Subclinical Hyperthyroidism | NEJM

To the Editor

In their Clinical Practice article, Biondi and Cooper (June 21 issue)1 state that Graves’ disease is a common cause of endogenous subclinical hyperthyroidism, accounting for 40% of cases in populations with adequate iodine intake. The authors cite a review article2 that references original articles reporting a prevalence of Graves’ disease that is much lower than 40% (<10%) among patients with subclinical hyperthyroidism.3 Indeed, although one study showed that 4 of 10 patients with a fully suppressed thyrotropin level did have underlying Graves’ disease, of the 20 patients who had a persistently partially suppressed thyrotropin level, only 1 (5%) had underlying Graves’ disease.4

Graves’ disease is implicated in a small but clinically significant proportion of patients with subclinical hyperthyroidism who have a fully suppressed thyrotropin level.2,4 However, only a minority of patients with a partially suppressed thyrotropin level have underlying Graves’ disease, and these patients are more likely to have underlying multinodular goiter or toxic adenoma than patients with a fully suppressed thyrotropin level.4,5

David M. Williams, M.R.C.P
Jeffrey W. Stephens, Ph.D., F.R.C.P.
David E. Price, M.D., F.R.C.P.
Morriston Hospital, Swansea, United Kingdom

No potential conflict of interest relevant to this letter was reported.

  1. 1. Biondi B, Cooper DS. Subclinical hyperthyroidism. N Engl J Med 2018;378:24112419.

  2. 2. Carlé A, Andersen SL, Boelaert K, Laurberg P. Management of endocrine disease — subclinical thyrotoxicosis: prevalence, causes and choice of therapy. Eur J Endocrinol 2017;176:R325R337.

  3. 3. Schouten BJ, Brownlie BE, Frampton CM, Turner JG. Subclinical thyrotoxicosis in an outpatient population — predictors of outcome. Clin Endocrinol (Oxf) 2011;74:257261.

  4. 4. Bjørndal MM, Sandmo Wilhelmsen K, Lu T, Jorde R. Prevalence and causes of undiagnosed hyperthyroidism in an adult healthy population: the Tromsø study. J Endocrinol Invest 2008;31:856860.

  5. 5. Chatterjee S, O’Malley BP, Price DE, Fielding AM, Aitken R. Low but detectable serum thyroid-stimulating hormone concentrations in ambulant subjects not receiving thyroxine. Ann Clin Biochem 2003;40:639642.

To the Editor

Mortality is increased among patients with hyperthyroidism, independent of the thyrotropin level1 and phenotype.2 In their article on subclinical hyperthyroidism, Biondi and Cooper advocate treating a 65-year-old woman with mild subclinical hyperthyroidism (thyrotropin level, 0.2 mU per liter) and some clinically aggravating factors. We think that this recommendation can be extended far beyond their suggestions.

In population-based, observational studies based on Danish databases and involving more than 230,000 patients (mean follow-up, 7 years), we have found an excess mortality of 36% (95% confidence interval [CI], 16 to 60) among patients with untreated subclinical hyperthyroidism.3 In patients who received treatment and were followed over a similar period, no excess mortality was shown. In patients who received treatment for hypothyroidism, every 6-month period of overtreatment (thyrotropin level <0.3 mU per liter) was associated with an excess mortality of 18% (95% CI, 15 to 21).4 Overall, this rate was independent of other preexisting conditions, sex, and whether the patient was younger than 65 years of age or 65 years or older.

These data provide strong support for treatment of all patients with verified subclinical hyperthyroidism, whether endogenous or exogenous. They also underscore the necessity of maintaining a normal thyrotropin level in patients during follow-up.

Laszlo Hegedüs, M.D., D.M.Sc.
Thomas H. Brix, M.D., Ph.D.
Mads Lillevang-Johansen, M.D.
Odense University Hospital, Odense, Denmark

No potential conflict of interest relevant to this letter was reported.

  1. 1. Laulund AS, Nybo M, Brix TH, Abrahamsen B, Jørgensen HL, Hegedüs L. Duration of thyroid dysfunction correlates with all-cause mortality: the OPENTHYRO Register Cohort. PLoS One 2014;9(10):e110437e110437.

  2. 2. Brandt F, Thvilum M, Almind D, et al. Graves’ disease and toxic nodular goiter are both associated with increased mortality but differ with respect to the cause of death: a Danish population-based register study. Thyroid 2013;23:408413.

  3. 3. Lillevang-Johansen M, Abrahamsen B, Jørgensen HL, Brix TH, Hegedüs L. Excess mortality in treated and untreated hyperthyroidism is related to cumulative periods of low serum TSH. J Clin Endocrinol Metab 2017;102:23012309.

  4. 4. Lillevang-Johansen M, Abrahamsen B, Jørgensen HL, Brix TH, Hegedüs L. Over- and under-treatment of hypothyroidism is associated with excess mortality: a register-based cohort study. Thyroid 2018;28:566574.

To the Editor

An important consideration that is missing from the differential diagnosis of Biondi and Cooper is laboratory interference. Spurious values of thyroid-function tests caused by interference with laboratory assays have been reported in relation to patient antibodies,1 paraproteins in multiple myeloma,2 and most importantly, supraphysiologic levels of biotin.

Biotin interferes with many common immunoassays.3 However, the manner in which biotin affects thyroid-function tests is particularly alarming, since it produces a biochemical picture consistent with Graves’ disease.4

The Recommended Dietary Allowance of biotin, which is also labeled as vitamin H, vitamin B7, and coenzyme R, is 300 μg daily, but it is available commercially in doses of up to 100,000 μg. Patients may not report biotin use, and often they are unaware of its common presence in products for hair and nail care.

Laboratories should report not only whether assays are vulnerable, but also the expected pattern. In order to avoid unnecessary testing, referrals, or treatment, I think clinicians should recommend that patients abstain from biotin supplements for 48 to 72 hours before a blood sample is obtained, or longer in patients who are taking megadoses of biotin or who have impaired renal function.

James D. Haddad, M.D.
Naval Hospital Jacksonville, Jacksonville, FL

No potential conflict of interest relevant to this letter was reported.

The views expressed in this letter are those of the author and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of Defense, or the U.S. government.

  1. 1. Lam L, Bagg W, Smith G, et al. Apparent hyperthyroidism caused by biotin-like interference from IgM anti-streptavidin antibodies. Thyroid 2018;28:10631067.

  2. 2. Antonopoulou M, Silverberg A. Spurious T3 thyrotoxicosis unmasking multiple myeloma. Case Rep Endocrinol 2013;2013:739302739302.

  3. 3. Samarasinghe S, Meah F, Singh V, et al. Biotin interference with routine clinical immunoassays: understand the causes and mitigate the risks. Endocr Pract 2017;23:989998.

  4. 4. De Roeck Y, Philipse E, Twickler TB, Van Gaal L. Misdiagnosis of Graves’ hyperthyroidism due to therapeutic biotin intervention. Acta Clin Belg 2018;73:372376.


The authors reply: Williams et al. take issue with the fact that we stated that 40% of patients with subclinical hyperthyroidism have Graves’ disease, with the remainder having toxic multinodular goiter or a solitary autonomously functioning thyroid nodule. Although precise percentages of each diagnosis are difficult to glean from the literature, we agree with Williams et al. that Graves’ disease occurs in a distinct minority of patients, especially in those with mild subclinical hyperthyroidism, in whom serum thyrotropin levels are not fully suppressed.

Hegedüs et al. cite their own study showing higher mortality among patients with untreated subclinical hyperthyroidism than among those who receive treatment.1 We did not include this study in our article because of the paradoxical nature of their findings. In their population, mortality among patients with untreated overt hyperthyroidism (hazard ratio, 1.03; 95% CI, 0.88 to 1.20) was the same as that observed among patients with treated overt hyperthyroidism (hazard ratio, 1.03; 95% CI, 0.93 to 1.15), and these rates of death were not different from those in the euthyroid control population. Because of space limitations, we were not able to describe their article fully. We cannot agree with their recommendation, which is based solely on observational data, to treat all patients with subclinical hyperthyroidism. We stand by published clinical practice guidelines that advocate individualized treatment decisions based on the level of serum thyrotropin, patient age, and coexisting conditions.

Haddad appropriately points out that ingestion of biotin can cause falsely low serum thyrotropin levels in immunoassays using streptavidin–biotin systems. In addition to affecting serum thyrotropin levels, artifactual values for free thyroxine, triiodothyronine (T3), free T3, prolactin, N-terminal pro–brain natriuretic peptide, and 25-hydroxyvitamin D may be observed.2 Since clinicians do not usually know the assay system being used in clinical chemical laboratory tests, patients should avoid biotin ingestion before undergoing routine laboratory testing. Furthermore, as was pointed out by Haddad, there are a host of other causes of spurious findings in thyroid-function tests,3 so results require clinical correlation and should never be interpreted in isolation.

Bernadette Biondi, M.D.
University of Naples Federico II, Naples, Italy

David S. Cooper, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD

Since publication of their article, the authors report no further potential conflict of interest.

  1. 1. Lillevang-Johansen M, Abrahamsen B, Jørgensen HL, Brix TH, Hegedüs L. Excess mortality in treated and untreated hyperthyroidism is related to cumulative periods of low serum TSH. J Clin Endocrinol Metab 2017;102:23012309.

  2. 2. Li D, Radulescu A, Shrestha RT, et al. Association of biotin ingestion with performance of hormone and nonhormone assays in healthy adults. JAMA 2017;318:11501160.

  3. 3. Koulouri O, Moran C, Halsall D, Chatterjee K, Gurnell M. Pitfalls in the measurement and interpretation of thyroid function tests. Best Pract Res Clin Endocrinol Metab 2013;27:745762.

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