Cochrane for Clinicians
Putting Evidence into Practice
Am Fam Physician. 2008 Apr 1;77(7):953-955.
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.
Should physicians recommend thyroid hormone therapy for any nonpregnant patient with subclinical hypothyroidism?
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.
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.
Background: Subclinical hypothyroidism is defined as an elevated serum thyroid-stimulating hormone (TSH) level with normal free thyroid hormone values. The prevalence of subclinical hypothyroidism is 4 to 8 percent in the general population, and up to 15 to 18 percent in women who are older than 60 years. There is considerable controversy regarding the morbidity, the clinical significance of subclinical hypothyroidism, and if such patients should be treated.
Objective: To assess the effects of thyroid hormone replacement for subclinical hypothyroidism.
Search strategy: The authors searched The Cochrane Library, Medline, Embase, and Lilacs. Ongoing trials databases, reference lists, and abstracts of congresses were scrutinized as well.
Selection criteria: All studies had to be randomized controlled trials comparing thyroid hormone replacement with placebo or no treatment in adults with subclinical hypothyroidism. Minimum duration of follow-up was one month.
Data collection and analysis: Two authors independently assessed trial quality and extracted data. Individual study authors were contacted for missing or additional information.
Main results: Twelve trials of six to 14 months' duration involving 350 people were included. Eleven trials investigated levothyroxine replacement with placebo and one study compared levothyroxine replacement with no treatment. The authors did not identify any trial that assessed (cardiovascular) mortality or morbidity. Seven studies evaluated symptoms, mood, and quality of life with no statistically significant improvement. One study showed a statistically significant improvement in cognitive function. Six studies assessed serum lipids, and there was a trend for reduction in some parameters following levothyroxine replacement. Some echocardiographic parameters improved after levothyroxine replacement therapy, such as myocardial relaxation, as indicated by a significant prolongation of the isovolumic relaxation time, as well as diastolic dysfunction. Only four studies reported adverse events with no statistically significant differences among groups.
Authors' conclusions: In current randomized controlled trials, levothyroxine replacement therapy for subclinical hypothyroidism did not result in improved survival or decreased cardiovascular morbidity. Data on health-related quality of life and symptoms did not demonstrate significant differences among intervention groups. Some evidence indicates that levothyroxine replacement improves some parameters of lipid profiles and left ventricular function.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of SystematicReviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the originalreviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (http://www.cochrane.org).
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. Over-treatment 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
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.
The Cochrane Abstract 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.
The series coordinator for AFP is Clarissa Kripke, MD, Department of Family and Community Medicine, University of California, San Francisco.
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