Cochrane for Clinicians

Putting Evidence into Practice

Subclinical Hypothyroidism

Brian Herrick, MD, University of California, San Francisco
Family Medicine Center at Lakeshore, San Francisco, California

The Cochrane Abstract on the next page is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Dr. Herrick presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab003419.html.

Clinical Scenario

A 65-year-old woman with a history of poorly controlled hypertension and mild, untreated depression presents with an elevated thyroid-stimulating hormone (TSH) level and normal free thyroxine (T4) and free triiodothyronine (T3) levels. She denies any symptoms related to hypothyroidism, but is wondering if she should start thyroid replacement therapy.

Clinical Question

Should physicians recommend thyroid hormone therapy for any nonpregnant patient with subclinical hypothyroidism?

Evidence-Based Answer

Although there is evidence that thyroid hormone therapy in patients with subclinical hypothyroidism may improve lipid profiles, cognitive function, and echographic left ventricular function, there is no evidence that this will decrease morbidity or mortality.

Practice Pointers

There has been conflicting evidence regarding the effect of the thyroid hormone levothyroxine (Synthroid) on cholesterol in persons with subclinical hypothyroidism. A meta-analysis of mostly nonrandomized trials showed that levothyroxine reduced serum total cholesterol by about 5 percent and low-density lipoprotein (LDL) cholesterol by 10 mg per dL (0.30 µmol per L). No improvements of high-density lipoprotein (HDL) cholesterol or triglyceride levels were demonstrated.1 In this Cochrane review, total cholesterol and subgroup LDL values greater than 155 mg per dL (4.00 µmol per L) showed significant improvement favoring the levothyroxine treatment group. In the treatment group, there were nonsignificant trends of lowered LDL, HDL, and triglyceride levels.2 There are no data pertaining to cardiovascular or other patient-oriented outcomes.

Patients with overt hypothyroidism have a higher incidence of heart failure, which is also hypothesized to occur in patients with subclinical hypothyroidism. In a systematic review, treatment with levothyroxine in patients with subclinical hypothyroidism improved measures of diastolic and systolic function, including isovolumic relaxation time, index of myocardial performance, cyclic variation index, and left ventricular ejection time. Although these improvements in physiologic outcomes were statistically significant, the clinical significance of this is not clear.2

No randomized trial has evaluated cardiovascular morbidity and mortality. A 12-year cohort study in the United States consisting of 3,233 community-dwelling participants 65 years and older with baseline serum TSH levels reported no significant difference in the risk of coronary heart disease, cerebrovascular disease, cardiovascular death, or all-cause death between euthyroid patients and those with subclinical or overt hypothyroidism.3

Another four-year cohort study of healthy patients 70 to 79 years of age found an increase in congestive heart failure over four years in participants with a baseline TSH greater than 7.0 mIU per L. There was no difference in coronary heart disease events, stroke, peripheral artery disease, or mortality. Incidence of chronic heart failure events was significantly increased in persons with a TSH of 7.0 mIU per L or greater.4

In a recent meta-analysis of observational studies (i.e., five prospective cohorts and nine case-control or cross-sectional studies), there was an increased risk of coronary heart disease in patients with an elevated TSH level but normal free T4 level compared with those who had a normal TSH. However, this risk was not significant when looking only at the prospective cohort studies, which are generally less subject to bias than case-control studies.5 A similar recent meta-analysis of four studies, limited to follow-up between four and 20 years, showed an increased risk of coronary heart disease and death from cardiovascular causes in patients with a TSH level greater than 5 mIU per L and a normal free T4 level, but no difference in all-cause mortality.6 The inconsistencies among the conclusions of the above trials highlight the need for randomized control trials to study the effect of levothyroxine on cardiovascular morbidity and mortality.

The current Cochrane review included only one trial that evaluated cognitive function, and it showed a small, but significant, improvement favoring levothyroxine treatment. Quality of life scores, emotional function scores, and symptom scores showed no difference upon conclusion of the analysis. The clinical significance of this difference in cognitive function is unclear.2

Only four studies in this Cochrane review evaluated adverse effects. None found any statistically significant differences, although there was a trend toward an increase in anxiety, a decrease in general health scores, and an increase in other side effects in the levothyroxine group. One of the most concerning risks of levothyroxine treatment is iatrogenic subclinical hyperthyroidism, which can occur in 14 to 21 percent of persons. Overtreatment probably contributes to reduced bone density and the development of osteoporosis.2

In 1998, the American College of Physicians recommended treatment on an individual basis (or repeating serum TSH yearly) for a TSH level between 5 and 10 mIU per L. Treatment should be considered if the thyroid peroxidase antibodies are positive or if the patient is symptomatic or has high cholesterol. Otherwise, yearly monitoring is advised.7

The 2004 report from the Consensus Conference Panel on Subclinical Thyroid Disease (CCPSTD) Independent Expert Panel does not recommend routine treatment for patients with TSH levels between 4.5 and 10 mIU per L, but thyroid function tests should be repeated at six- to 12-month intervals to monitor for changes in TSH levels. For TSH levels above 10 mIU per L, the evidence is too inconclusive to recommend for or against treatment.8 The CCPSTD recommendations are in parallel with the 2004 recommendations from the U.S. Preventive Services Task Force, which state that the benefit of treatment is inconsistent and the potential adverse effects of over-treatment may affect a substantial number of persons. Evidence is inconsistent for dyslipidemia, atherosclerosis, and a decreased quality of life in adults with subclinical hypothyroidism in the general population.9

Address correspondence to Brian Herrick, MD, at brian.herrick@ucsfmedctr.org. Reprints are not available from the author.

Author disclosure: Nothing to disclose

REFERENCES

1. Danese MD, Ladenson PW, Meinert CL, Powe NR. Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab. 2000;85(9):2993-3001.

2. Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007;(3):CD003419.

3. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006;295(9):1033-1041.

4. Rodondi N, Newman AB, Vittinghoff E, et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med. 2005;165(21):2460-2466.

5. Rodondi N, Aujesky D, Vittinghoff E, Cornuz J, Bauer DC. Subclinical hypothyroidism and the risk of coronary heart disease: a meta-analysis. Am J Med. 2006;119(7):541-551.

6. Singh S, Duggal J, Molnar J, Maldonado F, Barsano CP, Arora R. Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all-cause mortality: a meta-analysis. Int J Cardiol. In press.

7. Helfand M, Redfern CC. Clinical guideline, part 2. Screening for thyroid disease: an update. American College of Physicians [published correction appears in Ann Intern Med. 1999;130(3):246]. Ann Intern Med. 1998;129(2):144-158.

8. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291(2):228-238.

9. U.S. Preventive Services Task Force. Screening for thyroid disease: recommendation statement. Ann Intern Med. 2004;140(2):125-127.

Cochrane Briefs

Abstinence-Plus Programs for Prevention of HIV

Clinical Question

Do abstinence-plus programs prevent human immunodeficiency virus (HIV) infection?

Evidence-Based Answer

Abstinence-plus is sex education that includes information on abstinence, condom use, and contraception. Compared with a variety of controls-including usual care, no intervention, or other programs-there is no evidence of increased rates of pregnancy or sexually transmitted infection (STI). Based on limited data, abstinence-plus programs increase knowledge, reduce pregnancy rates, and decrease incidence of unprotected sex and frequency of sex.

Practice Pointers

Abstinence-plus interventions are designed to prevent, stop, or decrease sexual activity while promoting safer sex practices for persons who choose to engage in sex. In contrast, abstinence-only interventions promote abstinence as the only way to prevent HIV infection.

In this Cochrane review of randomized and quasi-randomized controlled trials of abstinence-plus interventions, the authors identified 39 studies with a total of 37,724 participants. All studies were conducted on adolescents or young adults in North America, and 37 studies were conducted in the United States. Most of the studies took place in urban schools or community centers, and the participants were primarily of ethnic minorities. Active parental consent was required by 28 of the studies. Interventions varied considerably, but they all promoted abstinence as the best choice and condom or contraception use for those who have sex. Control interventions also varied considerably. All interventions included information on HIV, STI prevention, sexual risks, and strategies for HIV prevention. Interventions ranged from a single session to programs that were three years in duration. Results were self-reported.

Because of methodologic differences, meta-analysis was not possible. There was no evidence that abstinence-plus programs increased the risk of HIV infection, and there were no adverse effects reported. Abstinence-plus education improved participants' knowledge of HIV across trials. Only two studies (with 1,700 participants, total) included STI screening as an outcome. No statistical differences were found among interventions. Limited evidence suggests that abstinence-plus programs reduce the incidence of pregnancy. Limited data also demonstrate a reduction in the incidence of unprotected intercourse and a reduced frequency of vaginal and anal sex.

In a previous review, the authors evaluated 13 trials of abstinence-only programs with a total of 15,940 U.S. adolescent participants.1 Compared with various controls, the abstinence-only programs did not reduce self-reported biologic (e.g., STIs) or behavioral (e.g., unprotected vaginal sex) outcomes in participants. One study in the review found increases in short- and long-term incidences of STIs, an increased rate of pregnancy, and an increased frequency of vaginal sex (4,652 participants).1 However, these findings of harm were limited to that one study.

clarissa kripke, MD

Source: Underhill K, Montgomery P, Operario D. Abstinence-plus programs for HIV infection prevention in high-income countries. Cochrane Database Syst Rev. 2008;(1):CD007006.

Author disclosure: Nothing to disclose.

REFERENCES

1. Underhill K, Operario D, Montgomery P. Abstinence-only programs for HIV infection prevention in high-income countries. Cochrane Database Syst Rev. 2007;(4):CD005421.

This clinical content conforms to AAFP criteria for evidence-based continuing medical education (EB CME). See CME Quiz on page 907.

The series coordinator for AFP is Clarissa Kripke, MD, Department of Family and Community Medicine, University of California, San Francisco.

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