Subclinical Thyroid Disease: Scientific Review and Guidelines for Diagnosis and Management | Atrial Fibrillation | JAMA | JAMA Network
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1.
Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado Thyroid Disease Prevalence Study.  Arch Intern Med.2000;160:526-534.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10695693&dopt=AbstractGoogle Scholar
2.
Cooper DS. Clinical practice: subclinical hypothyroidism.  N Engl J Med.2001;345:260-265.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11474665&dopt=AbstractGoogle Scholar
3.
Toft AD. Clinical practice: subclinical hyperthyroidism.  N Engl J Med.2001;345:512-516.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11519506&dopt=AbstractGoogle Scholar
4.
Surks MI, Ocampo E. Subclinical thyroid disease.  Am J Med.1996;100:217-223.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8629658&dopt=AbstractGoogle Scholar
5.
McDermott MT, Ridgway EC. Clinical perspective: subclinical hypothyroidism is mild thyroid failure and should be treated.  J Clin Endocrinol Metab.2001;86:4585-4590.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11600507&dopt=AbstractGoogle Scholar
6.
Chu JW, Crapo LM. Clinical perspective: the treatment of subclinical hypothyroidism is seldom necessary.  J Clin Endocrinol Metab.2001;86:4591-4599.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11600508&dopt=AbstractGoogle Scholar
7.
Baskin HJ. American Association of Clinical Endocrinologists guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism.  Endocr Practice.2002;8:458-467.Google Scholar
8.
Ladenson PW, Singer PA, Ain KB.  et al.  American Thyroid Association guidelines for detection of thyroid dysfunction.  Arch Intern Med.2000;160:1573-1575.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10847249&dopt=AbstractGoogle Scholar
9.
US Preventive Services Task Force, Agency for Healthcare Research and Quality Web site.  Third USPSTF strength of overall evidence. Available at: http://www.ahrq.gov/clinic/3rduspstf/prostatescr/prostaterr.htm#overall. Accessed December 9, 2002.
10.
Spencer CA, Takeuchi M, Kazarosyan M. Current status and performance goals for serum thyrotropin (TSH) assays.  Clin Chem.1996;42:2051-2052.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8969655&dopt=AbstractGoogle Scholar
11.
National Academy of Clinical Biochemistry Web site.  NACB laboratory medicine practice guidelines. Available at: http://www.nacb.org/lmpg/main.stm. Accessed December 9, 2002.
12.
Ross DS. Serum thyroid-stimulating hormone measurement for assessment of thyroid function and disease.  Endocrinol Metab Clin North Am.2001;30:245-264.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11444162&dopt=AbstractGoogle Scholar
13.
Surks MI, Oppenheimer JH. Metabolism of phenolic- and tyrosyl-ring labeled L-thyroxine in human beings and rats.  J Clin Endocrinol Metab.1971;33:612-618.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=5093766&dopt=AbstractGoogle Scholar
14.
Wong ET, Bradley SG, Schultz AL. Elevations of thyroid-stimulating hormone during acute nonthyroidal illness.  Arch Intern Med.1981;141:873-875.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7235805&dopt=AbstractGoogle Scholar
15.
Bhakri HL, Fisher R, Khadri A, MacMahon DG. Longitudinal study of thyroid function in acutely ill elderly patients using a sensitive TSH assay—defer testing until recovery.  Gerontology.1990;36:140-144.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2121624&dopt=AbstractGoogle Scholar
16.
Gharib H, Hodgson SF, Gastineau CF, Scholz DA, Smith LA. Reversible hypothyroidism in Addison's disease.  Lancet.1972;2:734-736.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4116146&dopt=AbstractGoogle Scholar
17.
Ismail AA, Burr WA, Walker PL. Acute changes in serum thyrotropin in treated Addison's disease.  Clin Endocrinol (Oxf).1989;30:225-230.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2591055&dopt=AbstractGoogle Scholar
18.
Ladenson PW, Braverman LE, Mazzaferri EL.  et al.  Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma.  N Engl J Med.1997;337:888-896.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9302303&dopt=AbstractGoogle Scholar
19.
Brennan MD, Klee GG, Preissner CM, Hay ID. Heterophilic serum antibodies: a cause for falsely elevated serum thyrotropin levels.  Mayo Clin Proc.1987;62:894-898.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3657306&dopt=AbstractGoogle Scholar
20.
Wood JM, Gordon DL, Rudinger AN, Brooks MM. Artifactual elevation of thyroid-stimulating hormone.  Am J Med.1991;90:261-262.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1996596&dopt=AbstractGoogle Scholar
21.
Ward G, McKinnon L, Badrick T, Hickman PE. Heterophilic antibodies remain a problem for the immunoassay laboratory.  Am J Clin Pathol.1997;108:417-421.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9322595&dopt=AbstractGoogle Scholar
22.
Beck-Peccoz P, Amr S, Menezes-Ferreira MM, Faglia G, Weintraub BD. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism: effect of treatment with thyrotropin-releasing hormone.  N Engl J Med.1985;312:1085-1090.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2984564&dopt=AbstractGoogle Scholar
23.
Hollowell JG, Staehling NW, Flanders WD.  et al.  Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III).  J Clin Endocrinol Metab.2002;87:489-499.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11836274&dopt=AbstractGoogle Scholar
24.
Vanderpump MP, Tunbridge WM, French JM.  et al.  The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey.  Clin Endocrinol (Oxf).1995;43:55-68.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7641412&dopt=AbstractGoogle Scholar
25.
Uy HL, Reasner CA, Samuels MH. Pattern of recovery of the hypothalamic-pituitary thyroid axis following radioiodine therapy in patients with Graves' disease.  Am J Med.1995;99:173-179.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7625422&dopt=AbstractGoogle Scholar
26.
Glinoer D, De Nayer P, Bourdoux P.  et al.  Regulation of maternal thyroid during pregnancy.  J Clin Endocrinol Metab.1990;71:276-282.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2116437&dopt=AbstractGoogle Scholar
27.
Wehmann RE, Gregerman RI, Burns WH, Saral R, Santos GW. Suppression of thyrotropin in the low-thyroxine state of severe nonthyroidal illness.  N Engl J Med.1985;312:546-552.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3881675&dopt=AbstractGoogle Scholar
28.
Franklyn JA, Black EG, Betteridge J, Sheppard MC. Comparison of second and third generation methods for measurement of serum thyrotropin in patients with overt hyperthyroidism, patients receiving thyroxine therapy and those with non-thyroidal illness.  J Clin Endocrinol Metab.1994;78:1368-1371.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8200938&dopt=AbstractGoogle Scholar
29.
Van den Berghe G, de Zegher F, Lauwers P. Dopamine and the sick euthyroid syndrome in critical illness.  Clin Endocrinol (Oxf).1994;41:731-737.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7889608&dopt=AbstractGoogle Scholar
30.
Benker G, Raida M, Olbricht T, Wagner R, Reinhardt W, Reinwein D. TSH secretion in Cushing's syndrome: relation to glucocorticoid excess, diabetes, goiter, and the "sick euthyroid syndrome."  Clin Endocrinol (Oxf).1990;33:777-786.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2128925&dopt=AbstractGoogle Scholar
31.
Hangaard J, Andersen M, Grodum E, Koldkjaer O, Hagen C. Pulsatile thyrotropin secretion in patients with Addison's disease during variable glucocorticoid therapy.  J Clin Endocrinol Metab.1996;81:2502-2507.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8675567&dopt=AbstractGoogle Scholar
32.
Lee E, Chen P, Rao H, Lee J, Burmeister LA. Effect of acute high dose dobutamine administration on serum thyrotropin (TSH).  Clin Endocrinol (Oxf).1999;50:487-492.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10468908&dopt=AbstractGoogle Scholar
33.
Sawin CT, Castelli WP, Hershman JM.  et al.  The aging thyroid: thyroid deficiency in the Framingham Study.  Arch Intern Med.1985;145:1386-1388.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4026469&dopt=AbstractGoogle Scholar
34.
Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom.  Clin Endocrinol (Oxf).1991;34:77-83.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2004476&dopt=AbstractGoogle Scholar
35.
Robuschi G, Safran M, Braverman LE.  et al.  Hypothyroidism in the elderly.  Endocr Rev.1987;8:142-153.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3301318&dopt=AbstractGoogle Scholar
36.
Kung AW, Janus ED. Thyroid dysfunction in ambulatory elderly Chinese subjects in an area of borderline iodine intake.  Thyroid.1996;6:111-114.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8733881&dopt=AbstractGoogle Scholar
37.
Sawin CT. Subclinical hypothyroidism in older persons.  Clin Geriatr Med.1995;11:231-238.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7606692&dopt=AbstractGoogle Scholar
38.
Laurberg P, Pedersen KM, Vestergaard H.  et al.  High incidence of multinodular toxic goiter in the elderly population in a low iodine intake area vs high incidence of Graves' disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland.  J Intern Med.1991;229:415-420.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2040867&dopt=AbstractGoogle Scholar
39.
Ross DS, Daniels GH, Gouveia D. The use and limitations of a chemiluminescent thyrotropin assay as a single thyroid function test in an outpatient endocrine clinic.  J Clin Endocrinol Metab.1990;71:764-769.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2394778&dopt=AbstractGoogle Scholar
40.
Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC. Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment.  Br J Gen Pract.1993;43:107-109.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8323787&dopt=AbstractGoogle Scholar
41.
Sawin CT, Geller A, Kaplan MM.  et al.  Low serum thyrotropin (thyroid-stimulating hormone) in older persons without hyperthyroidism.  Arch Intern Med.1991;151:165-168.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1985591&dopt=AbstractGoogle Scholar
42.
Stott DJ, McLellan AR, Finlayson J.  et al.  Elderly patients with suppressed serum TSH but normal free thyroid hormone levels usually have mild thyroid overactivity and are at increased risk of developing overt hyperthyroidism.  QJM.1991;78:77-84.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1670067&dopt=AbstractGoogle Scholar
43.
Sawin CT, Geller A, Wolf PA.  et al.  Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons.  N Engl J Med.1994;331:1249-1252.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7935681&dopt=AbstractGoogle Scholar
44.
Stanbury JB, Ermans AE, Bourdoux P.  et al.  Iodine-induced hyperthyroidism: occurrence and epidemiology.  Thyroid.1998;8:83-100.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9492158&dopt=AbstractGoogle Scholar
45.
Monzani F, DiBello V, Caraccio N.  et al.  Effect of levothyroxine on cardiac function and structure.  J Clin Endocrinol Metab.2001;86:1110-1115.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11238494&dopt=AbstractGoogle Scholar
46.
Kahaly GJ. Cardiovascular and atherogenic aspects of subclinical hypothyroidism.  Thyroid.2000;10:665-679.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11014311&dopt=AbstractGoogle Scholar
47.
Biondi B, Fazio S, Palmieri EA.  et al.  Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism.  J Clin Endocrinol Metab.1999;84:2064-2067.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10372711&dopt=AbstractGoogle Scholar
48.
Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of subclinical thyroid dysfunction on the heart.  Ann Intern Med.2002;137:904-914.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12458990&dopt=AbstractGoogle Scholar
49.
Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study.  Ann Intern Med.2000;132:270-278.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10681281&dopt=AbstractGoogle Scholar
50.
Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study.  Lancet.2001;358:861-865.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11567699&dopt=AbstractGoogle Scholar
51.
Danese MD, Ladenson PW, Meinert CL, Powe NR. Effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature.  J Clin Endocrinol Metab.2000;85:2993-3001.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10999775&dopt=AbstractGoogle Scholar
52.
Kanaya A, Harris F, Volpato S.  et al.  Association between thyroid dysfunction and total cholesterol level in an older biracial population.  Arch Intern Med.2002;162:773-779.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11926850&dopt=AbstractGoogle Scholar
53.
Zulewski H, Muller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls.  J Clin Endocrinol Metab.1997;82:771-776.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9062480&dopt=AbstractGoogle Scholar
54.
Monzani F, Caraccio N, DelGuerra P.  et al.  Neuromuscular symptoms and dysfunction in subclinical hypothyroid patients: beneficial effect of L-T4 replacement therapy.  Clin Endocrinol (Oxf).1999;51:237-242.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10468996&dopt=AbstractGoogle Scholar
55.
Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-thyroxine therapy in subclinical hypothyroidism: a double-blind, placebo-controlled trial.  Ann Intern Med.1984;101:18-24.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6428290&dopt=AbstractGoogle Scholar
56.
Meier C, Staub JJ, Roth CB.  et al.  TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double-blind, placebo-controlled trial (Basel Thyroid Study).  J Clin Endocrinol Metab.2001;86:4860-4866.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11600554&dopt=AbstractGoogle Scholar
57.
Kong WM, Sheikh MH, Lumb PJ.  et al.  A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism.  Am J Med.2002;112:348-354.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11904108&dopt=AbstractGoogle Scholar
58.
Bemben DA, Hamm RM, Morgan L, Winn P, Davis A, Barton E. Thyroid disease in the elderly, part 2: predictability of subclinical hypothyroidism.  J Fam Pract.1994;38:583-588.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8195732&dopt=AbstractGoogle Scholar
59.
Lindeman RD, Schade DS, LaRue A.  et al.  Subclinical hypothyroidism in a biethnic urban community.  J Am Geriatr Soc.1999;47:703-709.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10366170&dopt=AbstractGoogle Scholar
60.
Nystrom E, Caidahl K, Fager G, Wikkelso C, Lundberg PA, Lindstedt G. A double-blind cross-over 12-month study of L-thyroxine treatment of women with ‘subclinical' hypothyroidism.  Clin Endocrinol (Oxf).1988;29:63-76.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3073880&dopt=AbstractGoogle Scholar
61.
Huber G, Staub JJ, Meier C.  et al.  Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies.  J Clin Endocrinol Metab.2002;87:3221-3226.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12107228&dopt=AbstractGoogle Scholar
62.
Caraccio N, Ferrannini E, Monzani F. Lipoprotein profile in subclinical hypothyroidism: response to levothyroxine replacement, a randomized placebo-controlled study.  J Clin Endocrinol Metab.2002;87:1533-1538.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11932277&dopt=AbstractGoogle Scholar
63.
Haddow JE, Palomaki GE, Allan WC.  et al.  Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.  N Engl J Med.1999;341:549-555.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10451459&dopt=AbstractGoogle Scholar
64.
Wiersinga WM. Subclinical hypothyroidism and hyperthyroidism, I: prevalence and clinical relevance.  Neth J Med.1995;46:197-204.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7760971&dopt=AbstractGoogle Scholar
65.
Haden ST, Marqusee E, Utiger RD. Subclinical hyperthyroidism.  Endocrinologist.1996;6:322-327.Google Scholar
66.
Marqusee E, Haden ST, Utiger RD. Subclinical thyrotoxicosis.  Endocrinol Metab Clin North Am.1998;27:37-49.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9534026&dopt=AbstractGoogle Scholar
67.
Samuels MH. Subclinical thyroid disease in the elderly.  Thyroid.1998;8:803-813.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9777754&dopt=AbstractGoogle Scholar
68.
Tenerz A, Forberg R, Jansson R. Is a more active attitude warranted in patients with subclinical thyrotoxicosis?  J Intern Med.1990;228:229-233.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2401873&dopt=AbstractGoogle Scholar
69.
Auer J, Scheiber P, Mische T.  et al.  Subclinical hyperthyroidism as a risk factor for atrial fibrillation.  Am Heart J.2001;142:838-842.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11685172&dopt=AbstractGoogle Scholar
70.
Biondi B, Fazio S, Cuocolo A.  et al.  Impaired cardiac reserve and exercise capacity in patients receiving long-term thyrotropin suppressive therapy with levothyroxine.  J Clin Endocrinol Metab.1996;81:4224-4228.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8954019&dopt=AbstractGoogle Scholar
71.
Biondi B, Palmieri EA, Fazio S.  et al.  Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients.  J Clin Endocrinol Metab.2000;85:4701-4705.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11134131&dopt=AbstractGoogle Scholar
72.
Shapiro LE, Sievert R, Ong L.  et al.  Minimal cardiac effects in asymptomatic athyrotic patients chronically treated with thyrotropin (TSH)-suppressive doses of L-thyroxine (T4).  J Clin Endocrinol Metab.1997;82:2592-2595.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9253339&dopt=AbstractGoogle Scholar
73.
Boutin JM, Matte R, D'Amour P.  et al.  Characteristics of patients with normal T3 and T4 and a low TSH response to TRH.  Clin Endocrinol (Oxf).1986;25:579-588.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2887310&dopt=AbstractGoogle Scholar
74.
Faber J, Wiinberg N, Schiffer S, Mehlsen J. Haemodynamic changes following treatment of subclinical and overt hyperthyroidism.  Eur J Endocrinol.2001;145:391-396.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11580994&dopt=AbstractGoogle Scholar
75.
Grund FM, Niewoehner CB. Hyperthyroxinemia in patients receiving thyroid replacement therapy.  Arch Intern Med.1989;149:921-924.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2705841&dopt=AbstractGoogle Scholar
76.
Fazio S, Biondi B, Carella C.  et al.  Diastolic dysfunction in patients on thyroid-stimulating hormone suppressive therapy with levothyroxine: beneficial effect of beta-blockade.  J Clin Endocrinol Metab.1995;80:2222-2226.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7608283&dopt=AbstractGoogle Scholar
77.
Rockel M, Teuber J, Kaumeier S.  et al.  Correlation of "latent hyperthyroidism" with psychological and somatic changes [in German].  Klin Wochenschr.1987;65:264-273.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3586569&dopt=AbstractGoogle Scholar
78.
Schlote B, Schaaf L, Schmidt R.  et al.  Mental and physical state in subclinical hyperthyroidism: investigations in a normal working population.  Biol Psychiatry.1992;32:48-56.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1391296&dopt=AbstractGoogle Scholar
79.
Foldes J, Tarjan G, Szathmari M.  et al.  Bone mineral density in patients with endogenous subclinical hyperthyroidism: is this thyroid status a risk factor for osteoporosis?  Clin Endocrinol (Oxf).1993;39:521-527.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8252739&dopt=AbstractGoogle Scholar
80.
Foldes J, Lakatos P, Zsadanyi J, Horvath C. Decreased serum IGF-I and dehydroepiandrosterone sulphate may be risk factors for the development of reduced bone mass in postmenopausal women with endogenous subclinical hyperthyroidism.  Eur J Endocrinol.1997;136:277-281.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9100552&dopt=AbstractGoogle Scholar
81.
Faber J, Jensen IW, Petersen L.  et al.  Normalization of serum thyrotrophin by means of radioiodine treatment in subclinical hyperthyroidism: effect on bone loss in postmenopausal women.  Clin Endocrinol (Oxf).1998;48:285-290.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9578817&dopt=AbstractGoogle Scholar
82.
Mudde AH, Houben AJ, Nieuwenhuijzen Kruseman AC. Bone metabolism during antithyroid drug treatment of endogenous subclinical hyperthyroidism.  Clin Endocrinol (Oxf).1994;41:421-424.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7955452&dopt=AbstractGoogle Scholar
83.
Faber J, Galloe AM. Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treatment: a meta-analysis.  Eur J Endocrinol.1994;130:350-356.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8162163&dopt=AbstractGoogle Scholar
84.
Uzzan B, Campos J, Cucherat M.  et al.  Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis.  J Clin Endocrinol Metab.1996;81:4278-4289.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8954028&dopt=AbstractGoogle Scholar
85.
Bauer DC, Nevitt MC, Ettinger B, Stone K. Low thyrotropin levels are not associated with bone loss in older women: a prospective study.  J Clin Endocrinol Metab.1997;82:2931-2936.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9284722&dopt=AbstractGoogle Scholar
86.
Kumeda Y, Inaba M, Tahara H.  et al.  Persistent increase in bone turnover in Graves' patients with subclinical hyperthyroidism.  J Clin Endocrinol Metab.2000;85:4157-4161.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11095447&dopt=AbstractGoogle Scholar
87.
Pantazi H, Papapetrou PD. Changes in parameters of bone and mineral metabolism during therapy for hyperthyroidism.  J Clin Endocrinol Metab.2000;85:1099-1106.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10720046&dopt=AbstractGoogle Scholar
88.
Bauer DC, Ettinger B, Nevitt M, Stone KL.for the Study of Osteoporotic Fractures Research Group.  Risk for fracture in women with low serum levels of thyroid-stimulating hormone.  Ann Intern Med.2001;134:561-568.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12803168&dopt=AbstractGoogle Scholar
89.
Vestergaard P, Mosekilde L. Fractures in patients with hyperthyroidism and hypothyroidism: a nationwide follow-up study in 16,249 patients.  Thyroid.2002;12:411-419.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12097203&dopt=AbstractGoogle Scholar
90.
Staffurth JS, Gibberd MC, Fui SN. Arterial embolism in thyrotoxicosis with atrial fibrillation.  BMJ.1977;2:688-690.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=902055&dopt=AbstractGoogle Scholar
91.
Presti CF, Hart RG. Thyrotoxicosis, atrial fibrillation, and embolism, revisited.  Am Heart J.1989;117:976-977.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2929415&dopt=AbstractGoogle Scholar
92.
Forfar JC, Feek CM, Miller HC, Toft AD. Atrial fibrillation and isolated suppression of the pituitary-thyroid axis: response to specific antithyroid therapy.  Int J Cardiol.1981;1:43-48.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6800967&dopt=AbstractGoogle Scholar
93.
Leese GP, Jung RT, Guthrie C, Waugh N, Browning MC. Morbidity in patients on L-thyroxine: a comparison of those with a normal TSH to those with a suppressed TSH.  Clin Endocrinol (Oxf).1992;37:500-503.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1286519&dopt=AbstractGoogle Scholar
94.
Hallengren B, Elmstahl B, Berglund J.  et al.  No increase in fracture incidence in patients treated for thyrotoxicosis in Malmo during 1970-74: a 20-year population-based follow-up.  J Intern Med.1999;246:139-144.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10447782&dopt=AbstractGoogle Scholar
95.
Weetman AP. Graves' disease.  N Engl J Med.2000;343:1236-1248.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11071676&dopt=AbstractGoogle Scholar
96.
US Preventive Services Task Force.  Guide to Clinical Preventive Services, Third Edition: Periodic UpdatesRockville, Md: Agency for Healthcare Research and Quality; 2002. Publication 02-500.
Scientific Review and Clinical Applications
Clinician's Corner
January 14, 2004

Subclinical Thyroid Disease: Scientific Review and Guidelines for Diagnosis and Management

Author Affiliations

Author Affiliations: Departments of Medicine and Pathology, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY (Dr Surks); Center for Primary Care, Prevention, and Clinical Partnerships, Agency for Healthcare Research and Quality, Rockville, Md (Dr Ortiz); Thyroid Unit and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Daniels); Veterans Administration, Washington, DC (Dr Sawin); Harvard Medical School, Brigham and Women's Hospital, Division of Women's Health and Department of Medicine, Boston (Dr Col); Department of Medicine, Mount Sinai School of Medicine, New York, NY (Dr Cobin); Division of Medical Sciences, University of Birmingham, Birmingham, England (Dr Franklyn); Endocrinology and Diabetes Division, West Los Angeles VA Medical Center, University of California at Los Angeles School of Medicine (Dr Hershman); Endocrine Section, Washington Hospital Center, Washington, DC (Dr Burman); Department of Medicine, University of Texas Southwestern Medical Center at Dallas (Dr Denke); Research Development, Mayo Foundation, Rochester, Minn (Dr Gorman); Epidemiology, Loyola University Medical School, Chicago, Ill (Dr Cooper); and Cardiac Ultrasound, Washington Hospital Center, and Department of Medicine, Georgetown University Medical College, Washington, DC (Dr Weissman). Dr Denke is now with the University of Texas, San Antonio.

JAMA. 2004;291(2):228-238. doi:10.1001/jama.291.2.228
Abstract

Context Patients with serum thyroid-stimulating hormone (TSH) levels outside the reference range and levels of free thyroxine (FT4) and triiodothyronine (T3) within the reference range are common in clinical practice. The necessity for further evaluation, possible treatment, and the urgency of treatment have not been clearly established.

Objectives To define subclinical thyroid disease, review its epidemiology, recommend an appropriate evaluation, explore the risks and benefits of treatment and consequences of nontreatment, and determine whether population-based screening is warranted.

Data Sources MEDLINE, EMBASE, Biosis, the Agency for Healthcare Research and Quality, National Guideline Clearing House, the Cochrane Database of Systematic Reviews and Controlled Trials Register, and several National Health Services (UK) databases were searched for articles on subclinical thyroid disease published between 1995 and 2002. Articles published before 1995 were recommended by expert consultants.

Study Selection and Data Extraction A total of 195 English-language or translated papers were reviewed. Editorials, individual case studies, studies enrolling fewer than 10 patients, and nonsystematic reviews were excluded. Information related to authorship, year of publication, number of subjects, study design, and results were extracted and formed the basis for an evidence report, consisting of tables and summaries of each subject area.

Data Synthesis The strength of the evidence that untreated subclinical thyroid disease is associated with clinical symptoms and adverse clinical outcomes was assessed and recommendations for clinical practice developed. Data relating the progression of subclinical to overt hypothyroidism were rated as good, but data relating treatment to prevention of progression were inadequate to determine a treatment benefit. Data relating a serum TSH level higher than 10 mIU/L to elevations in serum cholesterol were rated as fair but data relating to benefits of treatment were rated as insufficient. All other associations of symptoms and benefit of treatment were rated as insufficient or absent. Data relating a serum TSH concentration lower than 0.1 mIU/L to the presence of atrial fibrillation and progression to overt hyperthyroidism were rated as good, but no data supported treatment to prevent these outcomes. Data relating restoration of the TSH level to within the reference range with improvements in bone mineral density were rated as fair. Data addressing all other associations of subclinical hyperthyroid disease and adverse clinical outcomes or treatment benefits were rated as insufficient or absent. Subclinical hypothyroid disease in pregnancy is a special case and aggressive case finding and treatment in pregnant women can be justified.

Conclusions Data supporting associations of subclinical thyroid disease with symptoms or adverse clinical outcomes or benefits of treatment are few. The consequences of subclinical thyroid disease (serum TSH 0.1-0.45 mIU/L or 4.5-10.0 mIU/L) are minimal and we recommend against routine treatment of patients with TSH levels in these ranges. There is insufficient evidence to support population-based screening. Aggressive case finding is appropriate in pregnant women, women older than 60 years, and others at high risk for thyroid dysfunction.

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