Subclinical Hypothyroidism

Shiva Kumar Gosi; Jasleen Kaur; Vishnu Garla

Subclinical Hypothyroidism

Earn CME/CE in your profession:

Free Review Questions

Continuing Education Activity

Subclinical hypothyroidism characteristically presents with normal thyroxine (T4) levels and elevated thyroid stimulating hormone (TSH) levels. The incidence of subclinical hypothyroidism is estimated at 3% to 15%, depending on the population studied. Minor fluctuations in T4 levels result in considerably larger fluctuations in TSH levels. Although TSH levels exhibit wide variability across the population, intra-individual variation remains minimal, which is secondary to a unique individual setpoint within the hypothalamic-pituitary axis for each person. This condition correlates with an increased risk of fatal and non-fatal coronary artery disease events, congestive heart failure, and fatal stroke. This activity reviews the evaluation and management of subclinical hypothyroidism, emphasizing the collaborative role of the interprofessional healthcare team in enhancing patient care. This activity also helps clinicians gain insights into distinguishing characteristics within relevant literature to maximize patient outcomes.

Objectives:

Identify the clinical features and laboratory parameters indicative of subclinical hypothyroidism in patients, including elevated levels of thyroid-stimulating hormone and normal free thyroxine (T4).
Screen at-risk populations, such as individuals with a family history of thyroid disorders, for subclinical hypothyroidism using appropriate laboratory tests.
Select the most suitable thyroid hormone replacement regimen and dosing strategy for patients with subclinical hypothyroidism, considering factors such as age, comorbidities, and medication adherence.
Collaborate with endocrinologists, primary care physicians, and other healthcare professionals to ensure shared decision-making and optimize the care for patients with subclinical hypothyroidism.

Introduction

Subclinical hypothyroidism characteristically presents with normal thyroxine (T4) levels and elevated thyroid stimulating hormone (TSH) levels.[1] Minor fluctuations in T4 levels result in considerably larger changes in TSH levels.[2] Although TSH levels exhibit wide variability across the population, intra-individual variation remains minimal, which is secondary to a unique individual setpoint within the hypothalamic-pituitary axis for each person.[3]

Most individuals have a log-linear relationship between TSH and T4. Still, some individuals can have a nonlinear relationship explaining the normal free T4 with TSH ≥10 mIU/L, while others may have a low T4 level.[4] Various studies have reported the incidence of subclinical hypothyroidism to be estimated at 3% to 10% and increasing to 18% to 20% in older patients, depending on the population studied.[5][6] The prevalence of subclinical hypothyroidism tends to be higher in women and older adults.[7] Observational studies have shown that subclinical hypothyroidism (with TSH ≥10 mIU/L) correlates with an increased risk of fatal and non-fatal coronary artery disease (CAD) events, congestive heart failure, and fatal stroke.[8][9][10]

The prevalence of this disorder is bound to increase due to the increased availability of high-sensitivity thyroid function testing. Levothyroxine is the second most commonly prescribed medication in the United States.[11] The increased recognition and treatment or trials with levothyroxine replacement therapy in patients with subclinical hypothyroidism could partly explain why. A study from the United Kingdom showed an increased trend toward treating hypothyroidism between 2005 and 2014, from 2.3% to 3.5% of the total population.[12]

Etiology

Subclinical hypothyroidism and hypothyroidism share the same etiologies. Worldwide, iodine deficiency is the most common cause of hypothyroidism. However, autoimmune thyroiditis (Hashimoto thyroiditis) is the most common cause of hypothyroidism in the United States. Other causes include post-surgical or post-ablative hypothyroidism, central hypothyroidism, and medication-induced hypothyroidism (lithium, amiodarone, checkpoint inhibitors, and tyrosine kinase inhibitors).[13][14] Higher levels of TSH also occur in individuals with obesity, with TSH levels declining with weight loss.[13][15][16]

Epidemiology

The prevalence of subclinical hypothyroidism varies from 3% to 15% based on the study population.[13][17] Statistical research demonstrates a higher incidence of subclinical hypothyroidism in women and older individuals. Individuals with type 2 diabetes mellitus are also more likely to develop subclinical hypothyroidism.[18] Vanderpump et al, in the Whickham survey, found 8% of women and 3% of men have subclinical hypothyroidism.[6] The risk of subclinical hypothyroidism progression to overt hypothyroidism is 2% to 6% per year.[13] This rate is 3% to 8% in individuals with TSH >10 mIU/L and thyroid peroxidase (TPO) antibody (TPOAb) positivity.[19] The risk of progression to overt hypothyroidism is higher in women, individuals with higher levels of TSH, and individuals with TPOAb positivity.[19][20]

Subclinical hypothyroidism resolved spontaneously in 46% of older participants after 4 years in a prospective study involving 459 individuals aged 65 and older. In another study involving 107 women and men aged 55 or older, spontaneous normalization of TSH occurred in 52% of the participants with TSH <10 mIU/L after a mean follow-up of 32 months.[21] Individuals with TSH <7 mIU/L and TPOAb negativity were more likely to have this resolution.[20]

History and Physical

Subclinical hypothyroidism is asymptomatic most of the time. However, it can present with symptoms of hypothyroidism.[13] Assessing hypothyroid symptoms influences whether thyroid replacement therapy is indicated. The clinical features of hypothyroidism are as follows:[22][14]

Integumentary: Dry skin, hair loss, loss of an outer third of eyebrows, and facial puffiness.
Respiratory: Sleep apnea and hoarseness of voice.
Gastrointestinal: Constipation, dysphagia, loss of appetite, and cholelithiasis.
Cardiovascular: Diastolic hypertension, bradycardia, pericardial effusions, decreased cardiac output, and dyslipidemia, which occur only in severe and sustained hypotension cases.
Neurological: Decreased attention span, pseudodementia, and entrapment neuropathies, with carpal tunnel syndrome being the most frequently encountered.
Musculoskeletal: Muscular weakness, cramps, stiffness, and fatigue.
Reproductive: Irregular periods, menorrhagia, and decreased libido.
Metabolic: Weight gain, cold intolerance, and hyponatremia.

Evaluation

The hallmark laboratory finding of subclinical hypothyroidism is an elevated TSH with a normal T4. However, non-thyroidal illness and some medications can cause an elevation of TSH, and they need to be ruled out before a diagnosis of subclinical hypothyroidism is established. In patients with TSH <10 mIU/L and normal free T4, thyroid blood work should be repeated in 3 to 6 months before initiation of therapy as almost half of these patients have a resolution of the thyroid abnormalities.[17]

TPO antibodies should be checked in patients. If positive for TPO antibodies, this may indicate an autoimmune etiology of hypothyroidism.[22] They correlate with a 2-fold increased risk of progression of subclinical hypothyroidism to overt hypothyroidism.[19][23] The TPO antibody titers decrease with time and do not need repetition. An ultrasound shows a heterogenous and/or atrophic thyroid gland in patients with autoimmune thyroid disease, but this test is not recommended for establishing the diagnosis.[13][24] Since subclinical hypothyroidism has potential associations with cardiovascular disease, congestive heart failure, and cognitive decline, patients should be evaluated for the risk of atherosclerotic cardiovascular disease and other comorbidities.[13]

Treatment / Management

The central question in treating subclinical hypothyroidism is whether to and when to initiate levothyroxine therapy. This decision is challenging, especially for older patients. The factors that need to be considered when deciding on levothyroxine therapy are age, extent of the elevation of TSH, associated cardiovascular risk factors, clinical symptoms of hypothyroidism, and presence of TPOAbs. As a significant proportion of patients with subclinical hypothyroidism have normalization of TSH levels, the first strategy is 'wait and watch.' [25] Repeating TSH levels in 2 to 3 months is essential to confirm sustained elevation of TSH before hormone replacement is initiated.

Both the American Thyroid Association (ATA) and the American Association of Clinical Endocrinology (AACE) recommend starting levothyroxine therapy under the following scenarios:[22]

TSH is >10 mIU/L
Presence of hypothyroid symptoms
Positive TPO antibody
Women of reproductive age

The age and cardiovascular status of patients should be considered. Treatment is recommended with levothyroxine in patients aged 70 or younger with TSH >10 mIU/L without a history of cardiovascular disease.[26] Patients with subclinical hypothyroidism do not need a full dose of levothyroxine replacement. Depending on the level of TSH elevation and symptoms, they can be started on 25 to 75 mcg levothyroxine. In individuals with a history of cardiovascular disease (without symptoms of active disease) and aged 70 or younger, the lowest dose of levothyroxine 25 mcg should be started to assess tolerability.

In individuals aged 70 or older, the decision is made on a case-by-case basis to initiate levothyroxine therapy based on symptoms and history of cardiovascular disease. Patients with TPO antibody positivity can also be started on levothyroxine replacement since these patients have a two-fold risk of progression to overt hypothyroidism. These recommendations do not apply to pregnant women or women trying to conceive. They should be started on levothyroxine replacement for mild thyroid dysfunction, especially when TPOAb is positive, due to a higher risk of worse pregnancy and fetal outcomes.[27][28][29] The threshold for replacement based on TSH values is also different in this population; further discussion on this topic is beyond the scope of this article.

In the Thyroid Hormone Replacement for Untreated older adults with subclinical hypothyroidism—a randomized placebo-controlled Trial (TRUST), a double-blinded, randomized, placebo-controlled trial, 737 adults who were aged 65 or older above with subclinical hypothyroidism (TSH between 4.60 and 19.99 mIU/L and free T4 within the reference range) were included. A total of 368 participants received low-dose levothyroxine of 50 mcg daily, except in patients with body weight less than 50 kg or a history of coronary artery disease. After 1 year, no difference was noted in the treatment and placebo groups for the hypothyroid symptoms scale and tiredness score. No differences were noted in terms of adverse effects.[30]

A Cochrane review in 2017 involving 350 patients from 12 small clinical trials over 6 to 14 months did not show improvement in symptoms, mood, or quality of life metrics with levothyroxine replacement. Improvement was noted in the lipid profile and some echocardiographic parameters, including myocardial relaxation. A difference in adverse events was reported in 4 clinical trials.[31] The Birmingham Elderly Thyroid Study, another randomized controlled trial by Parle et al in 94 community-dwelling individuals aged 65 or older, showed no improvement in cognitive function with low-dose levothyroxine replacement.[32] Grossman et al conducted a case-control study in 1558 individuals with subclinical hypothyroidism and TSH <10 mIU/L, showing an increased mortality risk with levothyroxine replacement. Factors associated with higher mortality were advanced age, senile dementia, history of cerebrovascular disease, congestive heart failure, and chronic renal failure. There was no higher risk of atrial fibrillation or femoral fractures.[33]

Though multiple studies have shown an increased risk of cardiovascular disease and mortality in elderly patients with subclinical hypothyroidism, no long-term clinical trials have evaluated the effect of levothyroxine replacement on these factors.[34] Treatment decisions should not be based solely on these factors.

Differential Diagnosis

Several non-thyroid factors can transiently elevate TSH levels, potentially leading to misdiagnosis as subclinical hypothyroidism. It is crucial to differentiate between these causes of non-thyroidal TSH elevation and true subclinical hypothyroidism. These factors include:

Aging associated with a rise in TSH concentration [35][36]
Nonthyroidal illness [37][38]
Laboratory assay interference [39][40]
Adrenal insufficiency
Chronic renal failure
Certain medications such as amiodarone, lithium, tyrosine kinase inhibitors, checkpoint inhibitors, metoclopramide, amphetamine, ritonavir, and St Johns wort [41][42]

Prognosis

Almost half of the patients with mild thyroid dysfunction have normalized thyroid function in 1 to 2 years. Almost 25% of these patients progress to overt hypothyroidism.[21][43] An increase in cardiovascular risk factors, cardiovascular events and mortality, congestive heart failure, and decline in renal function is associated with a diagnosis of subclinical hypothyroidism.[44][45][46]

Complications

Cardiovascular Risk

Hypothyroidism is associated with increased vascular resistance and decreased cardiac output.[47] Lack of triiodothyronine (T3) impairs the vasodilatory action of nitric oxide on the vasculature, resulting in increased vascular resistance.[48] Thyroid hormones have positive chronotropic action by directly stimulating the sinoatrial node and positive inotropic effect by modulating myocyte-specific regulatory proteins, increasing cardiac contractility. Lack of thyroid hormone results in bradycardia and decreased cardiac output.[49][50]

Rodondi et al studied 55,000 patients in a prospective cohort study and found that a TSH between 10.0 and 19.9 mIU/L correlated with an increased risk of coronary artery disease events (hazard ratio of 1.86; CI 1.28-2.80) and cardiovascular mortality (Hazard ratio of 1.58; CI 1.10-2.27).[51] However, Gusekloo et al showed that in older individuals (aged 85 or older), higher TSH levels were associated with a reduced mortality rate.[52] Rodondi et al studied 2730 individuals between the ages of 70 and 79 over a 4-year follow-up period and found a higher risk of congestive heart failure with TSH levels of 7.0 mIU/L or higher.[53] Adrees et al showed that the increased levels of systolic blood pressure (SBP) and diastolic BP (DBP), total cholesterol, triglyceride, LDL-cholesterol, lipoprotein(a), homocysteine, and carotid intima-media thickness were associated with subclinical hypothyroidism in 54 women, which normalized after 18 months of levothyroxine treatment and became similar to euthyroid women.[54]

Functional Capacity

Subclinical hypothyroidism has been associated with decreased muscular strength and exercise capacity. Mainenti et al randomized 23 women with subclinical hypothyroidism to receive levothyroxine or placebo. After 6 months of TSH normalization, an increase in exercise performance was noted in the treatment group.[55]

Cognitive Impairment

Hypothyroidism is associated with cognitive decline. Triiodothyronine plays a vital role in neuronal growth, migration, and myelination. However, studies have yielded conflicting results on the association of subclinical hypothyroidism and cognitive impairment. Pasqualetti et al, in their meta-analysis of 13 studies, found an increased risk of cognitive decline in patients aged 75 or younger with subclinical hypothyroidism.[56] In contrast, Akintola et al, in their meta-analysis of 15 studies, found no increased risk of cognitive impairment with subclinical hypothyroidism.[57]

Mood Disturbances

A meta-analysis by Zhao et al found an association between subclinical hypothyroidism and depression in participants aged 60 or younger and no association in individuals aged 60 or older. No change in depression scores was apparent with levothyroxine replacement.[58] Another meta-analysis by Loh et al involving 12,315 individuals also found a 1.7 times higher risk of depression scores associated with a diagnosis of subclinical hypothyroidism.[59]

Renal Function

Chonchol et al found the prevalence of subclinical hypothyroidism in patients with chronic kidney disease (CKD), not on dialysis, to be 18%. The presence of subclinical hypothyroidism in this population was associated with a progressive decline in the estimated glomerular filtration rate over 2 years.[60] Adrees et al showed that the decreased levels of estimated glomerular filtration rate and increased serum cystatin-C levels were associated with SH in 54 women, and treatment with hypothyroidism led to these levels becoming comparable to levels in euthyroid women.[54]

Deterrence and Patient Education

Patients should be counseled regarding the symptoms of hypothyroidism. They must be advised regarding treatment outcomes when TSH is below and above 10 mIU/L. Patients above 70 mIU/L with mild TSH elevation should be informed regarding the aging-related mild elevation in TSH concentrations, along with the lack of improvement shown in studies. Given the higher risk of cardiovascular risk factors, cardiovascular events, and morality, lifestyle changes should be advised.

Pearls and Other Issues

Below are pertinent pearls for managing subclinical hypothyroidism:

Subclinical hypothyroidism characteristically has an elevated TSH and normal T4. While most patients are asymptomatic, some may have symptoms of hypothyroidism.

Subclinical hypothyroidism requires differentiation from other causes of a transient elevation of TSH (age, medications, renal failure, non-thyroidal illness, and assay interference).

Subclinical hypothyroidism has potential correlations with an increased risk of cardiovascular disease, cognitive decline, and decreased functional capacity.

Treatment with levothyroxine should commence if the level of TSH is >10 mIU/L, with positive TPOAb, hypothyroid symptoms, or cardiovascular risk factors.

Enhancing Healthcare Team Outcomes

An interprofessional healthcare team is the best approach to subclinical hypothyroidism management. The central question in treating subclinical hypothyroidism is when to initiate levothyroxine therapy. Factors that need to be considered when deciding on levothyroxine therapy are age, the extent of the elevation of TSH, associated cardiovascular risk factors, clinical symptoms of hypothyroidism, and the presence of TPOAbs.

Details

References

[1]

Cooper DS. Clinical practice. Subclinical hypothyroidism. The New England journal of medicine. 2001 Jul 26:345(4):260-5 [PubMed PMID: 11474665]

[2]

Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruf J, Smyth PP, Spencer CA, Stockigt JR, Guidelines Committee, National Academy of Clinical Biochemistry. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid : official journal of the American Thyroid Association. 2003 Jan:13(1):3-126 [PubMed PMID: 12625976]

Level 1 (high-level) evidence

[3]

Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. The Journal of clinical endocrinology and metabolism. 2002 Mar:87(3):1068-72 [PubMed PMID: 11889165]

Level 3 (low-level) evidence

[4]

Rothacker KM, Brown SJ, Hadlow NC, Wardrop R, Walsh JP. Reconciling the Log-Linear and Non-Log-Linear Nature of the TSH-Free T4 Relationship: Intra-Individual Analysis of a Large Population. The Journal of clinical endocrinology and metabolism. 2016 Mar:101(3):1151-8. doi: 10.1210/jc.2015-4011. Epub 2016 Jan 6 [PubMed PMID: 26735261]

[5]

Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Archives of internal medicine. 2000 Feb 28:160(4):526-34 [PubMed PMID: 10695693]

[6]

Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clinical endocrinology. 1995 Jul:43(1):55-68 [PubMed PMID: 7641412]

Level 3 (low-level) evidence

[7]

Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). The Journal of clinical endocrinology and metabolism. 2002 Feb:87(2):489-99 [PubMed PMID: 11836274]

Level 3 (low-level) evidence

[8]

Chaker L, Baumgartner C, den Elzen WP, Ikram MA, Blum MR, Collet TH, Bakker SJ, Dehghan A, Drechsler C, Luben RN, Hofman A, Portegies ML, Medici M, Iervasi G, Stott DJ, Ford I, Bremner A, Wanner C, Ferrucci L, Newman AB, Dullaart RP, Sgarbi JA, Ceresini G, Maciel RM, Westendorp RG, Jukema JW, Imaizumi M, Franklyn JA, Bauer DC, Walsh JP, Razvi S, Khaw KT, Cappola AR, Völzke H, Franco OH, Gussekloo J, Rodondi N, Peeters RP, Thyroid Studies Collaboration. Subclinical Hypothyroidism and the Risk of Stroke Events and Fatal Stroke: An Individual Participant Data Analysis. The Journal of clinical endocrinology and metabolism. 2015 Jun:100(6):2181-91. doi: 10.1210/jc.2015-1438. Epub 2015 Apr 9 [PubMed PMID: 25856213]

[9]

Collet TH, Gussekloo J, Bauer DC, den Elzen WP, Cappola AR, Balmer P, Iervasi G, Åsvold BO, Sgarbi JA, Völzke H, Gencer B, Maciel RM, Molinaro S, Bremner A, Luben RN, Maisonneuve P, Cornuz J, Newman AB, Khaw KT, Westendorp RG, Franklyn JA, Vittinghoff E, Walsh JP, Rodondi N, Thyroid Studies Collaboration. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Archives of internal medicine. 2012 May 28:172(10):799-809. doi: 10.1001/archinternmed.2012.402. Epub [PubMed PMID: 22529182]

[10]

Rodondi N, Bauer DC, Cappola AR, Cornuz J, Robbins J, Fried LP, Ladenson PW, Vittinghoff E, Gottdiener JS, Newman AB. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study. Journal of the American College of Cardiology. 2008 Sep 30:52(14):1152-9. doi: 10.1016/j.jacc.2008.07.009. Epub [PubMed PMID: 18804743]

[11]

Fuentes AV, Pineda MD, Venkata KCN. Comprehension of Top 200 Prescribed Drugs in the US as a Resource for Pharmacy Teaching, Training and Practice. Pharmacy (Basel, Switzerland). 2018 May 14:6(2):. doi: 10.3390/pharmacy6020043. Epub 2018 May 14 [PubMed PMID: 29757930]

[12]

Razvi S, Korevaar TIM, Taylor P. Trends, Determinants, and Associations of Treated Hypothyroidism in the United Kingdom, 2005-2014. Thyroid : official journal of the American Thyroid Association. 2019 Feb:29(2):174-182. doi: 10.1089/thy.2018.0251. Epub 2019 Jan 25 [PubMed PMID: 30501570]

[13]

Peeters RP. Subclinical Hypothyroidism. The New England journal of medicine. 2017 Jun 29:376(26):2556-2565. doi: 10.1056/NEJMcp1611144. Epub [PubMed PMID: 28657873]

[14]

Chaker L, Razvi S, Bensenor IM, Azizi F, Pearce EN, Peeters RP. Hypothyroidism. Nature reviews. Disease primers. 2022 May 19:8(1):30. doi: 10.1038/s41572-022-00357-7. Epub 2022 May 19 [PubMed PMID: 35589725]

[15]

Wang X, Gao X, Han Y, Zhang F, Lin Z, Wang H, Teng W, Shan Z. Causal Association Between Serum Thyrotropin and Obesity: A Bidirectional, Mendelian Randomization Study. The Journal of clinical endocrinology and metabolism. 2021 Sep 27:106(10):e4251-e4259. doi: 10.1210/clinem/dgab183. Epub [PubMed PMID: 33754627]

[16]

Agnihothri RV, Courville AB, Linderman JD, Smith S, Brychta R, Remaley A, Chen KY, Simchowitz L, Celi FS. Moderate weight loss is sufficient to affect thyroid hormone homeostasis and inhibit its peripheral conversion. Thyroid : official journal of the American Thyroid Association. 2014 Jan:24(1):19-26. doi: 10.1089/thy.2013.0055. Epub [PubMed PMID: 23902316]

[17]

Pearce SH, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, Wemeau JL. 2013 ETA Guideline: Management of Subclinical Hypothyroidism. European thyroid journal. 2013 Dec:2(4):215-28. doi: 10.1159/000356507. Epub 2013 Nov 27 [PubMed PMID: 24783053]

[18]

Han C, He X, Xia X, Li Y, Shi X, Shan Z, Teng W. Subclinical Hypothyroidism and Type 2 Diabetes: A Systematic Review and Meta-Analysis. PloS one. 2015:10(8):e0135233. doi: 10.1371/journal.pone.0135233. Epub 2015 Aug 13 [PubMed PMID: 26270348]

Level 1 (high-level) evidence

[19]

Huber G, Staub JJ, Meier C, Mitrache C, Guglielmetti M, Huber P, Braverman LE. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. The Journal of clinical endocrinology and metabolism. 2002 Jul:87(7):3221-6 [PubMed PMID: 12107228]

[20]

Somwaru LL, Rariy CM, Arnold AM, Cappola AR. The natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study. The Journal of clinical endocrinology and metabolism. 2012 Jun:97(6):1962-9. doi: 10.1210/jc.2011-3047. Epub 2012 Mar 21 [PubMed PMID: 22438233]

[21]

Díez 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. The Journal of clinical endocrinology and metabolism. 2004 Oct:89(10):4890-7 [PubMed PMID: 15472181]

[22]

Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, Singer PA, Woeber KA, American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2012 Nov-Dec:18(6):988-1028 [PubMed PMID: 23246686]

Level 1 (high-level) evidence

[23]

Caturegli P, De Remigis A, Rose NR. Hashimoto thyroiditis: clinical and diagnostic criteria. Autoimmunity reviews. 2014 Apr-May:13(4-5):391-7. doi: 10.1016/j.autrev.2014.01.007. Epub 2014 Jan 13 [PubMed PMID: 24434360]

[24]

Ragusa F, Fallahi P, Elia G, Gonnella D, Paparo SR, Giusti C, Churilov LP, Ferrari SM, Antonelli A. Hashimotos' thyroiditis: Epidemiology, pathogenesis, clinic and therapy. Best practice & research. Clinical endocrinology & metabolism. 2019 Dec:33(6):101367. doi: 10.1016/j.beem.2019.101367. Epub 2019 Nov 26 [PubMed PMID: 31812326]

[25]

Calissendorff J, Falhammar H. To Treat or Not to Treat Subclinical Hypothyroidism, What Is the Evidence? Medicina (Kaunas, Lithuania). 2020 Jan 19:56(1):. doi: 10.3390/medicina56010040. Epub 2020 Jan 19 [PubMed PMID: 31963883]

[26]

Livingston EH. Subclinical Hypothyroidism. JAMA. 2019 Jul 9:322(2):180. doi: 10.1001/jama.2019.9508. Epub [PubMed PMID: 31287524]

[27]

Casey BM, Thom EA, Peaceman AM, Varner MW, Sorokin Y, Hirtz DG, Reddy UM, Wapner RJ, Thorp JM Jr, Saade G, Tita AT, Rouse DJ, Sibai B, Iams JD, Mercer BM, Tolosa J, Caritis SN, VanDorsten JP, Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. The New England journal of medicine. 2017 Mar 2:376(9):815-825. doi: 10.1056/NEJMoa1606205. Epub [PubMed PMID: 28249134]

Level 3 (low-level) evidence

[28]

Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid : official journal of the American Thyroid Association. 2002 Jan:12(1):63-8 [PubMed PMID: 11838732]

[29]

Maraka S, Ospina NM, O'Keeffe DT, Espinosa De Ycaza AE, Gionfriddo MR, Erwin PJ, Coddington CC 3rd, Stan MN, Murad MH, Montori VM. Subclinical Hypothyroidism in Pregnancy: A Systematic Review and Meta-Analysis. Thyroid : official journal of the American Thyroid Association. 2016 Apr:26(4):580-90. doi: 10.1089/thy.2015.0418. Epub 2016 Mar 3 [PubMed PMID: 26837268]

Level 1 (high-level) evidence

[30]

Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RGJ, Mooijaart SP, Sattar N, Aubert CE, Aujesky D, Bauer DC, Baumgartner C, Blum MR, Browne JP, Byrne S, Collet TH, Dekkers OM, den Elzen WPJ, Du Puy RS, Ellis G, Feller M, Floriani C, Hendry K, Hurley C, Jukema JW, Kean S, Kelly M, Krebs D, Langhorne P, McCarthy G, McCarthy V, McConnachie A, McDade M, Messow M, O'Flynn A, O'Riordan D, Poortvliet RKE, Quinn TJ, Russell A, Sinnott C, Smit JWA, Van Dorland HA, Walsh KA, Walsh EK, Watt T, Wilson R, Gussekloo J, TRUST Study Group. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. The New England journal of medicine. 2017 Jun 29:376(26):2534-2544. doi: 10.1056/NEJMoa1603825. Epub 2017 Apr 3 [PubMed PMID: 28402245]

[31]

Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement for subclinical hypothyroidism. The Cochrane database of systematic reviews. 2007 Jul 18:2007(3):CD003419 [PubMed PMID: 17636722]

Level 1 (high-level) evidence

[32]

Parle J, Roberts L, Wilson S, Pattison H, Roalfe A, Haque MS, Heath C, Sheppard M, Franklyn J, Hobbs FD. 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. The Journal of clinical endocrinology and metabolism. 2010 Aug:95(8):3623-32. doi: 10.1210/jc.2009-2571. Epub 2010 May 25 [PubMed PMID: 20501682]

Level 1 (high-level) evidence

[33]

Grossman A, Feldhamer I, Meyerovitch J. Treatment with levothyroxin in subclinical hypothyroidism is associated with increased mortality in the elderly. European journal of internal medicine. 2018 Apr:50():65-68. doi: 10.1016/j.ejim.2017.11.010. Epub 2017 Nov 23 [PubMed PMID: 29174213]

[34]

Bekkering GE, Agoritsas T, Lytvyn L, Heen AF, Feller M, Moutzouri E, Abdulazeem H, Aertgeerts B, Beecher D, Brito JP, Farhoumand PD, Singh Ospina N, Rodondi N, van Driel M, Wallace E, Snel M, Okwen PM, Siemieniuk R, Vandvik PO, Kuijpers T, Vermandere M. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ (Clinical research ed.). 2019 May 14:365():l2006. doi: 10.1136/bmj.l2006. Epub 2019 May 14 [PubMed PMID: 31088853]

Level 1 (high-level) evidence

[35]

Bremner AP, Feddema P, Leedman PJ, Brown SJ, Beilby JP, Lim EM, Wilson SG, O'Leary PC, Walsh JP. Age-related changes in thyroid function: a longitudinal study of a community-based cohort. The Journal of clinical endocrinology and metabolism. 2012 May:97(5):1554-62. doi: 10.1210/jc.2011-3020. Epub 2012 Feb 16 [PubMed PMID: 22344200]

[36]

Leng O, Razvi S. Hypothyroidism in the older population. Thyroid research. 2019:12():2. doi: 10.1186/s13044-019-0063-3. Epub 2019 Feb 8 [PubMed PMID: 30774717]

[37]

Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. The Journal of endocrinology. 2010 Apr:205(1):1-13. doi: 10.1677/JOE-09-0412. Epub 2009 Dec 16 [PubMed PMID: 20016054]

[38]

Farwell AP. Nonthyroidal illness syndrome. Current opinion in endocrinology, diabetes, and obesity. 2013 Oct:20(5):478-84. doi: 10.1097/01.med.0000433069.09294.e8. Epub [PubMed PMID: 23974778]

Level 3 (low-level) evidence

[39]

Favresse J, Burlacu MC, Maiter D, Gruson D. Interferences With Thyroid Function Immunoassays: Clinical Implications and Detection Algorithm. Endocrine reviews. 2018 Oct 1:39(5):830-850. doi: 10.1210/er.2018-00119. Epub [PubMed PMID: 29982406]

[40]

Koulouri O,Moran C,Halsall D,Chatterjee K,Gurnell M, Pitfalls in the measurement and interpretation of thyroid function tests. Best practice [PubMed PMID: 24275187]

[41]

Lamine F, De Giorgi S, Marino L, Michalaki M, Sykiotis GP. Subclinical hypothyroidism: new trials, old caveats. Hormones (Athens, Greece). 2018 Jun:17(2):231-236. doi: 10.1007/s42000-018-0004-x. Epub 2018 Apr 27 [PubMed PMID: 29858848]

[42]

Rizzo LFL, Mana DL, Serra HA. Drug-induced hypothyroidism. Medicina. 2017:77(5):394-404 [PubMed PMID: 29044016]

[43]

Díez JJ, Iglesias P, Burman KD. Spontaneous normalization of thyrotropin concentrations in patients with subclinical hypothyroidism. The Journal of clinical endocrinology and metabolism. 2005 Jul:90(7):4124-7 [PubMed PMID: 15811925]

[44]

Delitala AP, Fanciulli G, Maioli M, Delitala G. Subclinical hypothyroidism, lipid metabolism and cardiovascular disease. European journal of internal medicine. 2017 Mar:38():17-24. doi: 10.1016/j.ejim.2016.12.015. Epub 2016 Dec 28 [PubMed PMID: 28040402]

[45]

Inoue K, Ritz B, Brent GA, Ebrahimi R, Rhee CM, Leung AM. Association of Subclinical Hypothyroidism and Cardiovascular Disease With Mortality. JAMA network open. 2020 Feb 5:3(2):e1920745. doi: 10.1001/jamanetworkopen.2019.20745. Epub 2020 Feb 5 [PubMed PMID: 32031647]

[46]

Razvi S, Weaver JU, Vanderpump MP, Pearce SH. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of the Whickham Survey cohort. The Journal of clinical endocrinology and metabolism. 2010 Apr:95(4):1734-40. doi: 10.1210/jc.2009-1749. Epub 2010 Feb 11 [PubMed PMID: 20150579]

Level 3 (low-level) evidence

[47]

Biondi B, Palmieri EA, Lombardi G, Fazio S. Subclinical hypothyroidism and cardiac function. Thyroid : official journal of the American Thyroid Association. 2002 Jun:12(6):505-10 [PubMed PMID: 12165114]

[48]

Razvi S, Jabbar A, Pingitore A, Danzi S, Biondi B, Klein I, Peeters R, Zaman A, Iervasi G. Thyroid Hormones and Cardiovascular Function and Diseases. Journal of the American College of Cardiology. 2018 Apr 24:71(16):1781-1796. doi: 10.1016/j.jacc.2018.02.045. Epub [PubMed PMID: 29673469]

[49]

Sun ZQ, Ojamaa K, Coetzee WA, Artman M, Klein I. Effects of thyroid hormone on action potential and repolarizing currents in rat ventricular myocytes. American journal of physiology. Endocrinology and metabolism. 2000 Feb:278(2):E302-7 [PubMed PMID: 10662715]

[50]

Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. The New England journal of medicine. 2001 Feb 15:344(7):501-9 [PubMed PMID: 11172193]

[51]

Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J, Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010 Sep 22:304(12):1365-74. doi: 10.1001/jama.2010.1361. Epub [PubMed PMID: 20858880]

[52]

Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frölich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004 Dec 1:292(21):2591-9 [PubMed PMID: 15572717]

[53]

Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB, Bauer DC. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Archives of internal medicine. 2005 Nov 28:165(21):2460-6 [PubMed PMID: 16314541]

[54]

Adrees M, Gibney J, El-Saeity N, Boran G. Effects of 18 months of L-T4 replacement in women with subclinical hypothyroidism. Clinical endocrinology. 2009 Aug:71(2):298-303. doi: 10.1111/j.1365-2265.2008.03509.x. Epub 2008 Dec 15 [PubMed PMID: 19094068]

[55]

Mainenti MR, Vigário PS, Teixeira PF, Maia MD, Oliveira FP, Vaisman M. Effect of levothyroxine replacement on exercise performance in subclinical hypothyroidism. Journal of endocrinological investigation. 2009 May:32(5):470-3 [PubMed PMID: 19468264]

[56]

Pasqualetti G, Pagano G, Rengo G, Ferrara N, Monzani F. Subclinical Hypothyroidism and Cognitive Impairment: Systematic Review and Meta-Analysis. The Journal of clinical endocrinology and metabolism. 2015 Nov:100(11):4240-8. doi: 10.1210/jc.2015-2046. Epub 2015 Aug 25 [PubMed PMID: 26305618]

Level 1 (high-level) evidence

[57]

Akintola AA, Jansen SW, van Bodegom D, van der Grond J, Westendorp RG, de Craen AJ, van Heemst D. Subclinical hypothyroidism and cognitive function in people over 60 years: a systematic review and meta-analysis. Frontiers in aging neuroscience. 2015:7():150. doi: 10.3389/fnagi.2015.00150. Epub 2015 Aug 11 [PubMed PMID: 26321946]

Level 1 (high-level) evidence

[58]

Zhao T, Chen BM, Zhao XM, Shan ZY. Subclinical hypothyroidism and depression: a meta-analysis. Translational psychiatry. 2018 Oct 30:8(1):239. doi: 10.1038/s41398-018-0283-7. Epub 2018 Oct 30 [PubMed PMID: 30375372]

Level 1 (high-level) evidence

[59]

Loh HH, Lim LL, Yee A, Loh HS. Association between subclinical hypothyroidism and depression: an updated systematic review and meta-analysis. BMC psychiatry. 2019 Jan 8:19(1):12. doi: 10.1186/s12888-018-2006-2. Epub 2019 Jan 8 [PubMed PMID: 30621645]

Level 1 (high-level) evidence

[60]

Chonchol M, Lippi G, Salvagno G, Zoppini G, Muggeo M, Targher G. Prevalence of subclinical hypothyroidism in patients with chronic kidney disease. Clinical journal of the American Society of Nephrology : CJASN. 2008 Sep:3(5):1296-300. doi: 10.2215/CJN.00800208. Epub 2008 Jun 11 [PubMed PMID: 18550654]