subclinical hypothyroidism
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Etiology
- auto-immune
- pharmaceutical agents
- lithium
- amiodarone or pharmaceuticals containing iodide
Epidemiology
- 11% of elderly, 3% of younger population[9]
Clinical manifestations
- as the name would imply, patients with subclinical hypothyroidism are asymptomatic[40]
Laboratory
- normal levels of serum T3 & serum T4
- serum free T4 may be low-normal
- measurement of serum T3 is not necessary[1]
- increased levels of serum TSH*
- values of 5-15 mIU/L are characteristic
- repeat thyroid function tests 6-12 weeks after initial testing - values normalize in up to 30% of patients[1]
- anti-thyroid antibodies may herald a failing thyroid
- thyroid peroxidase antibody in serum
- thyroglobulin antibody in serum
- no indication to check serum thyroglobulin[43]
- lipid panel (elevated serum LDL cholesterol)
* normal range for serum TSH increases with age
Complications
- possible increased risk of atherosclerosis & myocardial infarction[2]
- increased risk of coronary artery disease & mortality[15]
- cardiovascular disease mediates associations of subclinical hypothyroidism with all-cause mortality in the US general population[35]
- adverse cardiovascular risks confined to patients < 65 years of age[19]
- in the elderly, subclinical hypothyroidism may be a good prognostic indicator[18]
- increased risk of mortality in the elderly (RR = 1.77)*[29]
- increased risk of adverse outcomes of pregnancy
- placental abruption (RR = 3.0)
- preterm delivery (RR = 1.8)
- respiratory distress
- admission to NICU
- increased risk of hip fracture in men (HR=2.3), but not women[13]
- no increase in risk of cognitive impairment[15][41]
* threshold serum TSH > 6.35 mIU/L[29]
Management
- patients are presumably mildly symptomatic & could benefit from treatment with thyroxine if
- serum TSH > 10 uIU/mL, or
- cardiovascular disease, or
- elevated serum LDL cholesterol, or
- pregnant or desire to become pregnant*, or
- family history of hypothyroidism, or
- goiter, or
- positive anti-thyroid antibodies makes it likely disorder will progress to frank hypothyroidism
- high symptom burden not a reason to treat subclinical hypothyroidism in the elderly[36]
- benefits of treatment may include:
- more favorable lipid profile
- reduced risk of cardiovascular events in patients < 70 years of age[8][13] (39% reduction)[13]
- some benefits of levothyroxine treatment in reducing cardiovascular events[26]
- supplementation with levothyroxine has not been shown to mitigate cardiovascular risk[1] (MKSAP17)
- no evidence to support treatment[1][4]
- USPSTF recommends against routine treatment[4]
- no benefit of levothyroxine for older adults with subclinical hypothyroidism unless serum TSH > 10 mIU/L[24][30][31][38]
- no evidence for treating elderly subjects with T4 to improve cognition[11][25]
- no benefit for treating elderly >+ 80 years of age[34]
- no benefit for prevention or treatment of mood disorders including depression or thyroid-related quality of life[27][37]
- benefit for treatment of dyslipidemia, diabetes is conflicting[26]
- older patients should not be treated with T4 solely for elevated serum TSH[1][16]
- higher serum TSH & lower serum free T4 in elderly Askenazni Jews is associated with extreme longevity[18]
- authors suggest treatment of subclinical hypothyroidism in the elderly may be harmful
- do not treat subclinical hypothyroidism unless serum TSH > 10 mIU/L[33][38]
- <10% of new levothyroxine prescriptions are for overt hypothyroidism
- mean TSH level at which levothyroxine is initiated is ~5.5 mIU/L[39]
- prognosis:
- may progress to overt hypothyroidism[4]
- 6%* with serum TSH of 5.0-9.0 mIU/L (52% normalize TSH)[5]
- 86%* with serum TSH of 15.0-19.9 mIU/L[5]
- serum TSH normalized in 61% of elderly with one instance of subclinical hypothyroidism & 40% of elderly with 2 instances separated by 1 year[44]
- normalization of serum TSH more likely in women negative for thyroid peroxidase antibody in serum[44] * progression to overt hypothyroidism within 3.5 years
- no evidence that early treatment is of benefit[4]
- TSH generally normalizes within 5 years if TSH < 10 mIU/L[7]
- in the elderly, resolution 46% with serum TSH of < 7 mIU/L, 10% with serum TSH > 7 mIUL[14]
- may progress to overt hypothyroidism[4]
* treatment of pregnant women with subclinical hypothyroidism associated with:
- reduced risk for pregnancy loss (11% vs 14%)
- increased risk for preterm delivery (7% vs 5%)
- increased risk for preeclampsia (5.5% vs 4%)
- increased risk for gestational diabetes (12% vs 9%)[22]
- no improvement in cognition of offspring[23]
Notes
- frequently overtreated[17]
More general terms
Additional terms
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2022.
Medical Knowledge Self Assessment Program (MKSAP) 20 American College of Physicians, Philadelphia 2025 - ↑ 2.0 2.1 Journal Watch 20(6):51, 2000 Hak AE et al Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med 132:270, 2000 PMID: https://pubmed.ncbi.nlm.nih.gov/10681281
- ↑ Solomon DH, in: UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
- ↑ 4.0 4.1 4.2 4.3 4.4 Journal Watch 24(5):41, 2004 US Preventive Services Task Force (USPSTF), Ann Intern Med 140:125, 2004 http://www.ahrq.gov/clinic/3rduspstf/thyroid/thyrrs.htm Helfand M, Ann Intern Med 140:128 <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/14734337 <Internet> http://www.endo-society.org/education/evidence-report.cfm
Surks MI et al Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 291:228, 2004 PMID: https://pubmed.ncbi.nlm.nih.gov/14722150 - ↑ 5.0 5.1 5.2 Journal Watch 24(23):174-75, 2004 Diez JJ, Iglesias P. Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab. 2004 Oct;89(10):4890-7. PMID: https://pubmed.ncbi.nlm.nih.gov/15472181
- ↑ Prescriber's Letter 12(1): 2005 Subclinical Hypothyroidism: To Treat or Not to Treat Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=210123&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 7.0 7.1 Journal Watch 25(6):50, 2005 Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, Cunningham FG. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol. 2005 Feb;105(2):239-45. PMID: https://pubmed.ncbi.nlm.nih.gov/15684146
- ↑ 8.0 8.1 Rodondi N et al, Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death Arch Intern Med 2005; 165:2460 PMID: https://pubmed.ncbi.nlm.nih.gov/16314541
Walsh JP et al, Subclinical thyroid function as a risk factor for cardiovascular disease Arch Intern Med 2005; 165:2467 PMID: https://pubmed.ncbi.nlm.nih.gov/16314542
Crapo LM Subclinical hypothyroidism and cardiovascular disease Arch Intern Med 2005; 165:2451 PMID: https://pubmed.ncbi.nlm.nih.gov/16314538 - ↑ 9.0 9.1 Surks MI & Hollowell JG Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: Implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab 2007, 92:4575 PMID: https://pubmed.ncbi.nlm.nih.gov/17911171
- ↑ Lazar L et al Natural history of thyroid function tests over 5 years in a large pediatric cohort. J Clin Endocrinol Metab 2009 May; 94:1678 PMID: https://pubmed.ncbi.nlm.nih.gov/19240148
- ↑ 11.0 11.1 Parle J et al. A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: The Birmingham Elderly Thyroid Study. J Clin Endocrinol Metab 2010 Aug; 95:3623. PMID: https://pubmed.ncbi.nlm.nih.gov/20501682
- ↑ Lee JS et al. Subclinical thyroid dysfunction and incident hip fracture in older adults. Arch Intern Med 2010 Nov 22; 170:1876 PMID: https://pubmed.ncbi.nlm.nih.gov/21098345
- ↑ 13.0 13.1 13.2 13.3 Razvi S et al. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med 2012 Apr 23 <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/22529180 <Internet> http://general-medicine.jwatch.org/cgi/content/full/2012/508/2?q=etoc_jwgenmed
Razvi S, Ingoe L, Keeka G, Oates C, McMillan C, Weaver JU. The beneficial effect of L-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial. J Clin Endocrinol Metab. 2007 May;92(5):1715-23. PMID: https://pubmed.ncbi.nlm.nih.gov/17299073
Villar HC, Saconato H, Valente O, Atallah AN Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD003419. PMID: https://pubmed.ncbi.nlm.nih.gov/17636722 - ↑ 14.0 14.1 Somwaru LL et al. The natural history of subclinical hypothyroidism in the elderly: The Cardiovascular Health Study. J Clin Endocrinol Metab 2012 Jun; 97:1962. <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/22438233 <Internet> http://jcem.endojournals.org/content/97/6/1962
- ↑ 15.0 15.1 15.2 Collet TH, Gussekloo J, Bauer DC, et al. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med 2012; 172(10):799-809 PMID: https://pubmed.ncbi.nlm.nih.gov/22529182
Burman KD. What is the clinical importance of subclinical hyperthyroidism? Comment on "Subclinical hyperthyroidism and the risk of coronary heart disease and mortality." Arch Intern Med 2012; 17(10):809-810 PMID: https://pubmed.ncbi.nlm.nih.gov/2252918 - ↑ 16.0 16.1 Journal Watch 25(2):18, 2005 Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frolich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004 Dec 1;292(21):2591-9. PMID: https://pubmed.ncbi.nlm.nih.gov/15572717
- ↑ 17.0 17.1 Taylor PN et al Falling Threshold for Treatment of Borderline Elevated Thyrotropin Levels - Balancing Benefits and Risks. Evidence From a Large Community-Based Study. JAMA Intern Med. Published online October 07, 2013. <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/24100714 <Internet> http://archinte.jamanetwork.com/article.aspx?articleid=1748795
- ↑ 18.0 18.1 18.2 Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab. 2009 Apr;94(4):1251-4 PMID: https://pubmed.ncbi.nlm.nih.gov/19158193
- ↑ 19.0 19.1 Ochs N, Auer R, Bauer DC et al Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med. 2008 Jun 3;148(11):832-45 PMID: https://pubmed.ncbi.nlm.nih.gov/18490668
- ↑ Biondi B Natural history, diagnosis and management of subclinical thyroid dysfunction. Best Pract Res Clin Endocrinol Metab. 2012 Aug;26(4):431-46. PMID: https://pubmed.ncbi.nlm.nih.gov/22863386
- ↑ Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012 Mar 24;379(9821):1142-54. Review. PMID: https://pubmed.ncbi.nlm.nih.gov/22273398
- ↑ 22.0 22.1 Maraka S, Mwangi R, McCoy RG et al Thyroid hormone treatment among pregnant women with subclinical hypothyroidism: US national assessment. BMJ 2017;356:i6865 <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/28122781 <Internet> http://www.bmj.com/content/356/bmj.i6865
- ↑ 23.0 23.1 Casey BM, Thom EA, Peaceman AM et al. Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. N Engl J Med 2017 Mar 2; 376:815. <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/28249134 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1606205
Cooper DS, Pearce EN. Subclinical hypothyroidism and hypothyroxinemia in pregnancy
still no answers. N Engl J Med 2017 Mar 2; 376:876. <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/28249140 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMe1615312 - ↑ 24.0 24.1 Biondi B, Cappola AR, Cooper DS. Subclinical hypothyroidism: a review. JAMA. 2019;322(2):153-160 PMID: https://pubmed.ncbi.nlm.nih.gov/31287527 Review. https://jamanetwork.com/journals/jama/fullarticle/2737687
- ↑ 25.0 25.1 Ojala AK, Schalin-Jantti C, Pitkala KH et al Serum thyroid-stimulating hormone and cognition in older people. Age Ageing. 2016 Jan;45(1):155-7. PMID: https://pubmed.ncbi.nlm.nih.gov/26601696
- ↑ 26.0 26.1 26.2 Javed Z, Sathyapalan T. Levothyroxine treatment of mild subclinical hypothyroidism: a review of potential risks and benefits. Ther Adv Endocrinol Metab. 2016 Feb;7(1):12-23. Review. PMID: https://pubmed.ncbi.nlm.nih.gov/26885359 Free PMC Article
- ↑ 27.0 27.1 Feller M, Snel M, Moutzouri E et al. Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism: a systematic review and meta-analysis. JAMA. 2018;320(13):1349-1359 PMID: https://pubmed.ncbi.nlm.nih.gov/30285179 PMCID: PMC6233842 Free PMC article https://jamanetwork.com/journals/jama/fullarticle/2705188
- ↑ Toft AD. Subclinical Hyperthyroidism. N Engl J Med 2001; 345:512-516. August 16, 2001 <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/11519506 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMcp010145
- ↑ 29.0 29.1 29.2 Grossman A, Weiss A, Koren-Morag N, et al. Subclinical thyroid disease and mortality in the elderly: a retrospective cohort study. Am J Med. 2016;129:423-430 PMID: https://pubmed.ncbi.nlm.nih.gov/26714213
- ↑ 30.0 30.1 Stott DJ, Rodondi N, Kearney PM et al for the TRUST Study Group Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. N Engl J Med 2017; 376:2534-2544. June 29, 2017 <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/28402245 Free Article <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1603825
Peeters RP Subclinical Hypothyroidism. N Engl J Med 2017; 376:2556-2565. June 29, 2017 <PubMed> PMID: https://pubmed.ncbi.nlm.nih.gov/28657873 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMcp1611144 - ↑ 31.0 31.1 Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
- ↑ Bekkering GE, Agoritsas T, Lytvyn L et al Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ 2019;365:l2006 PMID: https://pubmed.ncbi.nlm.nih.gov/31088853 https://www.bmj.com/content/365/bmj.l2006
- ↑ 33.0 33.1 Vadiveloo T, Donnan PT, Cochrane L, Leese GP. The Thyroid Epidemiology, Audit, and Research Study (TEARS): morbidity in patients with endogenous subclinical hyperthyroidism. J Clin Endocrinol Metab. 2011 May;96(5):1344-51. PMID: https://pubmed.ncbi.nlm.nih.gov/21346066
- ↑ 34.0 34.1 Mooijaart SP, Du Puy RS, Stott DJ et al Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism. JAMA. Published online October 30, 2019 PMID: https://pubmed.ncbi.nlm.nih.gov/31664429 https://jamanetwork.com/journals/jama/fullarticle/2753909
- ↑ 35.0 35.1 Inoue K, Ritz B, Brent GA et al Association of Subclinical Hypothyroidism and Cardiovascular Disease With Mortality. JAMA Netw Open. 2020;3(2):e1920745. Feb 7. PMID: https://pubmed.ncbi.nlm.nih.gov/32031647 Free Article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2760440
- ↑ 36.0 36.1 de Montmollin M, Feller M, Beglinger S L-Thyroxine Therapy for Older Adults With Subclinical Hypothyroidism and Hypothyroid Symptoms: Secondary Analysis of a Randomized Trial. Ann Intern Med. 2020. May 5 PMID: https://pubmed.ncbi.nlm.nih.gov/32365355 https://annals.org/aim/article-abstract/2765669/l-thyroxine-therapy-older-adults-subclinical-hypothyroidism-hypothyroid-symptoms-secondary
- ↑ 37.0 37.1 Wildisen L, Feller M, Del Giovane C et al Effect of Levothyroxine Therapy on the Development of Depressive Symptoms in Older Adults With Subclinical Hypothyroidism. An Ancillary Study of a Randomized Clinical Trial. JAMA Netw Open. 2021;4(2):e2036645 Feb 10 PMID: https://pubmed.ncbi.nlm.nih.gov/33566107 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2776099
- ↑ 38.0 38.1 38.2 Brito JP, Ross JS, El Kawkgi OM et al Levothyroxine Use in the United States, 2008-2018. JAMA Intern Med. Published online June 21, 2021 PMID: https://pubmed.ncbi.nlm.nih.gov/34152370 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2781311
Silverstein WK, Grady D Overuse of Levothyroxine in Patients With Subclinical Hypothyroidism. Time to "Leve"-Out-Thyroxine. JAMA Intern Med. Published online June 21, 2021 PMID: https://pubmed.ncbi.nlm.nih.gov/34152358 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2781314 - ↑ 39.0 39.1 Brito JP et al. Levothyroxine use in the United States, 2008-2018. JAMA Intern Med 2021 Jun 21; PMID: https://pubmed.ncbi.nlm.nih.gov/34152370 PMCID: PMC8218227 (available on 2022-06-21) https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2781311
- ↑ 40.0 40.1 Carle A, Karmisholt JS, Knudsen N et al. Does subclinical hypothyroidism add any symptoms? Evidence from a Danish population-based study. Am J Med 2021 Sep; 134:1115 PMID: https://pubmed.ncbi.nlm.nih.gov/33872585 https://www.amjmed.com/article/S0002-9343(21)00222-9/fulltext
- ↑ 41.0 41.1 van Vliet NA, van Heemst D, Almeida OP et al. Association of thyroid dysfunction with cognitive function: An individual participant data analysis. JAMA Intern Med 2021 Sep 7; [e-pub]. PMID: https://pubmed.ncbi.nlm.nih.gov/34491268 PMCID: PMC8424529 Free PMC article https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2783799
- ↑ 42.0 42.1 Tabatabaie V, Surks MI. The aging thyroid. Curr Opin Endocrinol Diabetes Obes. 2013 Review. PMID: https://pubmed.ncbi.nlm.nih.gov/23974775
- ↑ 43.0 43.1 NEJM Knowledge+
- ↑ 44.0 44.1 44.2 van der Spoel E, van Vliet NA, Poortvliet RKE et al. Incidence and determinants of spontaneous normalization of subclinical hypothyroidism in older adults. J Clin Endocrinol Metab 2024 Mar; 109:e1167. PMID: https://pubmed.ncbi.nlm.nih.gov/37862463 PMCID: PMC10876405 Free PMC article https://academic.oup.com/jcem/article/109/3/e1167/7325863
- ↑ Biondi B, Cappola AR. Subclinical hypothyroidism in older individuals. Lancet Diabetes Endocrinol. 2022 Feb;10(2):129-141. PMID: https://pubmed.ncbi.nlm.nih.gov/34953533 Review.
- ↑ Urgatz B, Razvi S. Subclinical hypothyroidism, outcomes and management guidelines: a narrative review and update of recent literature. Curr Med Res Opin. 2023;39:351-365. PMID: https://pubmed.ncbi.nlm.nih.gov/36632720
- ↑ Ross DS. Treating hypothyroidism is not always easy: When to treat subclinical hypothyroidism, TSH goals in the elderly, and alternatives to levothyroxine monotherapy. J Intern Med. 2022 Feb;291(2):128-140. PMID: https://pubmed.ncbi.nlm.nih.gov/34766382 Free article. Review. https://onlinelibrary.wiley.com/doi/10.1111/joim.13410