Subclinical thyroid disorders are commonly encountered in the primary care setting. This article aims to review the latest evidence and guidelines pertaining to the management of subclinical hypo- and hyperthyroidism, in particular the important decision of when treatment should be considered.
GarberJRCobinRHGharibHHennesseyJVKleinIMechanickJI. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract2012;18(6):988–1028 doi: 10.4158/EP12280.GL.
SurksMIOrtizEDanielsGHSawinCTColNFCobinRH. Subclinical thyroid disease: Scientific review and guidelines for diagnosis and management. JAMA2004;291(2):228–38 doi: 10.1001/jama.291.2.228.
WongETBradleySGSchultzAL. Elevations of thyroid-stimulating hormone during acute nonthyroidal illness. Arch Intern Med1981;141(7):873–5 doi: 10.1001/archinte.1981.00340070053012.
6.
Beck-PeccozPAmrSMenezes-FerreiraMMFagliaGWeintraubBD. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. N Engl J Med1985;312(17):1085–90 doi: 10.1056/NEJM198504253121703.
7.
PersaniLFerrettiEBorgatoSFagliaGBeck-PeccozP. Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J Clin Endocrinol Metab2000;85(10):3631–5 doi: 10.1210/jc.85.10.3631.
8.
AbdullatifHDAshrafA P. Reversible subclinical hypothyroidism in the presence of adrenal insufficiency. Endocr Pract2006;12(5):572–5 doi: 10.4158/EP.12.5.572.
9.
StrykerTDMolitchME. Reversible hyperthyrotropinemia, hyperthyroxinemia, and hyperprolactinemia due to adrenal insufficiency. Am J Med1985;79(2):271–6 doi: 10.1016/0002-9343(85)90022-1.
SurksMIOcampoE. Subclinical thyroid disease. Am J Med1996;100(2):217–23 doi: 10.1016/S0002-9343(97)89462-4.
14.
BiondiBCooperDS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev2008;29(1):76–131 doi: 10.1210/er.2006-0043.
15.
HollowellJGStaehlingNWFlandersWDHannonWHGunterEWSpencerCA. 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 Metab2002;87(2):489–99 doi: 10.1210/jcem.87.2.8182.
16.
ChuoAMLLimJKH. Thyroid dysfunction in elderly patients. Ann Acad Med Singapore2003;32(1):96–100.
17.
WartofskyLDickeyRA. The evidence for a narrower thyrotropin reference range is compelling. J Clin Endocrinol Metab2005;90(9):5483–8 doi: 10.1210/jc.2005-0455.
18.
SurksMIGoswamiGDanielsGH. The thyrotropin reference range should remain unchanged. J Clin Endocrinol Metab2005;90(9):5489–96 doi: 10.1210/jc.2005-0170.
19.
BrabantGBeck-PeccozPJarzabBLaurbergPOrgiazziJSzabolcsI. Is there a need to redefine the upper normal limit of TSH?Eur J Endocrinol2006;154(5):633–7 doi: 10.1530/eje.1.02136.
20.
VanderpumpMPTunbridgeWMFrenchJMAppletonDBatesDClarkF. The incidence of thyroid disorders in the community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol1995;43(1):55–68 doi: 10.1111/j.1365-2265.1995.tb01894.x.
21.
DiezJJIglsiasPBurmanKD. Spontaneous normalization of thyrotropin concentrations in patients with subclinical hypothyroidism. J Clin Endocrinol Metab2005;90(7):4124–7 doi: 10.1210/jc.2005-0375.
22.
RosenthalMJHuntWCGarryPJGoodwinJS. Thyroid failure in the elderly: Microsomal antibodies as discriminant for therapy. JAMA1987;258(2):209–13 doi: 10.1001/jama.1987.03400020051029.
23.
DíezJJIglesiasP. 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 Metab2004;89(10):4890–7 doi: 10.1210/jc.2003-032061.
24.
HuberGStaubJJMeierCMitracheCGuglielmettiMHuberP. Prospective study of the spontaneous course of subclinical hypothyroidism: Prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab2002;87(7):3221–6 doi: 10.1210/jcem.87.7.8678.
25.
KabadiUM. ‘Subclinical hypothyroidism’. Natural course of the syndrome during a prolonged follow-up study. Arch Intern Med1993;153(8):957–61 doi: 10.1001/archinte.1993.00410080025004.
26.
MooreDC. Natural course of ‘subclinical’ hypothyroidism in childhood and adolescence. Arch Pediatr Adolesc Med1996;150(3):293–7 doi: 10.1001/archpedi.1996.02170280063012.
27.
RallisonMLDobynsBMMeikleAWBishopMLyonJLStevensW. Natural history of thyroid abnormalities: Prevalence, incidence, and regression of thyroid diseases in adolescents and young adults. Am J Med1991;91(4):363–70 doi: 10.1016/0002-9343(91)90153-O.
28.
UtigerRD. Vanishing hypothyroidism. N Engl J Med. 1992;326(8):562–3 doi: 10.1056/NEJM199202203260810.
29.
MeyerovitchJRotman-PikielnyPSherfMBattatELevyYSurksMI. Serum thyrotropin measurements in the community: Five-year follow-up in a large network of primary care physicians. Arch Intern Med2007;167(14):1533–8 doi: 10.1001/archinte.167.14.1533.
30.
CappolaARFriedL PArnoldAMDaneseMDKullerLHBurkeGL. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA2006;295(9):1033–41 doi: 10.1001/jama.295.9.1033.
31.
SgarbiJAMatsumuraLKKasamatsuTSFerreiraSRMacielRMB. Subclinical thyroid dysfunctions are independent risk factors for mortality in a 7.5-year follow-up: The Japanese-Brazilian thyroid study. Eur J Endocrinol2010;162(3):569–77 doi: 10.1530/EJE-09-0845.
32.
BoekholdtSMTitanSMWiersingaWMChatterjeeKBasartDCGLubenR. Initial thyroid status and cardiovascular risk factors: The EPIC-Norfolk prospective population study. Clin Endocrinol2010;72(3):404–10 doi: 10.1111/j.1365-2265.2009.03640.x.
33.
RodondiNNewmanABVittinghoffEde RekeneireNSatterfieldSHarrisTB. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med2005;165(21):2460–6 doi: 10.1001/archinte.165.21.2460.
34.
OchsNAuerRBauerDCNanchenDGusseklooJCornuzJ. Meta-analysis: Subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med2008;148(11):832–45 doi: 10.7326/0003-4819-148-11-200806030-00225.
35.
RazviSShakoorAVanderpumpMWeaverJUPearceSHS. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: A metaanalysis. J Clin Endocrinol Metab2008;93(8):2998–3007 doi: 10.1210/jc.2008-0167.
36.
McQuadeCSkugorMBrennanDMHoarBStevensonCHoogwerfBJ. Hypothyroidism and moderate subclinical hypothyroidism are associated with increased all-cause mortality independent of coronary heart disease risk factors: A PreCIS database study. Thyroid2011;21(8):837–43 doi: 10.1089/thy.2010.0298.
37.
RazviSWeaverJUButlerTJPearceSHS. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med2012;172(10):811–7 doi: 10.1001/archinternmed.2012.1159.
38.
RodondiNden ElzenWPJBauerDCCappolaARRazviSWalshJ P. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA2010;304(12):1365–74 doi: 10.1001/jama.2010.1361.
39.
RazviSWeaverJUVanderpumpMPPearceSHS. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: Reanalysis of the Whickham Survey cohort. J Clin Endocrinol Metab2010;95(4):1734–40 doi: 10.1210/jc.2009-1749.
40.
GencerBColletT-HVirginiVAuerRRodondiN. Subclinical thyroid dysfunction among prospective cohort studies and cardiovascular outcomes. Endocr Metab Immune Disord Drug Targets. 2013;13(1):4–12 doi: 10.2174/1871530311313010003.
41.
TsengF-YLinW-YLinC-CLeeL-TLiT-CSungP-K. Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults. J Am Coll Cardiol2012;60(8):730–7 doi: 10.1016/j.jacc.2012.03.047.
42.
HylandKAArnoldAMLeeJSCappolaAR. Persistent subclinical hypothyroidism and cardiovascular risk in the elderly: The cardiovascular health study. J Clin Endocrinol Metab2013;98(2):533–40 doi: 10.1210/jc.2012-2180.
43.
MonzaniFICaraccioNKozàkowàMDardanoAVittoneFVirdisA. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: A double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2004 May 1;89(5):2099–106 doi: 10.1210/jc.2003-031669.
44.
KvetnyJHeldgaardPEBladbjergEMGramJ. Subclinical hypothyroidism is associated with a low-grade inflammation, increased triglyceride levels and predicts cardiovascular disease in males below 50 years. Clin Endocrinol2004;61(2):232–8 doi: 10.1111/j.1365-2265.2004.02088.x.
45.
CikimASOflazHOzbeyNCikimKUmmanSMericM. Evaluation of endothelial function in subclinical hypothyroidism and subclinical hyperthyroidism. Thyroid2004;14(8):605–9 doi: 10.1089/1050725041692891.
CaiYRenYShiJ. Blood pressure levels in patients with subclinical thyroid dysfunction: A meta-analysis of cross-sectional data. Hypertens Res2011;34(10):1098–105 doi: 10.1038/hr.2011.91.
48.
HakAEPolsHAVisserTJDrexhageHAHofmanAWittemanJC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: The Rotterdam Study. Ann Intern Med2000;132(4):270–8 doi: 10.7326/0003-4819-132-4-200002150-00030.
49.
ImaizumiMAkahoshiMIchimaruSNakashimaEHidaASodaM. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab2004;89(7):3365–70 doi: 10.1210/jc.2003-031089.
50.
BindelsAJGHWestendorpRGJFrolichMSeidellJCBlokstraASmeltAHM. The prevalence of subclinical hypothyroidism at different total plasma cholesterol levels in middle aged men and women: A need for case-finding?Clin Endocrinol1999;50(2):217–20 doi: 10.1046/j.1365-2265.1999.00638.x.
51.
KanayaAMHarrisFVolpatoSPerez-StableEJHarrisTBauerDC. Association between thyroid dysfunction and total cholesterol level in an older biracial population: The health, aging and body composition study. Arch Intern Med2002;162(7):773–9 doi: 10.1001/archinte.162.7.773.
52.
VierhapperHNardiAGrosserPRaberWGesslA. Low-density lipoprotein cholesterol in subclinical hypothyroidism. Thyroid2000;10(11):981–4 doi: 10.1089/thy.2000.10.981.
53.
RodondiNBauerDCCappolaARCornuzJRobbinsJFriedL P. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure: The cardiovascular health study. J Am Coll Cardiol2008;52(14):1152–9 doi: 10.1016/j.jacc.2008.07.009.
54.
GencerBColletTHVirginiVBauerDCGusseklooJCappolaAR. Subclinical thyroid dysfunction and the risk of heart failure events: An individual participant data analysis from 6 prospective cohorts. Circulation2012; 126(9): 1040–9 doi: 10.1161/CIRCULATIONAHA.112.096024.
55.
CorreiaNMullallySCookeGTunTKPhelanNFeeneyJ. Evidence for a specific defect in hippocampal memory in overt and subclinical hypothyroidism. J Clin Endocrinol Metab2009;94(10):3789–97 doi: 10.1210/jc.2008-2702.
56.
GilnoerD. The regulation of thyroid function in pregnancy: Pathways of endocrine adaptation from physiology to pathology. Endocr Rev1997;18(3):404–33 doi: 10.1210/edrv.18.3.0300.
57.
LazarusJH. Thyroid function in pregnancy. Br Med Bull.72011;97(1):137–48 doi: 10.1093/bmb/ldq039.
58.
BrentGA. Maternal thyroid function: Interpretation of thyroid function tests in pregnancy. Clin Obstet Gynecol1997;40(1):3–15.
59.
De GrootLAbalovichMAlexanderEKAminoNBarbourLCobinRH. Management of thyroid dysfunction during pregnancy and postpartum: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab2012;97(8):2543–65 doi: 10.1210/jc.2011-2803.
60.
AllanWCHaddowJEPalomakiGEWilliamsJRMitchellMLHermosRJ. Maternal thyroid deficiency and pregnancy complications: Implications for population screening. J Med Screen2000;7(3):127–30 doi: 10.1136/jms.7.3.127.
61.
LeungASMillarLKKooningsPPMontoroMMestmanJH. Perinatal outcome in hypothyroid pregnancies. Int J Obstet Gynecol1993;81(3):349–53.
62.
AbalovichMGutierrezSAlcarazGMaccalliniGGarciaALevalleO. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid2002;12(1):63–8 doi: 10.1089/105072502753451986.
63.
LiYShanZTengWYuXLiYFanC. Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25–30 months. Clin Endocrinol2010;72(6):825–9 doi: 10.1111/j.1365-2265.2009.03743.x.
64.
ReidSMMiddletonPCossichMCCrowtherCABainE. Interventions for clinical and subclinical hypothyroidism pre-pregnancy and during pregnancy. Cochrane Database Syst Rev2013;5:CD007752 doi: 10.1002/14651858.CD007752.pub3.
65.
SurksMIHollowellJG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: Implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab2007;92(12):4575–82 doi: 10.1210/jc.2007-1499.
66.
PasqualettiGTogniniSPoliniACaraccioNMonzaniF. Is subclinical hypothyroidism a cardiovascular risk factor in the elderly?J Clin Endocrinol Metab2013;98(6):2256–66 doi: 10.1210/jc.2012-3818.
67.
NanchenDGusseklooJWestendorpRGJStottDJJukemaJWTrompetS. Subclinical thyroid dysfunction and the risk of heart failure in older persons at high cardiovascular risk. J Clin Endocrinol Metab2012;97(3):852–61 doi: 10.1210/jc.2011-1978.
68.
GusseklooJvan ExcelECraenAMeindersAFrolichMWestendorpR. Thyroid status, disability and cognitive function, and survival in old age. JAMA2004;292:2591–9. doi: 10.1001/jama.292.21.2591.
69.
BiondiB. The normal TSH reference range: What has changed in the last decade?J Clin Endocrinol Metab2013;98(9):3584–7 doi: 10.1210/jc.2013-2760.
70.
SurksMI. Subclinical thyroid dysfunction: A joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. J Clin Endocrinol Metab2005;90(1):581–5; discussion 586–587 doi: 10.1210/jc.2004-1869.
71.
McDermottMTRidgwayEC. Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab2001;86(10):4585–90 doi: 10.1210/jcem.86.10.7959.
72.
HennesseyJ VEvaulJETsengYCBurmanKDWartofskyL. L-thyroxine dosage: A reevaluation of therapy with contemporary preparations. Ann Intern Med1986;105(1):11–5 doi: 10.7326/0003-4819-105-1-11.
73.
FishLHSchwartzHLCavanaughJSteffesMWBantleJPOppenheimerJH. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med1987;316(13):764–70 doi: 10.1056/NEJM198703263161302.
74.
RosenbaumRLBarzelUS. Clinical hypothyroidism in the elderly—a preventable disorder?J Am Geriatr Soc1981;29(5):221–3.
75.
MillerMJPanCBarzelUS. The prevalence of subclinical hypothyroidism in adults with low-normal blood thyroxine levels. N Y State J Med1990;90(11):541–4.
76.
MeierCStaubJJRothCBGuglielmettiMKunzMMiserezAR. 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 Metab2001;86(10):4860–6 doi: 10.1210/jcem.86.10.7973.
77.
TeixeiraPFSReutersVSFerreiraMMAlmeidaC PReisFAAMeloBA. Treatment of subclinical hypothyroidism reduces atherogenic lipid levels in a placebo-controlled double-blind clinical trial. Horm Metab Res2008;40(1):50–5 doi: 10.1055/s-2007-993216.
78.
RodondiNBauerDC. Subclinical hypothyroidism and cardiovascular risk: How to end the controversy. J Clin Endocrinol Metab2013;98(6):2267–9 doi: 10.1210/jc.2013-1875.
79.
ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29–. Identifier NCT 01660126, Thyroid Hormone Replacement for Subclinical Hypothyroidism; 2012 Aug 6 [cited 2014 Jun 30]; [about 4 screens]. Available from: http://clinicaltrials.gov/show/NCT01660126.
80.
BiondiBPalmieriEAKlainMSchlumbergerMFilettiSLombardiG. Subclinical hyperthyroidism: Clinical features and treatment options. Eur J Endocrinol2005;152(1): 1–9 doi: 10.1530/eje.1.01809.
81.
CooperDS. Approach to the patient with subclinical hyperthyroidism. J Clin Endocrinol Metab2007;92(1):3–9 doi: 10.1210/jc.2006-2472.
82.
LewisGFAlessiCAImperialJGRefetoffS. Low serum free thyroxine index in ambulating elderly is due to a resetting of the threshold of thyrotropin feedback suppression. J Clin Endocrinol Metab1991;73(4):843–9 doi: 10.1210/jcem-73-4-843.
83.
PapiGPearceENBravermanLEBetterleCRotiE. A clinical and therapeutic approach to thyrotoxicosis with thyroid-stimulating hormone suppression only. Am J Med2005;118(4):349–61 doi: 10.1016/j.amjmed.2005.01.004.
84.
BiondiBFilettiSSchlumbergerM. Thyroid-hormone therapy and thyroid cancer: A reassessment. Nat Clin Pract Endocrinol Metab2005;1(1): 32–40 doi: 10.1038/ncpendmet0020.
85.
CooperDSDohertyGMHaugenBRKloosRTLeeSLMandelSJ. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid2006;16(2):109–42 doi: 10.1089/thy.2006.16.109.
86.
SomwaruLLArnoldAMJoshiNFriedL PCappolaAR. High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over. J Clin Endocrinol Metab2009;94(4):1342–5 doi: 10.1210/jc.2008-1696.
87.
ParleJVFranklynJACrossKWJonesSRSheppardMC. Thyroxine prescription in the community: Serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment. Br J Gen Pract J R Coll Gen Pract. 1993;43(368):107–9.
88.
MarquseeEHadenSTUtigerRD. Subclinical thyrotoxicosis. Endocrinol Metab Clin North Am1998;27(1):37–49.
89.
ParleJ VFranklynJACrossKWJonesSCSheppardMC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol1991;34(1):77–83 doi: 10.1111/j.1365-2265.1991.tb01739.x.
90.
BagchiNBrownTRParishRF. Thyroid dysfunction in adults over age 55 years. A study in an urban US community. Arch Intern Med1990;150(4):785–7 doi: 10.1001/archinte.150.4.785.
91.
TunbridgeWMEveredDCHallRAppletonDBrewisMClarkF. The spectrum of thyroid disease in a community: The Whickham survey. Clin Endocrinol1977;7(6):481–93 doi: 10.1111/j.1365-2265.1977.tb01340.x.
92.
BellRJRivera-WollLDavisonSLToplissDJDonathSDavisSR. Well-being, health-related quality of life and cardiovascular disease risk profile in women with subclinical thyroid disease — a community-based study. Clin Endocrinol2007;66(4):548–56 doi: 10.1111/j.1365-2265.2007.02771.x.
93.
BembenDAHammRMMorganLWinnPDavisABartonE. Thyroid disease in the elderly. Part 2. Predictability of subclinical hypothyroidism. J Fam Pract1994;38(6):583–8.
94.
WilsonGRCurryRW. Subclinical thyroid disease. Am Fam Physician2005;72(8):1517–24.
95.
DuggalJSinghSBarsanoCPAroraR. Cardiovascular risk with subclinical hyperthyroidism and hypothyroidism: Pathophysiology and management. J Cardiometab Syndr2007;2:198–206 doi: 10.1111/j.1559-4564.2007.06583.x.
96.
WoeberKA. Observations concerning the natural history of subclinical hyperthyroidism. Thyroid2005;15(7):687–91 doi: 10.1089/thy.2005.15.687.
97.
YangLJiangDQiWZhangTFengYGaoL. Subclinical hyperthyroidism and the risk of cardiovascular events and all-cause mortality: An updated meta-analysis of cohort studies. Eur J Endocrinol2012;167(1):75–84 doi: 10.1530/EJE-12-0015.
98.
BiondiBFazioSCarellaCAmatoGCittadiniALupoliG. Cardiac effects of long term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab1993;77(2):334–8 doi: 10.1210/jcem.77.2.8345037.
99.
GulluSAltuntasFDincerIErolCKamelN. Effects of TSH-suppressive therapy on cardiac morphology and function: Beneficial effects of the addition of betablockade on diastolic dysfunction. Eur J Endocrinol2004;150(5):655–61 doi: 10.1530/eje.0.1500655.
100.
SmitJWAEustatia-RuttenCFACorssmitEPMPereiraAMFrolichMBleekerGB. Reversible diastolic dysfunction after long-term exogenous subclinical hyperthyroidism: A randomized, placebo-controlled study. J Clin Endocrinol Metab2005;90(11):6041–7 doi: 10.1210/jc.2005-0620.
101.
ShargorodskyMSerovSGavishDLeibovitzEHarpazDZimlichmanR. Long-term thyrotropin-suppressive therapy with levothyroxine impairs small and large artery elasticity and increases left ventricular mass in patients with thyroid carcinoma. Thyroid2006;16(4):381–6 doi: 10.1089/thy.2006.16.381.
102.
ForfarJCFeekCMMillerHCToftAD. Atrial fibrillation and isolated suppression of the pituitary-thyroid axis: Response to specific antithyroid therapy. Int J Cardiol1981;1(1):43–8 doi: 10.1016/0167-5273(81)90047-4.
103.
MercuroGPanzutoMGBinaALeoMCabulaRPetriniL. Cardiac function, physical exercise capacity, and quality of life during long-term thyrotropin-suppressive therapy with levothyroxine: Effect of individual dose tailoring. J Clin Endocrinol Metab2000;85(1):159–64 doi: 10.1210/jcem.85.1.6298.
104.
BiondiBFazioSCuocoloASabatiniDNicolaiELombardiG. Impaired cardiac reserve and exercise capacity in patients receiving long-term thyrotropin suppressive therapy with levothyroxine. J Clin Endocrinol Metab1996;81(12):4224–8 doi: 10.1210/jcem.81.12.8954019.
105.
PortellaRBda C SilvaJLWagmanMBde OliveiraF PBuescuAVaismanM. Exercise performance in young and middle-aged female patients with subclinical hyperthyroidism. Thyroid2006;16(8):731–5 doi: 10.1089/thy.2006.16.731.
106.
SgarbiJAVillaçaFGGarbelineBVillarHERomaldiniJH. The effects of early antithyroid therapy for endogenous subclinical hyperthyroidism in clinical and heart abnormalities. J Clin Endocrinol Metab2003;88(4):1672–7 doi: 10.1210/jc.2002-021046.
107.
BiondiBPalmieriEAFazioSCoscoCNoceraMSaccaL. Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab2000;85(12):4701–5 doi: 10.1210/jcem.85.12.7085.
108.
PetrettaMBonaduceDSpinelliLVicarioMLNuzzoVMarcianoF. Cardiovascular haemodynamics and cardiac autonomic control in patients with subclinical and overt hyperthyroidism. Eur J Endocrinol2001;145(6):691–6 doi: 10.1530/eje.0.1450691.
109.
TamerISarginMSarginHSekerMBabalikETekceM. The evaluation of left ventricular hypertrophy in hypertensive patients with subclinical hyperthyroidism. Endocr J2005;52(4):421–5 doi: 10.1507/endocrj.52.421.
110.
ColletT-HGusseklooJBauerDCden ElzenWPJCappolaARBalmerP. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med2012;172(10):799–809 doi: 10.1001/archinternmed.2012.402.
111.
HeeringaJHoogendoornEHvan der DeureWMHofmanAPeetersR PHopWC. High-normal thyroid function and risk of atrial fibrillation: The Rotterdam study. Arch Intern Med2008;168(20):2219–24 doi: 10.1001/archinte.168.20.2219.
112.
SawinCTGellerAWolfPABelangerAJBakerEBacharachP. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med1994;331:1249–52 doi: 10.1056/NEJM199411103311901.
113.
TenerzAForbergRJanssonR. Is a more active attitude warranted in patients with subclinical thyrotoxicosis?J Intern Med1990;228(3):229–33 doi: 10.1111/j.1365-2796.1990.tb00223.x.
114.
AuerJScheibnerPMischeTLangstegerWEberOEberB. Subclinical hyperthyroidism as a risk factor for atrial fibrillation. Am Heart J2001;142(5):838–42 doi: 10.1067/mhj.2001.119370.
115.
ParleJ VMaisonneuvePSheppardMCBoylePFranklynJA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: A 10-year cohort study. Lancet2001;358(9285):861–5 doi: 10.1016/S0140-6736(01)06067-6.
116.
FoldesJTarjanGSzathmariMVargaFKrasznaiIHorvathC. Bone mineral density in patients with endogenous subclinical hyperthyroidism: Is this thyroid status a risk factor for osteoporosis?Clin Endocrinol1993;39(5):521–7 doi: 10.1111/j.1365-2265.1993.tb02403.x.
117.
GurlekAGedikO. Effect of endogenous subclinical hyperthyroidism on bone metabolism and bone mineral density in premenopausal women. Thyroid1999;9(6):539–43 doi: 10.1089/thy.1999.9.539.
118.
UzzanBCamposJCucheratMNonyPBoisselJ PPerretGY. Effects on bone mass of long term treatment with thyroid hormones: A meta-analysis. J Clin Endocrinol Metab1996;81(12):4278–89 doi: 10.1210/jcem.81.12.8954028.
119.
FaberJGalloeAM. Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treatment: A meta-analysis. Eur J Endocrinol1994;130(4):350–6 doi: 10.1530/eje.0.1300350.
120.
KungAWYeungSS. Prevention of bone loss induced by thyroxine suppressive therapy in postmenopausal women: The effect of calcium and calcitonin. J Clin Endocrinol Metab1996;81(3):1232–6.
121.
MarcocciCGoliaFVignaliEPincheraA. Skeletal integrity in men chronically treated with suppressive doses of L-thyroxine. J Bone Miner Res1997;12(1):72–7 doi: 10.1359/jbmr.1997.12.1.72.
122.
FranklynJABetteridgeJDaykinJHolderROatesGDParleJV. Long-term thyroxine treatment and bone mineral density. Lancet1992;340(8810):9–13 doi: 10.1016/0140-6736(92)92423-D.
123.
GorresGKaimAOtteAGotzeMMuller-BrandJ. Bone mineral density in patients receiving suppressive doses of thyroxine for differentiated thyroid carcinoma. Eur J Nucl Med1996;23(6):690–2 doi: 10.1007/BF00834532.
124.
Bauer DC, Ettinger B, Nevitt MC, Stone KL, Study of Osteoporotic Fractures Research Group. Risk for fracture in women with low serum levels of thyroid-stimulating hormone. Ann Intern Med2001;134(7):561–8 doi: 10.7326/0003-4819-134-7-200104030-00009.
125.
FlynnRWBonellieSRJungRTMacDonaldTMMorrisADLeeseG P. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab2010;95(1):186–93 doi: 10.1210/jc.2009-1625.
126.
LeeseG PJungRTGuthrieCWaughNBrowningMC. Morbidity in patients on L-thyroxine: A comparison of those with a normal TSH to those with a suppressed TSH. Clin Endocrinol1992;37(6):500–3 doi: 10.1111/j.1365-2265.1992.tb01480.x.
127.
FaberJJensenIWPetersenLNygaardBHegedusLSiersbaek-NielsenK. Normalization of serum thyrotrophin by means of radioiodine treatment in subclinical hyperthyroidism: Effect on bone loss in postmenopausal women. Clin Endocrinol1998;48(3):285–90 doi: 10.1046/j.1365-2265.1998.00427.x.
128.
MuddeAHHoubenAJKrusemanAC Nieuwenhuijzen. Bone metabolism during anti-thyroid drug treatment of endogenous subclinical hyperthyroidism. Clin Endocrinol1994;41(4):421–4 doi: 10.1111/j.1365-2265.1994.tb02571.x.
129.
KumedaYInabaMTaharaHKuriokaYIshikawaTMoriiH. Persistent increase in bone turnover in Graves' patients with subclinical hyperthyroidism. J Clin Endocrinol Metab2000;85(11):4157–61 doi: 10.1210/jcem.85.11.6979.
130.
LeeJSBuzkováPFinkHAVuJCarboneLChenZ. Subclinical thyroid dysfunction and incident hip fracture in older adults. Ann Intern Med2010;170(21):1876–83 doi: 10.1001/archinternmed.2010.424.
131.
GarinMCArnoldAMLeeJSRobbinsJCappolaAR. Subclinical thyroid dysfunction and hip fracture and bone mineral density in older adults: The cardiovascular health study. J Clin Endocrinol Metab2014:jc20141051 doi: 10.1210/jc.2014-1051.
132.
YonemODokmetasHSAslanSMErselcanT. Is antithyroid treatment really relevant for young patients with subclinical hyperthyroidism?Endocr J2002; 49(3):307–14 doi: 10.1507/endocrj.49.307.
133.
KalmijnSMehtaKMPolsHAHofmanADrexhageHABretelerMM. Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study. Clin Endocrinol2000;53:733–7 doi: 10.1046/j.1365-2265.2000.01146.x.
134.
DobertNHamschoNMenzelCPetersJFrolichLTsolakisA. Subclinical hyperthyroidism in dementia and correlation of the metabolic index in FDG-PET. Acta Med Austriaca2003;30:130–3.
135.
BensenorIMLotufoPAMenezesPRScazufcaM. Subclinical hyperthyroidism and dementia: The Sao Paulo Ageing & Health Study (SPAH). BMC Public Health2010;10:298 doi: 10.1186/1471-2458-10-298.
136.
RobertsLMPattisonHRoalfeAFranklynJWilsonSHobbsFDR. Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction?Ann Intern Med2006;145(8):573–81 doi: 10.7326/0003-4819-145-8-200610170-00006.
137.
Van der CammenTJMMattace-RasoFvan HarskampFde JagerM-C. Lack of association between thyroid disorders and Alzheimer's disease in older persons: A cross-sectional observational study in a geriatric outpatient population. J Am Geriatr Soc2003;51(6) doi: 10.1046/j.1365-2389.2003.51278.x.
138.
BallabioMPoshychindaMEkinsRP. Pregnancy-induced changes in thyroid function: Role of human chorionic gonadotropin as putative regulator of maternal thyroid. J Clin Endocrinol Metab1991;73(4):824–31 doi: 10.1210/jcem-73-4-824.
139.
YeoC PKhooDHEngPHTanHKYoSLJacobE. Prevalence of gestational thyrotoxicosis in Asian women evaluated in the 8th to 14th weeks of pregnancy: Correlations with total and free beta human chorionic gonadotrophin. Clin Endocrinol2001;55(3):391–8 doi: 10.1046/j.1365-2265.2001.01353.x.
140.
GoodwinTMMontoroMMestmanJHPerkaryAEHershmanJM. The role of chorionic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum. J Clin Endocrinol Metab1992;75(5):1333–7 doi: 10.1210/jcem.75.5.1430095.
141.
YamazakiKSatoKShizumeKKanajiYItoYObaraT. Potent thyrotropic activity of human chorionic gonadotropin variants in terms of 125I incorporation and de novo synthesized thyroid hormone release in human thyroid follicles. J Clin Endocrinol Metab1995;80(2):473–9 doi: 10.1210/jc.80.2.473.
142.
KimuraMAminoNTamakiHItoEMitsudaNMiyaiK. Gestational thyrotoxicosis and hyperemesis gravidarum: Possible role of hCG with higher stimulating activity. Clin Endocrinol1993;38(4):345–50 doi: 10.1111/j.1365-2265.1993.tb00512.x.
143.
HershmanJM. Human chorionic gonadotropin and the thyroid: Hyperemesis gravidarum and trophoblastic tumors. Thyroid1999;9(7):653–7 doi: 10.1089/thy.1999.9.653.
144.
BahnRSBurchHBCooperDSGarberJRGreenleeMCKleinI. Hyperthyroidism and other causes of thyrotoxicosis: Management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid2011;21(6):593–646 doi: 10.1089/thy.2010.0417.
145.
LaurbergPBournaudCKarmisholtJOrgiazziJ. Management of Graves' hyperthyroidism in pregnancy: Focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy. Eur J Endocrinol2009;160(1):1–8 doi: 10.1530/EJE-08-0663.
PalaciosSSPascual-CorralesEGalofreJC. Management of subclinical hyperthyroidism. Int J Endocrinol Metab2012;10(2):490–6 doi: 10.5812/ijem.3447.
148.
BestJDChanVKhooRTengCSWangCYeungRT. Incidence of hypothyroidism after radioactive iodine therapy for thyrotoxicosis in Hong Kong Chinese. Clin Radiol1981;32(1):57–61 doi: 10.1016/S0009-9260(81)80253-X.
149.
GooldenAWStewartJS. Long-term results from graded low dose radioactive iodine therapy for thyrotoxicosis. Clin Endocrinol1986;24(2):217–22 doi: 10.1111/j.1365-2265.1986.tb00765.x.
150.
FaberJWiinbergNSchifterSMehlsenJ. Haemodynamic changes following treatment of subclinical and overt hyperthyroidism. Eur J Endocrinol2001;145(4):391–6 doi: 10.1530/eje.0.1450391.
151.
HoogendoornEHden HeijerMvan DijkAPJHermusAR. Subclinical hyperthyroidism: To treat or not to treat?Postgrad Med J2004;80(945):394–8 doi: 10.1136/pgmj.2003.017095.
152.
ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29–. Identifier NCT 0151723, Does Radioiodine Treatment Prevent Atrial Fibrillation and Bone Loss in Endogenous Subclinical Hyperthyroidism?; 2005 Sep 8 [cited 2014 Jul 9]; [about 4 screens]. Available from: http://clinicaltrials.gov/show/NCT0151723.
153.
ISRCTN [Internet]. London: Current Controlled Trials, c/o BioMed Central. 2010. Identifier ISRCTN66874446, UK Trial of Radioiodine Intervention in Subclinical Hyperthyroidism; 2005 Dec 16 [cited 2014 Jun 30]; [1 page]. Available from: http://www.controlled-trials.com/ISRCTN66874446.