medications are the problem, not the solution, and a failure to recognize this phenomenon can lead to unnecessary and sometimes harmful polypharmacy. Stimulants in some children can lead to increased agitation, anger outbursts, and impulsivity. Trying a medication holiday for several days can sometimes reveal the need to back off rather than add medications.

• Family is expecting improvement for non-ADHD symptoms. Asking what particular behaviors the family is hoping to improve can sometimes expose a situation in which parents expect change in non-ADHD domains. Unfortunately, there is no pill to make kids respect their parents more or want to do their homework. Being clear from the outset about what behaviors are and are not medication responsive can sometimes prevent this problem.

• There is substance abuse. In addition to the potential problem of abuse of the stimulants described previously, other substances such as cannabis can sabotage the benefits of medications.

• There is over-reliance on medications as the sole modality of treatment. ADHD is best treated using a wide range of strategies. Nonpharmacological interventions such as exercise, good nutrition and sleep, parent behavioral training, organizational help, regular reading, screen time reduction, and school supports are critical components of a comprehensive treatment approach.

• There is parental psychopathology. In our opinion, this area is one of the most frequently neglected aspects of child mental health treatment and can have huge implications. ADHD in particular is known to have very high heritability (similar to height). If a mother or father shares the condition, their struggles can frequently contribute to an environment that can exacerbate the child’s symptoms. A pattern in which the ADHD symptoms are more prominent at home compared with school is one clue to look in this direction. When addressing parental psychopathology, it can be important not to come off as blaming the parents for their child’s problems, but rather to convey how challenging dealing with ADHD can be as a parent and how they need to be functioning at their highest mental level as well.

Of course, sometimes the medication truly is not working, and it is time to try something else.

Dr. David C. Rettew is associate professor of psychiatry and pediatrics, director of the child and adolescent psychiatry fellowship, and director of the pediatric psychiatry clinic at the University of Vermont, Burlington.

Welcome to a new column designed to provide practical advice regarding issues related to child mental health. It will be a joint effort, featuring contributions from several child psychiatrists working at the University of Vermont and the Vermont Center for Children, Youth, and Families. While psychopharmacology will certainly be a part of many of the columns, all of us here feel strongly that medications should be only one part of a comprehensive family-oriented plan. We encourage you to submit questions that you would like us address in future issues to [email protected].
 

Case summary

A 10-year-old boy presents for a follow-up appointment. He was diagnosed by another pediatrician in the practice 2 months ago with attention-deficit/hyperactivity disorder (ADHD) and now returns to the office with continued symptoms and a complaint from the mother that medication "isn’t working." The boy was started on an extended-release preparation of methylphenidate at 18 mg to take each morning. The child is in the fifth grade and weighs 80 lb (36 kg). He lives with his mother and 8-year-old brother. The father is no longer involved in the patient’s life, which puts added stress on the mother. The diagnosis of ADHD was made by the pediatrician based upon the history, the child’s hyperactive and intrusive behavior in the office, and the results of a standardized rating scale that was completed by the mother, who now requests that the pediatrician "try something different."

Discussion

Many children and adolescents respond extremely well to ADHD medications. Some, however, do not, and the parental complaint that the "medication isn’t working" is a frequent expression heard in pediatrician offices across the country. It is also one of the primary reasons a family is referred to a child psychiatrist. In the course of performing hundreds of these consultations, I have found that there are several possibilities to consider before assuming the medication simply isn’t effective.

We will start with simpler problems and work our way toward more challenging reasons.

• The dose is too low. Methylphenidate often needs to be dosed over 1 mg/kg/day to be effective. If the patient reports minimal response to the medication while experiencing no side effects, an increase may certainly be reasonable.

• The medication is working but wearing off. Despite the advertisements of long-acting stimulants continuing their therapeutic effect for 10-12 hours, many children seem to lose the benefit of the medication much faster. Gathering some data from the school or asking the mother about weekend mornings compared with evenings can be useful. If indeed such a wear-off is found, adding a dose of an immediate-release stimulant in the early afternoon may help.

• Symptoms are being caused by something other than ADHD. Hyperactivity due to exposures such as lead may not change your management of the symptoms, but certainly could necessitate other types of intervention. Chronic sleep problems and inadequate nutrition, especially when it comes to breakfast, also should be queried and can lead to problems with concentration.

• There is psychiatric comorbidity. Unlike many differentials in other specialties, psychiatric differential diagnosis is often a matter of "and" rather than "or." Anxiety disorders, for example, can frequently masquerade as ADHD or be present in addition to ADHD. Oppositional behavior is also very commonly present with ADHD and suggests additional types of treatment.

• There is noncompliance. This problem can surface frequently in two ways. Older children may be responsible at home for taking their medications and forget or refuse to do so. I often ask, "Are you taking the medication every single day?" Diversion is also a potential problem from the parents or for an adolescent. Checking if the refills are occurring on time can provide a clue here, and some states have systems to check for duplicate prescriptions from multiple clinicians.

• Side effects are appearing as untreated ADHD. Sometimes medications are the problem, not the solution, and a failure to recognize this phenomenon can lead to unnecessary and sometimes harmful polypharmacy. Stimulants in some children can lead to increased agitation, anger outbursts, and impulsivity. Trying a medication holiday for several days can sometimes reveal the need to back off rather than add medications.

• Family is expecting improvement for non-ADHD symptoms. Asking what particular behaviors the family is hoping to improve can sometimes expose a situation in which parents expect change in non-ADHD domains. Unfortunately, there is no pill to make kids respect their parents more or want to do their homework. Being clear from the outset about what behaviors are and are not medication responsive can sometimes prevent this problem.

• There is substance abuse. In addition to the potential problem of abuse of the stimulants described previously, other substances such as cannabis can sabotage the benefits of medications.

• There is over-reliance on medications as the sole modality of treatment. ADHD is best treated using a wide range of strategies. Nonpharmacological interventions such as exercise, good nutrition and sleep, parent behavioral training, organizational help, regular reading, screen time reduction, and school supports are critical components of a comprehensive treatment approach.

• There is parental psychopathology. In our opinion, this area is one of the most frequently neglected aspects of child mental health treatment and can have huge implications. ADHD in particular is known to have very high heritability (similar to height). If a mother or father shares the condition, their struggles can frequently contribute to an environment that can exacerbate the child’s symptoms. A pattern in which the ADHD symptoms are more prominent at home compared with school is one clue to look in this direction. When addressing parental psychopathology, it can be important not to come off as blaming the parents for their child’s problems, but rather to convey how challenging dealing with ADHD can be as a parent and how they need to be functioning at their highest mental level as well.

Of course, sometimes the medication truly is not working, and it is time to try something else.

Dr. David C. Rettew is associate professor of psychiatry and pediatrics, director of the child and adolescent psychiatry fellowship, and director of the pediatric psychiatry clinic at the University of Vermont, Burlington.

Welcome to a new column designed to provide practical advice regarding issues related to child mental health. It will be a joint effort, featuring contributions from several child psychiatrists working at the University of Vermont and the Vermont Center for Children, Youth, and Families. While psychopharmacology will certainly be a part of many of the columns, all of us here feel strongly that medications should be only one part of a comprehensive family-oriented plan. We encourage you to submit questions that you would like us address in future issues to [email protected].
 

Case summary

A 10-year-old boy presents for a follow-up appointment. He was diagnosed by another pediatrician in the practice 2 months ago with attention-deficit/hyperactivity disorder (ADHD) and now returns to the office with continued symptoms and a complaint from the mother that medication "isn’t working." The boy was started on an extended-release preparation of methylphenidate at 18 mg to take each morning. The child is in the fifth grade and weighs 80 lb (36 kg). He lives with his mother and 8-year-old brother. The father is no longer involved in the patient’s life, which puts added stress on the mother. The diagnosis of ADHD was made by the pediatrician based upon the history, the child’s hyperactive and intrusive behavior in the office, and the results of a standardized rating scale that was completed by the mother, who now requests that the pediatrician "try something different."

Discussion

Many children and adolescents respond extremely well to ADHD medications. Some, however, do not, and the parental complaint that the "medication isn’t working" is a frequent expression heard in pediatrician offices across the country. It is also one of the primary reasons a family is referred to a child psychiatrist. In the course of performing hundreds of these consultations, I have found that there are several possibilities to consider before assuming the medication simply isn’t effective.

We will start with simpler problems and work our way toward more challenging reasons.

• The dose is too low. Methylphenidate often needs to be dosed over 1 mg/kg/day to be effective. If the patient reports minimal response to the medication while experiencing no side effects, an increase may certainly be reasonable.

• The medication is working but wearing off. Despite the advertisements of long-acting stimulants continuing their therapeutic effect for 10-12 hours, many children seem to lose the benefit of the medication much faster. Gathering some data from the school or asking the mother about weekend mornings compared with evenings can be useful. If indeed such a wear-off is found, adding a dose of an immediate-release stimulant in the early afternoon may help.

• Symptoms are being caused by something other than ADHD. Hyperactivity due to exposures such as lead may not change your management of the symptoms, but certainly could necessitate other types of intervention. Chronic sleep problems and inadequate nutrition, especially when it comes to breakfast, also should be queried and can lead to problems with concentration.

• There is psychiatric comorbidity. Unlike many differentials in other specialties, psychiatric differential diagnosis is often a matter of "and" rather than "or." Anxiety disorders, for example, can frequently masquerade as ADHD or be present in addition to ADHD. Oppositional behavior is also very commonly present with ADHD and suggests additional types of treatment.

• There is noncompliance. This problem can surface frequently in two ways. Older children may be responsible at home for taking their medications and forget or refuse to do so. I often ask, "Are you taking the medication every single day?" Diversion is also a potential problem from the parents or for an adolescent. Checking if the refills are occurring on time can provide a clue here, and some states have systems to check for duplicate prescriptions from multiple clinicians.

• Side effects are appearing as untreated ADHD. Sometimes medications are the problem, not the solution, and a failure to recognize this phenomenon can lead to unnecessary and sometimes harmful polypharmacy. Stimulants in some children can lead to increased agitation, anger outbursts, and impulsivity. Trying a medication holiday for several days can sometimes reveal the need to back off rather than add medications.

• Family is expecting improvement for non-ADHD symptoms. Asking what particular behaviors the family is hoping to improve can sometimes expose a situation in which parents expect change in non-ADHD domains. Unfortunately, there is no pill to make kids respect their parents more or want to do their homework. Being clear from the outset about what behaviors are and are not medication responsive can sometimes prevent this problem.

• There is substance abuse. In addition to the potential problem of abuse of the stimulants described previously, other substances such as cannabis can sabotage the benefits of medications.

• There is over-reliance on medications as the sole modality of treatment. ADHD is best treated using a wide range of strategies. Nonpharmacological interventions such as exercise, good nutrition and sleep, parent behavioral training, organizational help, regular reading, screen time reduction, and school supports are critical components of a comprehensive treatment approach.

• There is parental psychopathology. In our opinion, this area is one of the most frequently neglected aspects of child mental health treatment and can have huge implications. ADHD in particular is known to have very high heritability (similar to height). If a mother or father shares the condition, their struggles can frequently contribute to an environment that can exacerbate the child’s symptoms. A pattern in which the ADHD symptoms are more prominent at home compared with school is one clue to look in this direction. When addressing parental psychopathology, it can be important not to come off as blaming the parents for their child’s problems, but rather to convey how challenging dealing with ADHD can be as a parent and how they need to be functioning at their highest mental level as well.

Of course, sometimes the medication truly is not working, and it is time to try something else.

Dr. David C. Rettew is associate professor of psychiatry and pediatrics, director of the child and adolescent psychiatry fellowship, and director of the pediatric psychiatry clinic at the University of Vermont, Burlington.

EVIDENCE SUMMARY

A systematic review by the Agency for Healthcare Research and Quality of adult female outpatients with SUI examined the effectiveness of PFMT, electrical stimulation, magnetic stimulation, and vaginal cones compared with no active treatment or sham treatment to produce continence (90% to 100% symptom reduction) or improve symptoms (at least 50% patient-reported symptom reduction).¹ The TABLE summarizes the results.¹ Investigators also assessed improvement in patient-reported QOL.

Pelvic floor muscle training improves continence, quality of life

A meta-analysis of 10 RCTs demonstrated that PFMT produced continence more often than placebo, and a meta-analysis of 6 RCTs found that PFMT improved SUI symptoms.¹ PFMT regimens ranged in duration from 8 weeks to 6 months, including unsupervised treatment (8 to 12 repetitions, 3 to 10 times a day) and supervised treatment (as long as an hour, as often as 3 times a week).¹

Both unsupervised and supervised PFMT produced similar results. One RCT evaluating QOL measures found that PFMT improved activity and reduced psychological impact (number needed to treat [NNT]=1; 95% confidence interval [CI], 1-2).¹

A meta-analysis of 7 RCTs found that intravaginal electrical stimulation increased continence compared with sham treatment.1 A meta-analysis of 8 RCTs found that intravaginal electrical stimulation also improved SUI symptoms.¹ All of the trials used electrical stimulation at frequencies between 4 and 50 Hz for 15 to 20 minutes, 1 to 3 times daily for 4 to 15 weeks.

Pelvic floor muscle training increases urinary continence and improves symptoms of stress urinary incontinence and quality of life.

Percutaneous electrical stimulation improves symptoms

A meta-analysis of 3 RCTs found that percutaneous electrical stimulation improved SUI symptoms compared with no active treatment. Four RCTs found that electrical stimulation improved QOL, although a meta-analysis couldn’t be performed because of clinical heterogeneity.¹

A meta-analysis of 3 RCTs found that magnetic stimulation at frequencies of 10 to 18.5 Hz given over 1 to 8 weeks didn’t increase continence. A meta-analysis of an additional 3 RCTs concluded that magnetic stimulation improved continence, but the individual studies reported conflicting results and were heterogenous.¹

Two RCTs evaluating QOL scores found conflicting results. One study found a mean difference of 3.9 points on the 100-point Incontinence Quality of Life Questionnaire (95% CI, 2.08-5.72; minimal clinically important difference rated 2-5 points).¹

Vaginal cones are ineffective and not well-tolerated

Two RCTs found that vaginal cones didn’t improve continence or QOL compared with no treatment. Investigators reported high discontinuation rates and adverse effects with the cones, which weighed 20 to 70 g and were worn for 20 minutes a day for as long as 24 weeks.¹

RECOMMENDATIONS

The National Institute for Health and Care Excellence recommends PFMT comprising at least 8 contractions 3 times daily for at least 3 months as first-line therapy for women with SUI.² They don’t recommend electrical stimulation or intravaginal devices for women who can actively contract their pelvic floor muscles. The American College of Obstetricians and Gynecologists recommends PFMT as first-line therapy for women with SUI and states that PFMT is more effective than electrical stimulation or vaginal cones.³

EVIDENCE SUMMARY

A systematic review by the Agency for Healthcare Research and Quality of adult female outpatients with SUI examined the effectiveness of PFMT, electrical stimulation, magnetic stimulation, and vaginal cones compared with no active treatment or sham treatment to produce continence (90% to 100% symptom reduction) or improve symptoms (at least 50% patient-reported symptom reduction).¹ The TABLE summarizes the results.¹ Investigators also assessed improvement in patient-reported QOL.

Pelvic floor muscle training improves continence, quality of life

A meta-analysis of 10 RCTs demonstrated that PFMT produced continence more often than placebo, and a meta-analysis of 6 RCTs found that PFMT improved SUI symptoms.¹ PFMT regimens ranged in duration from 8 weeks to 6 months, including unsupervised treatment (8 to 12 repetitions, 3 to 10 times a day) and supervised treatment (as long as an hour, as often as 3 times a week).¹

Both unsupervised and supervised PFMT produced similar results. One RCT evaluating QOL measures found that PFMT improved activity and reduced psychological impact (number needed to treat [NNT]=1; 95% confidence interval [CI], 1-2).¹

A meta-analysis of 7 RCTs found that intravaginal electrical stimulation increased continence compared with sham treatment.1 A meta-analysis of 8 RCTs found that intravaginal electrical stimulation also improved SUI symptoms.¹ All of the trials used electrical stimulation at frequencies between 4 and 50 Hz for 15 to 20 minutes, 1 to 3 times daily for 4 to 15 weeks.

Pelvic floor muscle training increases urinary continence and improves symptoms of stress urinary incontinence and quality of life.

Percutaneous electrical stimulation improves symptoms

A meta-analysis of 3 RCTs found that percutaneous electrical stimulation improved SUI symptoms compared with no active treatment. Four RCTs found that electrical stimulation improved QOL, although a meta-analysis couldn’t be performed because of clinical heterogeneity.¹

A meta-analysis of 3 RCTs found that magnetic stimulation at frequencies of 10 to 18.5 Hz given over 1 to 8 weeks didn’t increase continence. A meta-analysis of an additional 3 RCTs concluded that magnetic stimulation improved continence, but the individual studies reported conflicting results and were heterogenous.¹

Two RCTs evaluating QOL scores found conflicting results. One study found a mean difference of 3.9 points on the 100-point Incontinence Quality of Life Questionnaire (95% CI, 2.08-5.72; minimal clinically important difference rated 2-5 points).¹

Vaginal cones are ineffective and not well-tolerated

Two RCTs found that vaginal cones didn’t improve continence or QOL compared with no treatment. Investigators reported high discontinuation rates and adverse effects with the cones, which weighed 20 to 70 g and were worn for 20 minutes a day for as long as 24 weeks.¹

RECOMMENDATIONS

The National Institute for Health and Care Excellence recommends PFMT comprising at least 8 contractions 3 times daily for at least 3 months as first-line therapy for women with SUI.² They don’t recommend electrical stimulation or intravaginal devices for women who can actively contract their pelvic floor muscles. The American College of Obstetricians and Gynecologists recommends PFMT as first-line therapy for women with SUI and states that PFMT is more effective than electrical stimulation or vaginal cones.³

EVIDENCE SUMMARY

A systematic review by the Agency for Healthcare Research and Quality of adult female outpatients with SUI examined the effectiveness of PFMT, electrical stimulation, magnetic stimulation, and vaginal cones compared with no active treatment or sham treatment to produce continence (90% to 100% symptom reduction) or improve symptoms (at least 50% patient-reported symptom reduction).¹ The TABLE summarizes the results.¹ Investigators also assessed improvement in patient-reported QOL.

Pelvic floor muscle training improves continence, quality of life

A meta-analysis of 10 RCTs demonstrated that PFMT produced continence more often than placebo, and a meta-analysis of 6 RCTs found that PFMT improved SUI symptoms.¹ PFMT regimens ranged in duration from 8 weeks to 6 months, including unsupervised treatment (8 to 12 repetitions, 3 to 10 times a day) and supervised treatment (as long as an hour, as often as 3 times a week).¹

Both unsupervised and supervised PFMT produced similar results. One RCT evaluating QOL measures found that PFMT improved activity and reduced psychological impact (number needed to treat [NNT]=1; 95% confidence interval [CI], 1-2).¹

A meta-analysis of 7 RCTs found that intravaginal electrical stimulation increased continence compared with sham treatment.1 A meta-analysis of 8 RCTs found that intravaginal electrical stimulation also improved SUI symptoms.¹ All of the trials used electrical stimulation at frequencies between 4 and 50 Hz for 15 to 20 minutes, 1 to 3 times daily for 4 to 15 weeks.

Pelvic floor muscle training increases urinary continence and improves symptoms of stress urinary incontinence and quality of life.

Percutaneous electrical stimulation improves symptoms

A meta-analysis of 3 RCTs found that percutaneous electrical stimulation improved SUI symptoms compared with no active treatment. Four RCTs found that electrical stimulation improved QOL, although a meta-analysis couldn’t be performed because of clinical heterogeneity.¹

A meta-analysis of 3 RCTs found that magnetic stimulation at frequencies of 10 to 18.5 Hz given over 1 to 8 weeks didn’t increase continence. A meta-analysis of an additional 3 RCTs concluded that magnetic stimulation improved continence, but the individual studies reported conflicting results and were heterogenous.¹

Two RCTs evaluating QOL scores found conflicting results. One study found a mean difference of 3.9 points on the 100-point Incontinence Quality of Life Questionnaire (95% CI, 2.08-5.72; minimal clinically important difference rated 2-5 points).¹

Vaginal cones are ineffective and not well-tolerated

Two RCTs found that vaginal cones didn’t improve continence or QOL compared with no treatment. Investigators reported high discontinuation rates and adverse effects with the cones, which weighed 20 to 70 g and were worn for 20 minutes a day for as long as 24 weeks.¹

RECOMMENDATIONS

The National Institute for Health and Care Excellence recommends PFMT comprising at least 8 contractions 3 times daily for at least 3 months as first-line therapy for women with SUI.² They don’t recommend electrical stimulation or intravaginal devices for women who can actively contract their pelvic floor muscles. The American College of Obstetricians and Gynecologists recommends PFMT as first-line therapy for women with SUI and states that PFMT is more effective than electrical stimulation or vaginal cones.³

Laboratory mistakes are not defined as diagnostic errors, but they contribute significantly to the thousands of medical errors that occur every year.¹ Part of the problem: While accurate interpretation of lab tests often depends on the use of statistical concepts we all learned in medical training, it is difficult to find the time to incorporate these principles into a busy practice.

Overuse of lab tests presents problems, as well. Because “normal ranges” for test results are based on statistical analysis, as many as 5% of patients in a standard distribution fall outside of the range.² It is important to order only the tests you really need, as extra testing automatically means more false positive results.

This article was written with such pitfalls in mind. In the pages that follow, we focus on 8 types of tests family physicians rely on regularly—all cases in which test results are reliable only if comorbidities, pre- and post-test probabilities, and clinical context are carefully considered. To help you put these lab tests into the proper context, we’ve addressed a key question—and highlighted both pitfalls and pearls—about each.

1. Hemoglobin A1c: How does anemia affect it?

Hemoglobin A1c (HbA1c) can be measured in many ways, including high-performance liquid chromatography, boronate affinity, capillary electrophoresis, and immunoassay, all of which can provide equivalent values without significant variability.^3,4 In interpreting these tests, however, it is important to understand the effect that anemia has on HbA1c.

Two primary variables influencing HbA1c are the average glucose level and the average lifespan of red blood cells (RBCs). Normally, there is a direct correlation between average serum glucose and HbA1c.⁴ In patients with anemia, however, this relationship is less clear, and may be affected by erythropoiesis and RBC destruction.⁵ In iron deficiency anemia (IDA),^6,7 hemoglobin production falls secondary to iron stores, resulting in microcytic cells with a longer lifespan and elevated HbA1c. In at least one study,^5,7 HbA1c approached levels associated with diabetes (with increases as high as 1.5%) in nondiabetic patients, but resolved with treatment of IDA.

Increased destruction as well as increased production of RBCs lowers their lifespan, and in turn decreases HbA1c levels (TABLE 1).⁴ This can be seen in conditions such as splenomegaly and hemoglobinopathies. In patients with hemoglobinopathies, the percentage of hemoglobin A is significantly decreased, often to undetectable levels—thereby making HbA1c tests inaccurate. Hemoglobin electrophoresis and determination of glycation by capillary electrophoresis or high-performance liquid chromatography can be used instead, but neither is practical because of cost and limited availability.^4,8,9

THE TAKEAWAY: When you evaluate HbA1c test results, it is crucial to assess the patient for anemia and other conditions or comorbidities that can significantly affect RBC lifespan and skew test results.^2,4-6

2. D-dimer: When should you use it?

D-dimer is a fibrin degradation product that is increased when active clotting is present,10 and its assay—which has high sensitivity and low specificity—is widely used to screen for pulmonary embolism (PE) and deep vein thrombosis (DVT). While the minimal number of false negatives makes the D-dimer a good screening test, the higher rate of false positives makes it difficult to arrive at a definitive diagnosis. Appropriate use of the D-dimer assay is crucial to minimize the potential for adverse consequences, such as bleeding in patients who are subjected to unnecessary anticoagulation because of false positive results.

Further testing typically follows. A positive D-dimer test is commonly followed by a computed tomography (CT) scan of the chest or a ventilation/perfusion scan to establish a PE or DVT diagnosis. But this subsequent testing increases both the cost of health care and the patient’s radiation exposure. Use of these subsequent scans can be reduced by first considering the patient’s pretest probability for PE or DVT. The Wells’ Criteria (available at www.mdcalc.com/wells-criteriafor-pulmonary-embolism-pe/) and Geneva Score (Revised) (www.mdcalc.com/genevascore-revised-for-pulmonary-embolism/) can both be used for this purpose.^10,11

Nonfasting lipid values can offer useful information—particularly in patients who are unwilling or unable to return for fasting labs.Patients with high pretest probability should undergo immediate scanning, foregoing the D-dimer—which should be reserved for patients who have a low or moderate pretest probability but sufficient reason to suspect PE or DVT.^10-12

The low specificity of the D-dimer assay poses another challenge to its effective use. There are many things that can increase D-dimer levels, such as age, cancer, prolonged immobility, autoimmune disease, inflammation, sickle cell disease, pregnancy, trauma, and surgery.^13-15 All these factors must be taken into consideration prior to ordering this test.

In fact, one recent study found that using an age-adjusted D-dimer cutoff (patient’s age in years x 10 mcg/L)—rather than a conventional cutoff of 500 mcg/L—for patients older than 50 years reduces false positives without substantially increasing false negatives.¹⁶

Also of note: An anticoagulant can decrease D-dimer levels in plasma, so the test should not be used to rule out PE or DVT in patients who are undergoing anticoagulation.^13,15

THE TAKEAWAY: In evaluating patients for PE or DVT, use the Wells’ Criteria or Geneva Score (Revised) to determine a patient’s pretest probability of disease. Use the D-dimer assay to safely rule out these conditions in patients with a low or intermediate pretest probability, but go directly to scans for those with a high pretest probability.

3. Lipid panels: How important is fasting?

Patients are often instructed to report for fasting lab studies, specifically for lipid profiles. Traditionally, this had been defined as an 8- to 12-hour period without food.¹⁷ In clinical practice, however, this is often misinterpreted by patients, who may be confused about the duration of the fast or unsure about whether to eat or drink immediately before the test.

Studies investigating the effect of meals on lab values have found that triglycerides are consistently elevated postprandially, to a maximum of 12 hours.^18-21 The effect of the fasting state on total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol is more controversial; while some postprandial differences have been detected, the clinical relevance is equivocal.^18-21

Nonfasting lipid values can offer useful information, particularly in patients who are unwilling or unable to return for fasting labs. The US Preventive Services Task Force (USPSTF) supports this practice.²² Because guidelines for evaluation and treatment are based on fasting lipids, however, fasting lab work should be used, whenever possible, for initiating treatment and monitoring patients with abnormal values. If nonfasting lipids are used, it is crucial to factor in the postprandial effects on triglycerides and the subsequent difficulty of assessing LDL cholesterol levels.

THE TAKEAWAY: The clinical relevance of postprandial vs fasting lipid levels is equivocal. Nonfasting lipid panels have reasonable clinical utility in screening and initial treatment, particularly in cases in which obtaining fasting lab values may be problematic.^18,19

4. Mononucleoosis spot test: When should you use it?

The monospot test is a latex assay that causes hemagglutination of horse RBCs in the presence of heterophile antibodies characteristic of infectious mononucleosis.²³ The antibodies develop within the first 7 days of onset of symptoms, but do not peak for 2 to 5 weeks.²⁴ As a result, monospot testing yields a high incidence of false negatives during the first 2 weeks of active infection.²⁵ False negatives are also common in patients younger than 14 years. Heterophile antibodies may be present for up to a year after active infection.²⁴

Patients at increased risk for splenic rupture, such as athletes, pose considerable diagnostic difficulty.²⁶ When there is strong clinical suspicion of mononucleosis despite a negative monospot test in such high-risk individuals, follow-up testing is recommended to differentiate it from other mononucleosis-like illnesses (TABLE 2).²⁷ The optimal combination of Epstein-Barr virus (EBV) serologic testing consists of the antibody titration of 4 markers: immunoglobulins M (IgM) and G (IgG) to the viral capsid antigen, IgM to the early antigen, and antibody to Epstein-Barr nuclear antigen (EBNA).²⁸ Acute phase reactants in the setting of an antibody to EBNA could indicate reactivation. A positive test does not exclude other medical causes, however, because up to 20% of patients have acute phase antibodies that persist for years.²⁹

Digoxin levels need to be drawn at least 6 to 8 hours after the last dose is taken to allow for appropriate drug distribution. Appropriate diagnosis is important because of the significant morbidity associated with EBV. Risk of splenic injury is greatest between 4 and 21 days after onset of symptoms but persists at 7 weeks,²⁶ so conservative therapy followed by monospot retesting one week later is a reasonable approach.

Mononucleosis or routine tonsillitis? It is important to note that there is no evidence that a positive monospot test will affect the management or outcome of routine tonsillitis, raising questions of the utility of the test in such cases. A better approach: Reserve testing for patients with additional findings—ie, splenomegaly—or whose symptoms have persisted ≥ 2 weeks.

THE TAKEAWAY: Wait at least 2 weeks to conduct monospot testing in patients with routine tonsillitis. If strong clinical suspicion exists, proceed with specific IgM and IgG serologic testing.^24,25,27,28

5. Evaluating prescription drug levels: Which factors interfere?

Correct interpretation of lab tests conducted to measure prescription drug levels has major implications with regard to patient safety, particularly for medications with a narrow therapeutic index.

Conduct a confirmatory test before making decisions based on the results of urine drug screens.Most drug level tests measure the total concentration, which includes both bound and unbound (free) forms. The unbound forms are the active components of the drug; thus, for an accurate evaluation, it is important to be aware of factors that increase free drug concentration. Chief among them is low protein levels, or hypoalbuminemia.³⁰

Risk factors for hypoalbuminemia include significant burns, advanced age, pregnancy, malnutrition, and human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS).³⁰ HIV/AIDS is a particularly high risk because certain protease inhibitors are highly protein bound.

Drug protein binding is classified as low, moderate, or high. The main proteins involved in the process are albumin, alpha-1-acid glycoprotein, and lipoprotein. Medications that are highly protein bound (>80%) are the most affected by low protein levels: Problems can arise when drugs completely bind to all the available proteins and excess drug availability increases free drug levels.

Medications that are most likely to be affected by a high degree of protein binding include carbamazepine, cyclosporine, mycophenolic acid, phenytoin, protease inhibitors (with the exception of indinavir), tacrolimus, and valproic acid. It is important to consider free levels when you order medication assays for these drugs to avoid misinterpreting the serum levels as being too low-a scenario that raises the risk of drug toxicity and adverse outcomes.^30,31

A study of 119 phenytoin samples from 70 patients found significantly higher free phenytoin levels in patients with lower albumin levels.³² Higher free phenytoin levels were also seen in older patients and in those with diminished renal function (creatinine clearance <25 mL/min).³² The degree of protein binding is affected by both the serum drug concentration and the albumin level, with saturable protein binding occurring at higher drug levels.³³

Calculate phenytoin levels with this equation. To calculate corrected phenytoin levels in patients with low albumin levels, use the following formula, known as the Sheiner-Tozer equation:³⁴

Concentration adjusted=concentration reported/([adjustment x serum albumin] + 0.1); adjustment=0.2 for creatinine clearance ≥20 or 0.1 for creatinine clearance <20.

Additional causes of misinterpreted drug levels. While hypoalbuminemia plays a major role in the misinterpretation of drug levels, other factors affect serum drug concentration, as well. These include drug-drug interactions, which can significantly increase the concentration of the medications involved, and the timing of the test with regard to medication administration. Digoxin levels, in particular, need to be drawn at least 6 to 8 hours after the last dose is taken to allow for appropriate drug distribution.³⁵

THE TAKEAWAY: It is essential to consider free drug level monitoring in patients who either have hypoalbuminemia or have one or more risk factors for hypoalbuminemia to avoid falsely low estimation of drug levels.^36,37

6 Liver function tests: Necessary for patients on statin therapy?

Since statins gained US Food and Drug Administration (FDA) approval, the drugs have been associated with increased liver function tests (LFTs). Indeed, there had been a long-standing belief, based on clinical trials, that by monitoring alanine aminotransferase (ALT) and maintaining it at <3 times the upper limit normal (ULN), hepatotoxicity could be avoided.³⁸ In clinical practice, however, further ALT elevation is frequently allowed based on patient tolerability.

In February 2012, the FDA revised its safety data to reflect this practice.³⁹ The FDA update confirmed that routine LFT monitoring is unnecessary for patients on statins—and that it is not very effective in identifying or preventing liver damage.

Overall, serious hepatotoxicity is very rare, with an incidence ≤2 per 1 million patient-years.³⁹ The National Lipid Association Statin Safety Assessment Task Force recommends repeating LFTs that are 3 to 5 times the ULN within 6 months and continuing with the statin dose if the patient is asymptomatic.³⁸

THE TAKEAWAY: Routine liver function monitoring is not necessary for patients on statins. A better approach: Obtain baseline ALT levels, and repeat the testing only as clinically indicated thereafter.^38,39

7. Urine drug screens: Which factors affect their accuracy?

The gold standard for testing for drugs of abuse, urine drug screens (UDS) have good sensitivity and specificity, easy administration, and reasonable cost.⁴⁰ UDS can detect various narcotics, such as morphine, oxycodone, ,and methadone, and identify other illicit drugs, although which drugs and metabolites are tested for is laboratory- and test-specific.

Cross-reactivity. There are 6 currently available immunoassays, all of which use competitive binding between the sample drug and a drug chemically labeled with an enzyme, radioisotope, or fluorophore. The sample drug and labeled drug compete for substrate binding sites on drug-specific antibodies.^41,42 Similar to competitive binding for enzymatic reactions in the body, the substrate binding site can experience cross-reactivity—causing substances other than the drug in question to bind to the immunoglobulin, leading to a false positive result (TABLE 3).⁴³ Other factors that can alter the results include the cutoff value of the test and the absorption, distribution, metabolism, and excretion of the drug.⁴² Thus, a confirmatory test of gas chromatography-mass spectrometry is recommended before making decisions based on the results of UDS.^43-45

Routine screens for patients on chronic opioid therapy. Routine use of UDS in emergency departments is no longer recommended, based on evidence that the results are unlikely to have a significant effect on patient management.⁴⁶ For patients on chronic opioid therapy, however, routine screening has proven helpful in detecting prescription opioid abuse, illicit drug use, and diversion. Up to 34% of patients on prescription opioids have been found to be using illicit drugs, as well.⁴²

THE TAKEAWAY: Use UDS as a tool in managing patients on chronic opioid therapy, but before acting on results, assess for factors, such as the use of oral or topical medications and the cutoff value of the test, that may be associated with false positive or false negative results.^43-45

8. Thyroid function testing: When should you test?

Thyroid-stimulating hormone (TSH) is the first-line test when investigating presumed hyper- or hypothyroidism.^47,48 Third-generation chemiluminometric assays can reliably measure TSH concentrations <0.01 mU/L by using multiple antibodies to produce a sandwich-type effect on the molecule in question.⁴⁹

Retesting TSH to assess treatment response should be postponed until ≥2 months after any change in medication or dosing.TSH levels exhibit diurnal variation, however, and are affected by other medications, including steroids, opiates, and some antihistamines, among others, as well as comorbidities.^47,48 Chronic and acute conditions unrelated to thyroid disease can cause transient changes in TSH concentrations, and have the potential to modify the binding capacity of plasma thyroid hormone binding proteins.⁴⁸ Thus, TSH should be ordered for hospitalized patients only when clinical suspicion of a thyroid problem exists.⁴⁸ The USPSTF recommends against routine TSH screening for asymptomatic adults.⁴⁶

How to respond to abnormal results. For patients found to have abnormal TSH levels, free T4 (fT4) is the next test to order.^47,49 An fT4 assay is a superior indicator of thyroid status because it is not affected by changes in iodothyronine-binding proteins, which influence total hormone measurements.⁴⁹ The results will be elevated in hyperthyroidism and reduced in hypothyroidism.⁴⁷

Triiodothyronine (T3) measures can be useful in diagnosing Graves’ disease, in which T3 toxicosis may be the initial symptom—or an indication of a relapse. Because T3 is often a peripheral product, however, nonthyroid illnesses and medications can cause artifactually abnormal results.⁴⁹

Other thyroid-specific labs include thyroid ,antibodies such as antithyroid peroxidase, antithyroglobulin, and TSH receptor, both blocking and stimulating.⁴⁹ Thyroglobulin is a precursor form of thyroid hormone and should be measured when factitious hyperthyroidism is suspected. Management of hyper- and hypothyroidism often is independent of etiology. Retesting TSH to assess treatment response should be postponed until ≥2 months after any change in medication or dosing.⁵⁰

Thyroid studies can be very difficult to interpret. TSH should be the first test ordered. However, if TSH values do not match the clinical picture, fT4, T3, and other thyroid tests that are less affected by outside factors can be useful in identifying the cause.

THE TAKEAWAY: Routine TSH testing is not indicated for asymptomatic adults. When evaluating thyroid function is clinically indicated, TSH is the initial test of choice.^47,48,51

CORRESPONDENCE
Joshua Tessier, DO, Iowa Lutheran Family Medicine Residency, 840 East University Avenue, Des Moines, IA 50316; [email protected]

Laboratory mistakes are not defined as diagnostic errors, but they contribute significantly to the thousands of medical errors that occur every year.¹ Part of the problem: While accurate interpretation of lab tests often depends on the use of statistical concepts we all learned in medical training, it is difficult to find the time to incorporate these principles into a busy practice.

Overuse of lab tests presents problems, as well. Because “normal ranges” for test results are based on statistical analysis, as many as 5% of patients in a standard distribution fall outside of the range.² It is important to order only the tests you really need, as extra testing automatically means more false positive results.

This article was written with such pitfalls in mind. In the pages that follow, we focus on 8 types of tests family physicians rely on regularly—all cases in which test results are reliable only if comorbidities, pre- and post-test probabilities, and clinical context are carefully considered. To help you put these lab tests into the proper context, we’ve addressed a key question—and highlighted both pitfalls and pearls—about each.

1. Hemoglobin A1c: How does anemia affect it?

Hemoglobin A1c (HbA1c) can be measured in many ways, including high-performance liquid chromatography, boronate affinity, capillary electrophoresis, and immunoassay, all of which can provide equivalent values without significant variability.^3,4 In interpreting these tests, however, it is important to understand the effect that anemia has on HbA1c.

Two primary variables influencing HbA1c are the average glucose level and the average lifespan of red blood cells (RBCs). Normally, there is a direct correlation between average serum glucose and HbA1c.⁴ In patients with anemia, however, this relationship is less clear, and may be affected by erythropoiesis and RBC destruction.⁵ In iron deficiency anemia (IDA),^6,7 hemoglobin production falls secondary to iron stores, resulting in microcytic cells with a longer lifespan and elevated HbA1c. In at least one study,^5,7 HbA1c approached levels associated with diabetes (with increases as high as 1.5%) in nondiabetic patients, but resolved with treatment of IDA.

Increased destruction as well as increased production of RBCs lowers their lifespan, and in turn decreases HbA1c levels (TABLE 1).⁴ This can be seen in conditions such as splenomegaly and hemoglobinopathies. In patients with hemoglobinopathies, the percentage of hemoglobin A is significantly decreased, often to undetectable levels—thereby making HbA1c tests inaccurate. Hemoglobin electrophoresis and determination of glycation by capillary electrophoresis or high-performance liquid chromatography can be used instead, but neither is practical because of cost and limited availability.^4,8,9

THE TAKEAWAY: When you evaluate HbA1c test results, it is crucial to assess the patient for anemia and other conditions or comorbidities that can significantly affect RBC lifespan and skew test results.^2,4-6

2. D-dimer: When should you use it?

D-dimer is a fibrin degradation product that is increased when active clotting is present,10 and its assay—which has high sensitivity and low specificity—is widely used to screen for pulmonary embolism (PE) and deep vein thrombosis (DVT). While the minimal number of false negatives makes the D-dimer a good screening test, the higher rate of false positives makes it difficult to arrive at a definitive diagnosis. Appropriate use of the D-dimer assay is crucial to minimize the potential for adverse consequences, such as bleeding in patients who are subjected to unnecessary anticoagulation because of false positive results.

Further testing typically follows. A positive D-dimer test is commonly followed by a computed tomography (CT) scan of the chest or a ventilation/perfusion scan to establish a PE or DVT diagnosis. But this subsequent testing increases both the cost of health care and the patient’s radiation exposure. Use of these subsequent scans can be reduced by first considering the patient’s pretest probability for PE or DVT. The Wells’ Criteria (available at www.mdcalc.com/wells-criteriafor-pulmonary-embolism-pe/) and Geneva Score (Revised) (www.mdcalc.com/genevascore-revised-for-pulmonary-embolism/) can both be used for this purpose.^10,11

Nonfasting lipid values can offer useful information—particularly in patients who are unwilling or unable to return for fasting labs.Patients with high pretest probability should undergo immediate scanning, foregoing the D-dimer—which should be reserved for patients who have a low or moderate pretest probability but sufficient reason to suspect PE or DVT.^10-12

The low specificity of the D-dimer assay poses another challenge to its effective use. There are many things that can increase D-dimer levels, such as age, cancer, prolonged immobility, autoimmune disease, inflammation, sickle cell disease, pregnancy, trauma, and surgery.^13-15 All these factors must be taken into consideration prior to ordering this test.

In fact, one recent study found that using an age-adjusted D-dimer cutoff (patient’s age in years x 10 mcg/L)—rather than a conventional cutoff of 500 mcg/L—for patients older than 50 years reduces false positives without substantially increasing false negatives.¹⁶

Also of note: An anticoagulant can decrease D-dimer levels in plasma, so the test should not be used to rule out PE or DVT in patients who are undergoing anticoagulation.^13,15

THE TAKEAWAY: In evaluating patients for PE or DVT, use the Wells’ Criteria or Geneva Score (Revised) to determine a patient’s pretest probability of disease. Use the D-dimer assay to safely rule out these conditions in patients with a low or intermediate pretest probability, but go directly to scans for those with a high pretest probability.

3. Lipid panels: How important is fasting?

Patients are often instructed to report for fasting lab studies, specifically for lipid profiles. Traditionally, this had been defined as an 8- to 12-hour period without food.¹⁷ In clinical practice, however, this is often misinterpreted by patients, who may be confused about the duration of the fast or unsure about whether to eat or drink immediately before the test.

Studies investigating the effect of meals on lab values have found that triglycerides are consistently elevated postprandially, to a maximum of 12 hours.^18-21 The effect of the fasting state on total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol is more controversial; while some postprandial differences have been detected, the clinical relevance is equivocal.^18-21

Nonfasting lipid values can offer useful information, particularly in patients who are unwilling or unable to return for fasting labs. The US Preventive Services Task Force (USPSTF) supports this practice.²² Because guidelines for evaluation and treatment are based on fasting lipids, however, fasting lab work should be used, whenever possible, for initiating treatment and monitoring patients with abnormal values. If nonfasting lipids are used, it is crucial to factor in the postprandial effects on triglycerides and the subsequent difficulty of assessing LDL cholesterol levels.

THE TAKEAWAY: The clinical relevance of postprandial vs fasting lipid levels is equivocal. Nonfasting lipid panels have reasonable clinical utility in screening and initial treatment, particularly in cases in which obtaining fasting lab values may be problematic.^18,19

4. Mononucleoosis spot test: When should you use it?

The monospot test is a latex assay that causes hemagglutination of horse RBCs in the presence of heterophile antibodies characteristic of infectious mononucleosis.²³ The antibodies develop within the first 7 days of onset of symptoms, but do not peak for 2 to 5 weeks.²⁴ As a result, monospot testing yields a high incidence of false negatives during the first 2 weeks of active infection.²⁵ False negatives are also common in patients younger than 14 years. Heterophile antibodies may be present for up to a year after active infection.²⁴

Patients at increased risk for splenic rupture, such as athletes, pose considerable diagnostic difficulty.²⁶ When there is strong clinical suspicion of mononucleosis despite a negative monospot test in such high-risk individuals, follow-up testing is recommended to differentiate it from other mononucleosis-like illnesses (TABLE 2).²⁷ The optimal combination of Epstein-Barr virus (EBV) serologic testing consists of the antibody titration of 4 markers: immunoglobulins M (IgM) and G (IgG) to the viral capsid antigen, IgM to the early antigen, and antibody to Epstein-Barr nuclear antigen (EBNA).²⁸ Acute phase reactants in the setting of an antibody to EBNA could indicate reactivation. A positive test does not exclude other medical causes, however, because up to 20% of patients have acute phase antibodies that persist for years.²⁹

Digoxin levels need to be drawn at least 6 to 8 hours after the last dose is taken to allow for appropriate drug distribution. Appropriate diagnosis is important because of the significant morbidity associated with EBV. Risk of splenic injury is greatest between 4 and 21 days after onset of symptoms but persists at 7 weeks,²⁶ so conservative therapy followed by monospot retesting one week later is a reasonable approach.

Mononucleosis or routine tonsillitis? It is important to note that there is no evidence that a positive monospot test will affect the management or outcome of routine tonsillitis, raising questions of the utility of the test in such cases. A better approach: Reserve testing for patients with additional findings—ie, splenomegaly—or whose symptoms have persisted ≥ 2 weeks.

THE TAKEAWAY: Wait at least 2 weeks to conduct monospot testing in patients with routine tonsillitis. If strong clinical suspicion exists, proceed with specific IgM and IgG serologic testing.^24,25,27,28

5. Evaluating prescription drug levels: Which factors interfere?

Correct interpretation of lab tests conducted to measure prescription drug levels has major implications with regard to patient safety, particularly for medications with a narrow therapeutic index.

Conduct a confirmatory test before making decisions based on the results of urine drug screens.Most drug level tests measure the total concentration, which includes both bound and unbound (free) forms. The unbound forms are the active components of the drug; thus, for an accurate evaluation, it is important to be aware of factors that increase free drug concentration. Chief among them is low protein levels, or hypoalbuminemia.³⁰

Risk factors for hypoalbuminemia include significant burns, advanced age, pregnancy, malnutrition, and human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS).³⁰ HIV/AIDS is a particularly high risk because certain protease inhibitors are highly protein bound.

Drug protein binding is classified as low, moderate, or high. The main proteins involved in the process are albumin, alpha-1-acid glycoprotein, and lipoprotein. Medications that are highly protein bound (>80%) are the most affected by low protein levels: Problems can arise when drugs completely bind to all the available proteins and excess drug availability increases free drug levels.

Medications that are most likely to be affected by a high degree of protein binding include carbamazepine, cyclosporine, mycophenolic acid, phenytoin, protease inhibitors (with the exception of indinavir), tacrolimus, and valproic acid. It is important to consider free levels when you order medication assays for these drugs to avoid misinterpreting the serum levels as being too low-a scenario that raises the risk of drug toxicity and adverse outcomes.^30,31

A study of 119 phenytoin samples from 70 patients found significantly higher free phenytoin levels in patients with lower albumin levels.³² Higher free phenytoin levels were also seen in older patients and in those with diminished renal function (creatinine clearance <25 mL/min).³² The degree of protein binding is affected by both the serum drug concentration and the albumin level, with saturable protein binding occurring at higher drug levels.³³

Calculate phenytoin levels with this equation. To calculate corrected phenytoin levels in patients with low albumin levels, use the following formula, known as the Sheiner-Tozer equation:³⁴

Concentration adjusted=concentration reported/([adjustment x serum albumin] + 0.1); adjustment=0.2 for creatinine clearance ≥20 or 0.1 for creatinine clearance <20.

Additional causes of misinterpreted drug levels. While hypoalbuminemia plays a major role in the misinterpretation of drug levels, other factors affect serum drug concentration, as well. These include drug-drug interactions, which can significantly increase the concentration of the medications involved, and the timing of the test with regard to medication administration. Digoxin levels, in particular, need to be drawn at least 6 to 8 hours after the last dose is taken to allow for appropriate drug distribution.³⁵

THE TAKEAWAY: It is essential to consider free drug level monitoring in patients who either have hypoalbuminemia or have one or more risk factors for hypoalbuminemia to avoid falsely low estimation of drug levels.^36,37

6 Liver function tests: Necessary for patients on statin therapy?

Since statins gained US Food and Drug Administration (FDA) approval, the drugs have been associated with increased liver function tests (LFTs). Indeed, there had been a long-standing belief, based on clinical trials, that by monitoring alanine aminotransferase (ALT) and maintaining it at <3 times the upper limit normal (ULN), hepatotoxicity could be avoided.³⁸ In clinical practice, however, further ALT elevation is frequently allowed based on patient tolerability.

In February 2012, the FDA revised its safety data to reflect this practice.³⁹ The FDA update confirmed that routine LFT monitoring is unnecessary for patients on statins—and that it is not very effective in identifying or preventing liver damage.

Overall, serious hepatotoxicity is very rare, with an incidence ≤2 per 1 million patient-years.³⁹ The National Lipid Association Statin Safety Assessment Task Force recommends repeating LFTs that are 3 to 5 times the ULN within 6 months and continuing with the statin dose if the patient is asymptomatic.³⁸

THE TAKEAWAY: Routine liver function monitoring is not necessary for patients on statins. A better approach: Obtain baseline ALT levels, and repeat the testing only as clinically indicated thereafter.^38,39

7. Urine drug screens: Which factors affect their accuracy?

The gold standard for testing for drugs of abuse, urine drug screens (UDS) have good sensitivity and specificity, easy administration, and reasonable cost.⁴⁰ UDS can detect various narcotics, such as morphine, oxycodone, ,and methadone, and identify other illicit drugs, although which drugs and metabolites are tested for is laboratory- and test-specific.

Cross-reactivity. There are 6 currently available immunoassays, all of which use competitive binding between the sample drug and a drug chemically labeled with an enzyme, radioisotope, or fluorophore. The sample drug and labeled drug compete for substrate binding sites on drug-specific antibodies.^41,42 Similar to competitive binding for enzymatic reactions in the body, the substrate binding site can experience cross-reactivity—causing substances other than the drug in question to bind to the immunoglobulin, leading to a false positive result (TABLE 3).⁴³ Other factors that can alter the results include the cutoff value of the test and the absorption, distribution, metabolism, and excretion of the drug.⁴² Thus, a confirmatory test of gas chromatography-mass spectrometry is recommended before making decisions based on the results of UDS.^43-45

Routine screens for patients on chronic opioid therapy. Routine use of UDS in emergency departments is no longer recommended, based on evidence that the results are unlikely to have a significant effect on patient management.⁴⁶ For patients on chronic opioid therapy, however, routine screening has proven helpful in detecting prescription opioid abuse, illicit drug use, and diversion. Up to 34% of patients on prescription opioids have been found to be using illicit drugs, as well.⁴²

THE TAKEAWAY: Use UDS as a tool in managing patients on chronic opioid therapy, but before acting on results, assess for factors, such as the use of oral or topical medications and the cutoff value of the test, that may be associated with false positive or false negative results.^43-45

8. Thyroid function testing: When should you test?

Thyroid-stimulating hormone (TSH) is the first-line test when investigating presumed hyper- or hypothyroidism.^47,48 Third-generation chemiluminometric assays can reliably measure TSH concentrations <0.01 mU/L by using multiple antibodies to produce a sandwich-type effect on the molecule in question.⁴⁹

Retesting TSH to assess treatment response should be postponed until ≥2 months after any change in medication or dosing.TSH levels exhibit diurnal variation, however, and are affected by other medications, including steroids, opiates, and some antihistamines, among others, as well as comorbidities.^47,48 Chronic and acute conditions unrelated to thyroid disease can cause transient changes in TSH concentrations, and have the potential to modify the binding capacity of plasma thyroid hormone binding proteins.⁴⁸ Thus, TSH should be ordered for hospitalized patients only when clinical suspicion of a thyroid problem exists.⁴⁸ The USPSTF recommends against routine TSH screening for asymptomatic adults.⁴⁶

How to respond to abnormal results. For patients found to have abnormal TSH levels, free T4 (fT4) is the next test to order.^47,49 An fT4 assay is a superior indicator of thyroid status because it is not affected by changes in iodothyronine-binding proteins, which influence total hormone measurements.⁴⁹ The results will be elevated in hyperthyroidism and reduced in hypothyroidism.⁴⁷

Triiodothyronine (T3) measures can be useful in diagnosing Graves’ disease, in which T3 toxicosis may be the initial symptom—or an indication of a relapse. Because T3 is often a peripheral product, however, nonthyroid illnesses and medications can cause artifactually abnormal results.⁴⁹

Other thyroid-specific labs include thyroid ,antibodies such as antithyroid peroxidase, antithyroglobulin, and TSH receptor, both blocking and stimulating.⁴⁹ Thyroglobulin is a precursor form of thyroid hormone and should be measured when factitious hyperthyroidism is suspected. Management of hyper- and hypothyroidism often is independent of etiology. Retesting TSH to assess treatment response should be postponed until ≥2 months after any change in medication or dosing.⁵⁰

Thyroid studies can be very difficult to interpret. TSH should be the first test ordered. However, if TSH values do not match the clinical picture, fT4, T3, and other thyroid tests that are less affected by outside factors can be useful in identifying the cause.

THE TAKEAWAY: Routine TSH testing is not indicated for asymptomatic adults. When evaluating thyroid function is clinically indicated, TSH is the initial test of choice.^47,48,51

CORRESPONDENCE
Joshua Tessier, DO, Iowa Lutheran Family Medicine Residency, 840 East University Avenue, Des Moines, IA 50316; [email protected]

Laboratory mistakes are not defined as diagnostic errors, but they contribute significantly to the thousands of medical errors that occur every year.¹ Part of the problem: While accurate interpretation of lab tests often depends on the use of statistical concepts we all learned in medical training, it is difficult to find the time to incorporate these principles into a busy practice.

Overuse of lab tests presents problems, as well. Because “normal ranges” for test results are based on statistical analysis, as many as 5% of patients in a standard distribution fall outside of the range.² It is important to order only the tests you really need, as extra testing automatically means more false positive results.

This article was written with such pitfalls in mind. In the pages that follow, we focus on 8 types of tests family physicians rely on regularly—all cases in which test results are reliable only if comorbidities, pre- and post-test probabilities, and clinical context are carefully considered. To help you put these lab tests into the proper context, we’ve addressed a key question—and highlighted both pitfalls and pearls—about each.

1. Hemoglobin A1c: How does anemia affect it?

Hemoglobin A1c (HbA1c) can be measured in many ways, including high-performance liquid chromatography, boronate affinity, capillary electrophoresis, and immunoassay, all of which can provide equivalent values without significant variability.^3,4 In interpreting these tests, however, it is important to understand the effect that anemia has on HbA1c.

Two primary variables influencing HbA1c are the average glucose level and the average lifespan of red blood cells (RBCs). Normally, there is a direct correlation between average serum glucose and HbA1c.⁴ In patients with anemia, however, this relationship is less clear, and may be affected by erythropoiesis and RBC destruction.⁵ In iron deficiency anemia (IDA),^6,7 hemoglobin production falls secondary to iron stores, resulting in microcytic cells with a longer lifespan and elevated HbA1c. In at least one study,^5,7 HbA1c approached levels associated with diabetes (with increases as high as 1.5%) in nondiabetic patients, but resolved with treatment of IDA.

Increased destruction as well as increased production of RBCs lowers their lifespan, and in turn decreases HbA1c levels (TABLE 1).⁴ This can be seen in conditions such as splenomegaly and hemoglobinopathies. In patients with hemoglobinopathies, the percentage of hemoglobin A is significantly decreased, often to undetectable levels—thereby making HbA1c tests inaccurate. Hemoglobin electrophoresis and determination of glycation by capillary electrophoresis or high-performance liquid chromatography can be used instead, but neither is practical because of cost and limited availability.^4,8,9

THE TAKEAWAY: When you evaluate HbA1c test results, it is crucial to assess the patient for anemia and other conditions or comorbidities that can significantly affect RBC lifespan and skew test results.^2,4-6

2. D-dimer: When should you use it?

D-dimer is a fibrin degradation product that is increased when active clotting is present,10 and its assay—which has high sensitivity and low specificity—is widely used to screen for pulmonary embolism (PE) and deep vein thrombosis (DVT). While the minimal number of false negatives makes the D-dimer a good screening test, the higher rate of false positives makes it difficult to arrive at a definitive diagnosis. Appropriate use of the D-dimer assay is crucial to minimize the potential for adverse consequences, such as bleeding in patients who are subjected to unnecessary anticoagulation because of false positive results.

Further testing typically follows. A positive D-dimer test is commonly followed by a computed tomography (CT) scan of the chest or a ventilation/perfusion scan to establish a PE or DVT diagnosis. But this subsequent testing increases both the cost of health care and the patient’s radiation exposure. Use of these subsequent scans can be reduced by first considering the patient’s pretest probability for PE or DVT. The Wells’ Criteria (available at www.mdcalc.com/wells-criteriafor-pulmonary-embolism-pe/) and Geneva Score (Revised) (www.mdcalc.com/genevascore-revised-for-pulmonary-embolism/) can both be used for this purpose.^10,11

Nonfasting lipid values can offer useful information—particularly in patients who are unwilling or unable to return for fasting labs.Patients with high pretest probability should undergo immediate scanning, foregoing the D-dimer—which should be reserved for patients who have a low or moderate pretest probability but sufficient reason to suspect PE or DVT.^10-12

The low specificity of the D-dimer assay poses another challenge to its effective use. There are many things that can increase D-dimer levels, such as age, cancer, prolonged immobility, autoimmune disease, inflammation, sickle cell disease, pregnancy, trauma, and surgery.^13-15 All these factors must be taken into consideration prior to ordering this test.

In fact, one recent study found that using an age-adjusted D-dimer cutoff (patient’s age in years x 10 mcg/L)—rather than a conventional cutoff of 500 mcg/L—for patients older than 50 years reduces false positives without substantially increasing false negatives.¹⁶

Also of note: An anticoagulant can decrease D-dimer levels in plasma, so the test should not be used to rule out PE or DVT in patients who are undergoing anticoagulation.^13,15

THE TAKEAWAY: In evaluating patients for PE or DVT, use the Wells’ Criteria or Geneva Score (Revised) to determine a patient’s pretest probability of disease. Use the D-dimer assay to safely rule out these conditions in patients with a low or intermediate pretest probability, but go directly to scans for those with a high pretest probability.

3. Lipid panels: How important is fasting?

Patients are often instructed to report for fasting lab studies, specifically for lipid profiles. Traditionally, this had been defined as an 8- to 12-hour period without food.¹⁷ In clinical practice, however, this is often misinterpreted by patients, who may be confused about the duration of the fast or unsure about whether to eat or drink immediately before the test.

Studies investigating the effect of meals on lab values have found that triglycerides are consistently elevated postprandially, to a maximum of 12 hours.^18-21 The effect of the fasting state on total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol is more controversial; while some postprandial differences have been detected, the clinical relevance is equivocal.^18-21

Nonfasting lipid values can offer useful information, particularly in patients who are unwilling or unable to return for fasting labs. The US Preventive Services Task Force (USPSTF) supports this practice.²² Because guidelines for evaluation and treatment are based on fasting lipids, however, fasting lab work should be used, whenever possible, for initiating treatment and monitoring patients with abnormal values. If nonfasting lipids are used, it is crucial to factor in the postprandial effects on triglycerides and the subsequent difficulty of assessing LDL cholesterol levels.

THE TAKEAWAY: The clinical relevance of postprandial vs fasting lipid levels is equivocal. Nonfasting lipid panels have reasonable clinical utility in screening and initial treatment, particularly in cases in which obtaining fasting lab values may be problematic.^18,19

4. Mononucleoosis spot test: When should you use it?

The monospot test is a latex assay that causes hemagglutination of horse RBCs in the presence of heterophile antibodies characteristic of infectious mononucleosis.²³ The antibodies develop within the first 7 days of onset of symptoms, but do not peak for 2 to 5 weeks.²⁴ As a result, monospot testing yields a high incidence of false negatives during the first 2 weeks of active infection.²⁵ False negatives are also common in patients younger than 14 years. Heterophile antibodies may be present for up to a year after active infection.²⁴

Patients at increased risk for splenic rupture, such as athletes, pose considerable diagnostic difficulty.²⁶ When there is strong clinical suspicion of mononucleosis despite a negative monospot test in such high-risk individuals, follow-up testing is recommended to differentiate it from other mononucleosis-like illnesses (TABLE 2).²⁷ The optimal combination of Epstein-Barr virus (EBV) serologic testing consists of the antibody titration of 4 markers: immunoglobulins M (IgM) and G (IgG) to the viral capsid antigen, IgM to the early antigen, and antibody to Epstein-Barr nuclear antigen (EBNA).²⁸ Acute phase reactants in the setting of an antibody to EBNA could indicate reactivation. A positive test does not exclude other medical causes, however, because up to 20% of patients have acute phase antibodies that persist for years.²⁹

Digoxin levels need to be drawn at least 6 to 8 hours after the last dose is taken to allow for appropriate drug distribution. Appropriate diagnosis is important because of the significant morbidity associated with EBV. Risk of splenic injury is greatest between 4 and 21 days after onset of symptoms but persists at 7 weeks,²⁶ so conservative therapy followed by monospot retesting one week later is a reasonable approach.

Mononucleosis or routine tonsillitis? It is important to note that there is no evidence that a positive monospot test will affect the management or outcome of routine tonsillitis, raising questions of the utility of the test in such cases. A better approach: Reserve testing for patients with additional findings—ie, splenomegaly—or whose symptoms have persisted ≥ 2 weeks.

THE TAKEAWAY: Wait at least 2 weeks to conduct monospot testing in patients with routine tonsillitis. If strong clinical suspicion exists, proceed with specific IgM and IgG serologic testing.^24,25,27,28

5. Evaluating prescription drug levels: Which factors interfere?

Correct interpretation of lab tests conducted to measure prescription drug levels has major implications with regard to patient safety, particularly for medications with a narrow therapeutic index.

Conduct a confirmatory test before making decisions based on the results of urine drug screens.Most drug level tests measure the total concentration, which includes both bound and unbound (free) forms. The unbound forms are the active components of the drug; thus, for an accurate evaluation, it is important to be aware of factors that increase free drug concentration. Chief among them is low protein levels, or hypoalbuminemia.³⁰

Risk factors for hypoalbuminemia include significant burns, advanced age, pregnancy, malnutrition, and human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS).³⁰ HIV/AIDS is a particularly high risk because certain protease inhibitors are highly protein bound.

Drug protein binding is classified as low, moderate, or high. The main proteins involved in the process are albumin, alpha-1-acid glycoprotein, and lipoprotein. Medications that are highly protein bound (>80%) are the most affected by low protein levels: Problems can arise when drugs completely bind to all the available proteins and excess drug availability increases free drug levels.

Medications that are most likely to be affected by a high degree of protein binding include carbamazepine, cyclosporine, mycophenolic acid, phenytoin, protease inhibitors (with the exception of indinavir), tacrolimus, and valproic acid. It is important to consider free levels when you order medication assays for these drugs to avoid misinterpreting the serum levels as being too low-a scenario that raises the risk of drug toxicity and adverse outcomes.^30,31

A study of 119 phenytoin samples from 70 patients found significantly higher free phenytoin levels in patients with lower albumin levels.³² Higher free phenytoin levels were also seen in older patients and in those with diminished renal function (creatinine clearance <25 mL/min).³² The degree of protein binding is affected by both the serum drug concentration and the albumin level, with saturable protein binding occurring at higher drug levels.³³

Calculate phenytoin levels with this equation. To calculate corrected phenytoin levels in patients with low albumin levels, use the following formula, known as the Sheiner-Tozer equation:³⁴

Concentration adjusted=concentration reported/([adjustment x serum albumin] + 0.1); adjustment=0.2 for creatinine clearance ≥20 or 0.1 for creatinine clearance <20.

Additional causes of misinterpreted drug levels. While hypoalbuminemia plays a major role in the misinterpretation of drug levels, other factors affect serum drug concentration, as well. These include drug-drug interactions, which can significantly increase the concentration of the medications involved, and the timing of the test with regard to medication administration. Digoxin levels, in particular, need to be drawn at least 6 to 8 hours after the last dose is taken to allow for appropriate drug distribution.³⁵

THE TAKEAWAY: It is essential to consider free drug level monitoring in patients who either have hypoalbuminemia or have one or more risk factors for hypoalbuminemia to avoid falsely low estimation of drug levels.^36,37

6 Liver function tests: Necessary for patients on statin therapy?

Since statins gained US Food and Drug Administration (FDA) approval, the drugs have been associated with increased liver function tests (LFTs). Indeed, there had been a long-standing belief, based on clinical trials, that by monitoring alanine aminotransferase (ALT) and maintaining it at <3 times the upper limit normal (ULN), hepatotoxicity could be avoided.³⁸ In clinical practice, however, further ALT elevation is frequently allowed based on patient tolerability.

In February 2012, the FDA revised its safety data to reflect this practice.³⁹ The FDA update confirmed that routine LFT monitoring is unnecessary for patients on statins—and that it is not very effective in identifying or preventing liver damage.

Overall, serious hepatotoxicity is very rare, with an incidence ≤2 per 1 million patient-years.³⁹ The National Lipid Association Statin Safety Assessment Task Force recommends repeating LFTs that are 3 to 5 times the ULN within 6 months and continuing with the statin dose if the patient is asymptomatic.³⁸

THE TAKEAWAY: Routine liver function monitoring is not necessary for patients on statins. A better approach: Obtain baseline ALT levels, and repeat the testing only as clinically indicated thereafter.^38,39

7. Urine drug screens: Which factors affect their accuracy?

The gold standard for testing for drugs of abuse, urine drug screens (UDS) have good sensitivity and specificity, easy administration, and reasonable cost.⁴⁰ UDS can detect various narcotics, such as morphine, oxycodone, ,and methadone, and identify other illicit drugs, although which drugs and metabolites are tested for is laboratory- and test-specific.

Cross-reactivity. There are 6 currently available immunoassays, all of which use competitive binding between the sample drug and a drug chemically labeled with an enzyme, radioisotope, or fluorophore. The sample drug and labeled drug compete for substrate binding sites on drug-specific antibodies.^41,42 Similar to competitive binding for enzymatic reactions in the body, the substrate binding site can experience cross-reactivity—causing substances other than the drug in question to bind to the immunoglobulin, leading to a false positive result (TABLE 3).⁴³ Other factors that can alter the results include the cutoff value of the test and the absorption, distribution, metabolism, and excretion of the drug.⁴² Thus, a confirmatory test of gas chromatography-mass spectrometry is recommended before making decisions based on the results of UDS.^43-45

Routine screens for patients on chronic opioid therapy. Routine use of UDS in emergency departments is no longer recommended, based on evidence that the results are unlikely to have a significant effect on patient management.⁴⁶ For patients on chronic opioid therapy, however, routine screening has proven helpful in detecting prescription opioid abuse, illicit drug use, and diversion. Up to 34% of patients on prescription opioids have been found to be using illicit drugs, as well.⁴²

THE TAKEAWAY: Use UDS as a tool in managing patients on chronic opioid therapy, but before acting on results, assess for factors, such as the use of oral or topical medications and the cutoff value of the test, that may be associated with false positive or false negative results.^43-45

8. Thyroid function testing: When should you test?

Thyroid-stimulating hormone (TSH) is the first-line test when investigating presumed hyper- or hypothyroidism.^47,48 Third-generation chemiluminometric assays can reliably measure TSH concentrations <0.01 mU/L by using multiple antibodies to produce a sandwich-type effect on the molecule in question.⁴⁹

Retesting TSH to assess treatment response should be postponed until ≥2 months after any change in medication or dosing.TSH levels exhibit diurnal variation, however, and are affected by other medications, including steroids, opiates, and some antihistamines, among others, as well as comorbidities.^47,48 Chronic and acute conditions unrelated to thyroid disease can cause transient changes in TSH concentrations, and have the potential to modify the binding capacity of plasma thyroid hormone binding proteins.⁴⁸ Thus, TSH should be ordered for hospitalized patients only when clinical suspicion of a thyroid problem exists.⁴⁸ The USPSTF recommends against routine TSH screening for asymptomatic adults.⁴⁶

How to respond to abnormal results. For patients found to have abnormal TSH levels, free T4 (fT4) is the next test to order.^47,49 An fT4 assay is a superior indicator of thyroid status because it is not affected by changes in iodothyronine-binding proteins, which influence total hormone measurements.⁴⁹ The results will be elevated in hyperthyroidism and reduced in hypothyroidism.⁴⁷

Triiodothyronine (T3) measures can be useful in diagnosing Graves’ disease, in which T3 toxicosis may be the initial symptom—or an indication of a relapse. Because T3 is often a peripheral product, however, nonthyroid illnesses and medications can cause artifactually abnormal results.⁴⁹

Other thyroid-specific labs include thyroid ,antibodies such as antithyroid peroxidase, antithyroglobulin, and TSH receptor, both blocking and stimulating.⁴⁹ Thyroglobulin is a precursor form of thyroid hormone and should be measured when factitious hyperthyroidism is suspected. Management of hyper- and hypothyroidism often is independent of etiology. Retesting TSH to assess treatment response should be postponed until ≥2 months after any change in medication or dosing.⁵⁰

Thyroid studies can be very difficult to interpret. TSH should be the first test ordered. However, if TSH values do not match the clinical picture, fT4, T3, and other thyroid tests that are less affected by outside factors can be useful in identifying the cause.

THE TAKEAWAY: Routine TSH testing is not indicated for asymptomatic adults. When evaluating thyroid function is clinically indicated, TSH is the initial test of choice.^47,48,51

CORRESPONDENCE
Joshua Tessier, DO, Iowa Lutheran Family Medicine Residency, 840 East University Avenue, Des Moines, IA 50316; [email protected]

Burkitt lymphoma

Credit: Ed Uthman

Researchers say they’ve discovered how the protein STAT3 interferes with an antitumor mechanism in cells, thereby promoting the growth of lymphoma and other cancers.

The group made their discovery using the Epstein-Barr virus (EBV) as a tool to investigate cancer development.

“Our findings add to the short list of known mechanisms by which a key cellular antitumor barrier is breached by STAT3 prior to cancer development,” said Sumita Bhaduri-McIntosh, MD, PhD, of Stony Brook University School of Medicine in New York.

“Because STAT3 interferes with this innate antitumor mechanism in cells, the opposite occurs when blood cells are infected in the lab with the cancer-causing virus EBV, and the cells continue to divide—a necessary step in cancer development.”

Dr Bhaduri-McIntosh and her colleagues described their research in PNAS.

The team explained that STAT3 inhibits a cancer-suppressing cellular activity called the DNA damage response (DDR). Normally, this response pauses cell division, allowing for the repair of damaged DNA.

But this study showed that EBV not only causes DNA damage when it infects and replicates in cells; it also activates and increases STAT3 expression. This starts a chain reaction that leads to an “un-pause” in cell division, thereby promoting cell proliferation. This, in combination with other pro-proliferative effects of the virus, can lead to cancers.

The researchers found that DDR does detect replication stress-associated DNA damage resulting from EBV infection. But signaling downstream of ATR proteins is impaired by STAT3. And this leads to relaxation of the intra-S phase checkpoint of the cell cycle.

STAT3 interrupts signaling from ATR to the protein Chk1 by promoting the loss of Claspin, a protein that assists ATR to phosphorylate Chk1. The loss of Claspin, which facilitates cell proliferation, is mediated by caspase 7.

Previous research suggested that STAT3 and Chk1 are potential targets for cancer therapies. Dr Bhaduri-McIntosh’s team said their results provide new insight into anticancer drug development because they reveal a mechanistic link between these 2 proteins.

Dr Bhaduri-McIntosh emphasized that, because STAT3 is involved in most cancers, her group’s findings could potentially impact the prevention or treatment of several types of cancer—something her lab is investigating.

Burkitt lymphoma

Credit: Ed Uthman

Researchers say they’ve discovered how the protein STAT3 interferes with an antitumor mechanism in cells, thereby promoting the growth of lymphoma and other cancers.

The group made their discovery using the Epstein-Barr virus (EBV) as a tool to investigate cancer development.

“Our findings add to the short list of known mechanisms by which a key cellular antitumor barrier is breached by STAT3 prior to cancer development,” said Sumita Bhaduri-McIntosh, MD, PhD, of Stony Brook University School of Medicine in New York.

“Because STAT3 interferes with this innate antitumor mechanism in cells, the opposite occurs when blood cells are infected in the lab with the cancer-causing virus EBV, and the cells continue to divide—a necessary step in cancer development.”

Dr Bhaduri-McIntosh and her colleagues described their research in PNAS.

The team explained that STAT3 inhibits a cancer-suppressing cellular activity called the DNA damage response (DDR). Normally, this response pauses cell division, allowing for the repair of damaged DNA.

But this study showed that EBV not only causes DNA damage when it infects and replicates in cells; it also activates and increases STAT3 expression. This starts a chain reaction that leads to an “un-pause” in cell division, thereby promoting cell proliferation. This, in combination with other pro-proliferative effects of the virus, can lead to cancers.

The researchers found that DDR does detect replication stress-associated DNA damage resulting from EBV infection. But signaling downstream of ATR proteins is impaired by STAT3. And this leads to relaxation of the intra-S phase checkpoint of the cell cycle.

STAT3 interrupts signaling from ATR to the protein Chk1 by promoting the loss of Claspin, a protein that assists ATR to phosphorylate Chk1. The loss of Claspin, which facilitates cell proliferation, is mediated by caspase 7.

Previous research suggested that STAT3 and Chk1 are potential targets for cancer therapies. Dr Bhaduri-McIntosh’s team said their results provide new insight into anticancer drug development because they reveal a mechanistic link between these 2 proteins.

Dr Bhaduri-McIntosh emphasized that, because STAT3 is involved in most cancers, her group’s findings could potentially impact the prevention or treatment of several types of cancer—something her lab is investigating.

Burkitt lymphoma

Credit: Ed Uthman

Researchers say they’ve discovered how the protein STAT3 interferes with an antitumor mechanism in cells, thereby promoting the growth of lymphoma and other cancers.

The group made their discovery using the Epstein-Barr virus (EBV) as a tool to investigate cancer development.

“Our findings add to the short list of known mechanisms by which a key cellular antitumor barrier is breached by STAT3 prior to cancer development,” said Sumita Bhaduri-McIntosh, MD, PhD, of Stony Brook University School of Medicine in New York.

“Because STAT3 interferes with this innate antitumor mechanism in cells, the opposite occurs when blood cells are infected in the lab with the cancer-causing virus EBV, and the cells continue to divide—a necessary step in cancer development.”

Dr Bhaduri-McIntosh and her colleagues described their research in PNAS.

The team explained that STAT3 inhibits a cancer-suppressing cellular activity called the DNA damage response (DDR). Normally, this response pauses cell division, allowing for the repair of damaged DNA.

But this study showed that EBV not only causes DNA damage when it infects and replicates in cells; it also activates and increases STAT3 expression. This starts a chain reaction that leads to an “un-pause” in cell division, thereby promoting cell proliferation. This, in combination with other pro-proliferative effects of the virus, can lead to cancers.

The researchers found that DDR does detect replication stress-associated DNA damage resulting from EBV infection. But signaling downstream of ATR proteins is impaired by STAT3. And this leads to relaxation of the intra-S phase checkpoint of the cell cycle.

STAT3 interrupts signaling from ATR to the protein Chk1 by promoting the loss of Claspin, a protein that assists ATR to phosphorylate Chk1. The loss of Claspin, which facilitates cell proliferation, is mediated by caspase 7.

Previous research suggested that STAT3 and Chk1 are potential targets for cancer therapies. Dr Bhaduri-McIntosh’s team said their results provide new insight into anticancer drug development because they reveal a mechanistic link between these 2 proteins.

Dr Bhaduri-McIntosh emphasized that, because STAT3 is involved in most cancers, her group’s findings could potentially impact the prevention or treatment of several types of cancer—something her lab is investigating.