Subclinical Hypothyroidism: Controversies in Testing and Treatment

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Controversy exists over whether diagnostic screening and treatment for subclinical hypothyroidism are warranted.
Controversy exists over whether diagnostic screening and treatment for subclinical hypothyroidism are warranted.

Subclinical hypothyroidism is defined in American Thyroid Association (ATA)/American Academy of Clinical Endocrinology (AACE) guidelines as an elevated thyroid-stimulating hormone (TSH) level with a serum free thyroxine (T4) level within the reference range, when thyroid function has been stable for weeks or more, the hypothalamic-pituitary-thyroid axis is normal, and there is an absence of recent or ongoing severe illness.1 In the United States, subclinical hypothyroidism has an estimated prevalence of 4.3%.2 Although subclinical hypothyroidism is a biochemical diagnosis, some experts have suggested that the term is a misnomer, as it erroneously implies that symptoms and signs are always absent.3,4 According to results from a large questionnaire-based study of attendees at a Colorado health fair, individuals whose laboratory values indicated subclinical hypothyroidism reported more classic symptoms of hypothyroidism than euthyroid individuals.5

While there is wide agreement that patients with overt hypothyroidism should receive treatment, controversy has long ensued over whether diagnostic screening and treatment for subclinical hypothyroidism are warranted.6 In an editorial published in Lancet Diabetes Endocrinology, René Rodriguez-Gutierrez, MD, of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at the Mayo Clinic, in Rochester, Minnesota, and colleagues commented: "The treatment of individuals with mild, non-specific symptoms and the overdiagnosis of subclinical hypothyroidism, imprecise screening recommendations, and misinterpretation of normal thyroid-stimulating hormone variability could be contributing to levothyroxine overuse, imposing a substantial economic and treatment burden on millions of people.”7

Observational studies have shown that subclinical hypothyroidism is a risk factor for adverse clinical outcomes including overt hypothyroidism, coronary heart disease, cardiac failure, altered metabolic parameters, osteoporotic fractures, and decrements in neuropsychological function and quality of life.8 The evidence for an elevated risk of coronary heart disease, heart failure, and cerebrovascular disease is strongest in patients <65 years of age.8 However, the clinical benefit of diagnostic testing and levothyroxine replacement therapy has not been definitively demonstrated in clinical trials.9 Aside from a study in anti-thyroid antibody-negative pregnant women that demonstrated an increase in pregnancy loss,10 virtually no studies currently support the treatment of patients with subclinical hypothyroidism whose TSH levels are between 2.5 and 4.5 mIU/L.1 In the Whickham Survey, a population-based cross-sectional study of 2779 community-dwelling adults in northern England, levothyroxine replacement therapy in patients with subclinical hypothyroidism over an extended period of follow-up appeared to attenuate morbidity and mortality related to ischemic heart disease.11 In contrast, results from TRUST (Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial; ClinicalTrials.gov Identifier: NCT01660126) showed that levothyroxine replacement therapy failed to improve clinical symptom scores in older patients with subclinical hypothyroidism. In that study, 737 community-dwelling participants aged ≥65 years with TSH levels between 4.6 and 19.9 mIU/L and normal free thyroxine levels were randomly assigned to receive either levothyroxine or placebo. Although active treatment lowered TSH to normal levels, no significant differences were evinced in the Hypothyroid Symptoms score and Tiredness score on a standardized instrument for the assessment of thyroid-related quality-of-life. The authors noted that the trial was underpowered to determine the association between subclinical hypothyroidism and cardiovascular events or mortality.12

The debate over whether to test and treat for subclinical hypothyroidism is reflected by the divergent recommendations in guidelines issued by the US Preventive Services Task Force (USPSTF) and by the ATA/AACE. The USPSTF found adequate evidence that treatment of subclinical hypothyroidism does not provide clinically meaningful improvements in blood pressure, body mass index, bone mineral density, lipid levels, quality-of-life measures, or cognitive function, and there is inadequate evidence to determine whether screening for thyroid dysfunction in nonpregnant adults is clinically beneficial, particularly with regard to cardiovascular disease-related morbidity and mortality. However, the guideline notes that the focus of the USPSTF is on “asymptomatic populations that do not have known signs or symptoms of disease.”13 In contrast, ATA/AACE guidelines recommend “aggressive case-finding” in patients with specific clinical features, including family history of thyroid disease, history of neck irradiation or thyroid surgery, dyslipidemia, atrial fibrillation, unexplained weight loss, hyperprolactinemia, certain autoimmune disorders, and use of medications causing thyroid dysfunction. ATA/AACE does not recommend screening in the general population. The ATA/AACE guidelines recommend that most patients with a TSH level >10 mIU/L should receive treatment.1

In order to assess how endocrinologists in the community approach the treatment of patients with subclinical hypothyroidism, Endocrinology Advisor interviewed Michael Laidlaw, MD, a board-certified endocrinologist in private practice in Rocklin, California.

“I would say there are 2 major considerations regarding therapy in the nonpregnant adult person with laboratory-confirmed subclinical hypothyroidism,” Dr Laidlaw told Endocrinology Advisor. “Do they have symptoms consistent with hypothyroidism? And will treating this person with thyroid hormone to lower TSH into the reference range actually reduce cardiovascular morbidity and mortality? These 2 questions should be considered independently in my opinion. The symptoms for hypothyroidism — such as fatigue, dry skin, weight gain, and cold intolerance — tend to be nonspecific and may be found in a number of other conditions. More often than not, an endocrinologist will be presented with many of these symptoms by a patient who wants to know or already believes that this is due to a thyroid condition. It is reasonable in this scenario, in my opinion, to start low-dose thyroid hormone. The risks of therapy are minimal and there are at least a couple of benefits: relief of symptoms and confirmation of diagnosis. If, for example, thyroid functions tests — TSH and free T4 — are both within the reference range 6 weeks after initiating therapy, the diagnosis of hypothyroidism is confirmed for the most part if the symptoms have resolved. If, however, the symptoms remain, then one must rule out other common causes of fatigue, such as anemia or sleep apnea, other sleep disturbances, and so on. The second consideration for therapy is whether the treatment will reduce morbidity and mortality for cardiovascular disease. The answer to this in my opinion is less settled. I would think it would not be difficult by now to have had a prospective randomized controlled trial of treatment with levothyroxine and a nontreated control group for subclinical hypothyroidism to determine if there is a true reduction in morbidity and mortality with respect to cardiovascular disease in subclinical hypothyroidism. However, to my knowledge, no such trial or trials have been completed.”

References

  1. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012;18(6):988-1028.
  2. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87(2):489-499.
  3. Duntas LH. Subclinical hypothyroidism: a misnomer in search of a new name. Thyroid. 2001;11(4):361-362.
  4. Wiersinga WM. Guidance in subclinical hyperthyroidism and subclinical hypothyroidism: are we making progress? Eur Thyroid J. 2015;4(3):143-148.
  5. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160(4):526-534.
  6. Grossman A, Weiss A, Koren-Morag N, Shimon I, Beloosesky Y, Meyerovitch J. Subclinical thyroid disease and mortality in the elderly: a retrospective cohort study. Am J Med. 2016;129(4):423-430.
  7. Rodriguez-Gutierrez R, Maraka S, Ospina NS, Montori VM, Brito JP. Levothyroxine overuse: time for an about face? Lancet Diabetes Endocrinol. 2017;5(4):246-248.
  8. Redford C, Vaidya B. Subclinical hypothyroidism: should we treat? Post Reprod Health. 2017;23(2):55-62.
  9. McDermott MT, Ridgway EC. Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab. 2001;86(10):4585-4590.
  10. Negro R, Schwartz A, Gismondi R, Tinelli A, Mangieri T, Stagnaro-Green A. Increased pregnancy loss rate in thyroid antibody negative women with TSH levels between 2.5 and 5.0 in the first trimester of pregnancy. J Clin Endocrinol Metab. 2010;95(9):E44-E48.
  11. Razvi S, Weaver JU, Vanderpump MP, Pearce SHS. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of the Whickham Survey cohort. J Clin Endocrinol Metab. 2010;95(4):1734-1740.
  12. Stott DJ, Rodondi N, Kearney PM, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376:2534-2544.
  13. LeFevre ML, U.S. Preventive Services Task Force. Screening for thyroid dysfunction: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2015;162(9):641-650.
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