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
- ↑ Jump up to: 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.
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/10681281
- ↑ Solomon DH, in: UCLA Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 12-15, 2001
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/14722150 - ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/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
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/15684146
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/16314541
Walsh JP et al, Subclinical thyroid function as a risk factor for cardiovascular disease Arch Intern Med 2005; 165:2467 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16314542
Crapo LM Subclinical hypothyroidism and cardiovascular disease Arch Intern Med 2005; 165:2451 PMID: https://www.ncbi.nlm.nih.gov/pubmed/16314538 - ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/19240148
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/21098345
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/17636722 - ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/22438233 <Internet> http://jcem.endojournals.org/content/97/6/1962
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/2252918 - ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/15572717
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/24100714 <Internet> http://archinte.jamanetwork.com/article.aspx?articleid=1748795
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/19158193
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/22863386
- ↑ Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012 Mar 24;379(9821):1142-54. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22273398
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/28122781 <Internet> http://www.bmj.com/content/356/bmj.i6865
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/28249140 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMe1615312 - ↑ Jump up to: 24.0 24.1 Biondi B, Cappola AR, Cooper DS. Subclinical hypothyroidism: a review. JAMA. 2019;322(2):153-160 PMID: https://www.ncbi.nlm.nih.gov/pubmed/31287527 Review. https://jamanetwork.com/journals/jama/fullarticle/2737687
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/26601696
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/26885359 Free PMC Article
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/11519506 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMcp010145
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/26714213
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/28657873 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMcp1611144 - ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/31088853 https://www.bmj.com/content/365/bmj.l2006
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/21346066
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/31664429 https://jamanetwork.com/journals/jama/fullarticle/2753909
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/32031647 Free Article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2760440
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/32365355 https://annals.org/aim/article-abstract/2765669/l-thyroxine-therapy-older-adults-subclinical-hypothyroidism-hypothyroid-symptoms-secondary
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/33566107 Free article https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2776099
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/34152358 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2781314 - ↑ Jump up to: 39.0 39.1 Brito JP et al. Levothyroxine use in the United States, 2008-2018. JAMA Intern Med 2021 Jun 21; PMID: https://www.ncbi.nlm.nih.gov/pubmed/34152370 PMCID: PMC8218227 (available on 2022-06-21) https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2781311
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/33872585 https://www.amjmed.com/article/S0002-9343(21)00222-9/fulltext
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/34491268 PMCID: PMC8424529 Free PMC article https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2783799
- ↑ Jump up to: 42.0 42.1 Tabatabaie V, Surks MI. The aging thyroid. Curr Opin Endocrinol Diabetes Obes. 2013 Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23974775
- ↑ Jump up to: 43.0 43.1 NEJM Knowledge+
- ↑ Jump up to: 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://www.ncbi.nlm.nih.gov/pubmed/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://www.ncbi.nlm.nih.gov/pubmed/34953533 Review.