Indian Journal of Endocrinology and Metabolism

: 2013  |  Volume : 17  |  Issue : 9  |  Page : 636--642

Subclinical hypothyroidism: Controversies to consensus

Syed Abbas Raza1, Nasir Mahmood2,  
1 Department of Internal Medicine, Shaukat Khanum Hospital and Research Center, Lahore, Pakistan
2 Department of Internal Medicine, Junnah Hospital, Lahore, Pakistan

Correspondence Address:
Syed Abbas Raza
Department of Medicine, Shaukat Khanum Cancer Hospital and Research Center


Diagnoses of subclinicaal hypothyroidism (SCH) is biochemically made, when serum thyroid stimulating hormone (TSH) levels is elevated while free thyroid hormone levels are within normal reference range. SCH is diagnosed after excluding all other causes of elevated TSH levels. Symptoms of SCH may vary from being asymptomatic to having mild nonspecific symptoms. The risk of progression to overt hypothyroidism is related to number of factors including initial serum TSH concentration, presence of auto antibodies, family history and presence goiter. Various screening recommendations for thyroid function assessment are in practice. There are still controversies surrounding SCH and associated risk of various cardiovascular diseases (CVDs), pregnancy outcomes, neuropsychiatric issues, metabolic syndrome, and dyslipidemia. Consensus will require more large randomized clinical studies involving various age groups and medical condition, especially in developing countries. All these efforts will definitely improve our understanding of disease and ultimately patient outcomes.

How to cite this article:
Raza SA, Mahmood N. Subclinical hypothyroidism: Controversies to consensus.Indian J Endocr Metab 2013;17:636-642

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Raza SA, Mahmood N. Subclinical hypothyroidism: Controversies to consensus. Indian J Endocr Metab [serial online] 2013 [cited 2020 Jan 28 ];17:636-642
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Subclinical hypothyroidism (SCH) is biochemically diagnosed when there is a persistently high TSH level, while circulating free thyroid hormone levels are within range. [1],[2] Other terms for this condition are mild hypothyroidism, early thyroid failure, preclinical hypothyroidism, and decreased thyroid reserve. [3] The prevalence of SCH is 3-8%, which increases with age, more prevalent in females; but it approaches to males after 6 th decade. [4],[5] Presence of thyroid antibody raises the risk of developing subclinical and then progressing to overt hypothyroidism. Role of iodine is somewhat controversial and iodine sufficient area have higher incidence of developing SCH than the iodine insufficient, especially studies done in Europe. [6]

Medical condition which can lead to biochemical diagnoses of SCH [1] [Table 1] Include. Chronic autoimmune thyroiditis, persistently elevated TSH in subacute thyroiditis, postpartum thyroiditis and painless thyroiditis, injury to thyroid, partial thyroidectomy (other neck surgery), radioactive iodine/external radiotherapy exposure, drugs causing impairment of thyroid function (iodine and iodine-containing medications, e.g., amiodarone, radiographic, contrast agents, lithium carbonate, cytokines (especially interferon-α), aminoglutethimide, ethionamide, sulfonamides, and sulfonylureas), inadequate replacement therapy for overt hypothyroidism, (inadequate dosage, noncompliance, drug interactions (iron, calcium carbonate, cholestyramine, fiber, dietary soy, etc.), increased thyroxine (T4) clearance (phenobarbital, phenytoin, carbamazepine, etc.), malabsorption), infiltration of thyroid, (amyloidosis, sarcoidosis, hemochromatosis, Riedel's thyroiditis, cystinosis, acquired immunodeficiency syndrome (AIDS), primary thyroid lymphoma), central hypothyroidism, toxic substances, industrial and environmental agents, and mutations of TSH receptor gene like G α gene mutations. Transient rise in TSH levels can be seen in granulomatous, postpartum, and silent thyroiditis cases. [5]{Table 1}

 Diagnosis and Natural Progression of Disease

SCH is a biochemical diagnoses when there is persistently high TSH levels, while circulating free thyroid hormone levels are within range. [1],[2] Single high reading of TSH should be repeated after 4-6 weeks, as there is transient fluctuation in TSH in different medical/physiological conditions. Controversies surround the upper normal limit of TSH level too, while traditionally most of the laboratories consider 4 mU/L as upper limit, there are some expert/organization that are advocating levels of 2.5-3 mU/L as true upper limits. There is also a physiological rise in TSH with age and levels of 6-8 mU/L could be considered in individuals >80 years of age. [8]

Certain conditions which do not qualify to be labeled as Subclinical Hypothyroidism based on the natural history include

When recovering from nonthyroidal illness, recovery phase of subacute/painless/postpartum thyroiditis, assay variability, heterophilic antibodies, and rheumatoid factor interfering with TSH measurements, [9] autoantibodies causing TSH-anti-TSH immunoglobulin (Ig)G complexes (Macro-TSH) lacks biologic activity but may be immunoreactive, and cause spuriously high TSH values (often >100 mU/L) in euthyroid individuals, [10],[11],[12] untreated adrenal insufficiency, rare mutations of TSH receptor, TSH producing pituitary adenomas, and resistance to thyroid hormone (commonly presenting as elevated TSH is associated with elevated serum free T4 and/or T3) and central hypothyroidism, in which up to 25% of patients have a mildly elevated serum TSH ≤10 mU/L and a low or low normal free T4.

Symptoms of thyroid disease are vague and different in various cultural backgrounds, so it is the biochemical evidence which makes/roles out the diagnoses of subclinical vs overt hypothyroidism. In one study done in Pakistan, most common symptoms for SCH were "weakness" and "lethargy". [13]

Overall, progression from subclinical to overt hypothyroidism is very high, the incidence range from 33 to 55% in prospective studies with nearly 10-20 years of follow-up. [4],[14],[15] This progression rate is considered to be around 2.6-4.3% each year. [4] Presence of thyroid autoantibodies, [14],[16],[17] goiter, underlying autoimmune diseases, and prior exposure to radioactive iodine/radiation are considered high risk for conversion into overt hypothyroidism.

While in few individual, TSH may normalize within 2 years, this is more commonly seen in individuals with negative antithyroid antibodies and serum TSH levels of <10 mU/L. [18]

 Disease Burden in Region

Thyroid diseases are one of the most commonest endocrine disorders. Developing countries are equally affected as developed countries. According to one study, the prevalence of hypothyroidism and SCH in Pakistani population is 4.1 and 5.4%, respectively and female is predominant gender. [19] Data from few other countries reveal similar prevalence 4-8% in Brazil, [20] which are comparable to prevalence of 3-8% in USA. [21] However, in India there have been much higher reported cases in study by Hari Kumar et al., where they published as high as 30%. [22] Study on school going children in Pakistan showed prevalence of 8.43%, [23] which is higher as compared to 1.7% in US children. [24] India has estimated 42 million people suffering from thyroid diseases, [25] with prevalence of SCH as high as 9.4% with female dominance of 11.4 vs 6.2% in men. [26]

 Discussion: Controversies to Consensus

Due to lack of randomized prospective clinical trials, it is difficult to formulate the consensus on creating guidelines managing SCH. Below we discuss some of the data available in this regard.

Subclinical hypothyroidism and pregnancy

There is insufficient evidence to recommend the use of one intervention for clinical or SCH prepregnancy or during pregnancy over another, for improving maternal, fetal, neonatal, and childhood outcomes.

Thyroid hormone disturbances have known to have adverse effect in pregnancy outcomes. That is why thyroid function assessment is relevant in reproductive dysfunction. [27] Our review of literature revealed that SCH increased the rate of miscarriage/fetal death and later it adversely affects the cognitive development of offspring. Though universal screening for thyroid hormone abnormalities in pregnancy is not routinely recommended at present, but thyroid function must be assessed in those having reproductive dysfunction and treated as appropriate.

Although it is evident from current literature that pregnancy outcomes are worse in women with overt hypothyroidism vs SCH. Studies done in individuals with SCH show an increased risk of preterm birth/pregnancy loss (almost two-fold), [28] association of impaired cognitive development in children, [29] and severe preeclampsia. [30]

Subclinical hypothyroid and mental dysfunction in young females

Though there is evidence of mental dysfunction related to working memory in SCH in young females, but this link is still under debate. Results of one study comparing young females with SCH and controls revealed that SCH females had greater susceptibility for unpleasant emotional stimulation, inward attention and increased anxiety for physical danger. Electroencephalogram (EEG) done in this study showed reduced alpha activity in resting state and increased beta-2 activity during stimulation, which means that SCH females had higher levels of arousal and greater susceptibility to negative emotions than controls. [31] These conclusions support the need for further studies.

Subclinical hypothyroidism and bone health

Thyroid hormone and TSH play an important role in bone mineral homeostasis and bone growth. Thyroid hormone has direct effect on stimulation of bone resorption through osteoclast function. Overt hyperthyroidism is associated with increased bone turnover and an increased risk of osteoporosis and fracture, [32] but SCH effects on bone are not well-established. Results of one study conducted to determine the impact of SCH on bone health in children demonstrated no significant impairment in bone health which is evaluated by lumbar spine dual-energy X-ray absorptiometry (DXA) and phalangeal quantitative ultrasound (QUS). [33]

Subclinical hypothyroidism and risk of heart failure

SCH and cardiovascular risk, which is well-recognized in young, is still debated in the elderly (>65 year). [34] Thyroid dysfunction, that is, both high and suppressed TSH, is one of the exacerbating condition in heart failure and American Heart Association (AHA) recommend its determination as a precipitating factor in heart failure patients. Results of six prospective cohorts in the United States and Europe revealed that risk of heart failure were increased in patients with high TSH particularly when it is above 10 mIU/L. [35]

Subclinical hypothyroidism and cardiovascular risk

Risk of cardiovascular disease in overt hypothyroidism is more established than in SCH. Although, there are observational studies [36,37,38,39,40] that suggest increased risk of coronary heart disease in SCH, but others unable to substantiate this relationship. [41],[42] In one study when myocardial perfusion by contrast enhanced echocardiography and intima media thickness was compared between SCH and normal thyroid females, there was myocardial hypoperfusion and increased intima media thickness in SCH females which suggest it as cardiovascular disease (CVD) risk. [43]

In a meta-analysis involving 25,977 participants out of which 2,020 were with SCH (seven prospective cohort studies) revealed a significant trend of increased risk of coronary heart disease (CHD) events at higher serum TSH concentrations. [44] This increased risk was not affected based on gender, age, or presence of preexisting CVD. Participants with TSH ≥10 mU/L had a significant increase in CHD events (38.4 versus 20.3 events/1,000 person, heart rate (HR) 1.89, 95% CI 1.28-2.80) when compared with euthyroid subjects. Contrary to that patients having serum TSH ranging from 4.5 to 6.9 mU/L were not associated with an increased risk (HR 1.00, 95% CI 0.96-1.43).

There are other cardiovascular risk factors associated with SCH. [45],[46],[47],[48],[49],[50] Cardiovascular defects such as diastolic dysfunction and increased peripheral vascular resistance are seen both in overt as well as SCH. [51] While association with left ventricular mass or function was no different in individuals with serum TSH ranging from 3.5 to 10 mU/L compared to those with normal TSH. [52]

Subclinical hypothyroidism and cholesterol metabolism

A cross-sectional study (25,862 participants, median age 56 years), revealed individuals with serum TSH between 5.1 and 10 mU/L had significantly higher mean total cholesterol concentrations compared with euthyroid individuals (5.6 versus 5.8 mmol/L). [53] There are studies revealing a link between elevated TSH and cholesterol concentrations (total and LDL cholesterol). [43] This risk has not been substantiated with CVD outcome risk.

But it is still an unresolved clinical challenge in even older population, that is, age >85 years, where due to lack of large randomized trial to determine cardiovascular end points and negative impact of possible overtreatment, this population still need to be carefully followed with wait and see policy. [34] Meta-analysis of one prospective study showed that elderly individuals (>85 years) in the Netherlands with untreated SCH actually had a lower rate of cardiovascular and all-cause mortality. [54]

Subclinical hypothyroidism in polycystic ovarian syndrome

Our review of literature revealed variable contribution of SCH in dyslipidemia and insulin resistance in females with PCOS. One of the trial conducted in Namik Kemal University Medical Faculty, Turkey, revealed that females with SCH and PCOS have higher triglyceride (TG) and insulin levels compared to PCOS females with normal thyroid function test (TFT), which are statistically significant and it concluded that patients with PCOS and SCH should be evaluated for dyslipidemia and insulin resistance. [55] Another trial revealed that PCOS females with SCH have higher levels of low density lipoprotein (LDL) cholesterol, while all other parameters of lipid profile and phenotypic manifestations are not altered by SCH. [56]

Subclinical hypothyroidism and metabolic syndrome

Weight gain or failure to lose weight is one of the most common features of overt and subclinical hypothyroidism. Role of thyroid hormone is vital in lipid synthesis, mobilization, and metabolism. A trial conducted in Ege University Medical School, Izmir, Turkey revealed that metabolic syndrome frequency is increased in overt and subclinical hypothyroidism patients. [57]

Subclinical hypothyroidism and mortality

One of the controversial areas in literature is relationship between all-cause mortality and SCH. You can find studies in support [38],[39],[58],[59],[60] as well as inconclusive evidence. [41],[61] Meta-analysis of patient from 11 prospective cohort studies revealed risk of cardiovascular mortality increased with higher concentrations of TSH and was significantly increased in participants with TSH concentrations ≥10 mU/L, but not all cause mortality (HR 1.58, 95% CI 1.10-2.27). [44] In contrast, minimal elevations of TSH ranging from 4.5 to 6.9 mU/L were not associated with cardiovascular or all-cause mortality.

Subclinical hypothyroidism and neuropsychiatric issues

There are several reports linking SCH with neuropsychiatric diseases, [62,63,64,65] while there are many including a large study of primary care patients in England do not support this observation. [15],[66],[67],[68] Link between SCH and some of the neuropsychiatric disorders are exhibited in these studies, higher frequency of neuromuscular symptoms (weakness, paresthesias, fatigue, and cramps), [69] defects in verbal memory and executive functioning, [70],[71] and increased risk of Alzheimer disease (AD) in women but not in men (in population-based study). [72]

Defects in verbal memory and executive functioning were noted in individuals with SCH [70],[71] and these defects were corrected with T4 therapy. This was possible linked to abnormal hippocampal function rather than general cognitive slowing.

In contrast to above findings, another study (>2,000 elderly individuals), it was found that in individuals with TFT in subclinical range (4.5 to <7.0 mU/L), gait speed and walking endurance was better than individuals with TSH values within the normal range (0.4 to <4.5 mU/L). [73]

Sub clinical and weight gain

Weight changes remain the one of the most important manifestation of thyroid diseases. Weight loss in hyperthyroidism as well as weight gain in overt hypothyroidism is well-established. But only few studies look into weight fluctuation in SCH. There are three studies which reveal increasing serum TSH level within the normal range resulting in modest increase in body weight. [74],[75],[76]

Other important association

Although our knowledge regarding SCH remains limited due to lack of randomized clinical trials, but there are some date to show association of higher risk of unprovoked deep venous thrombosis (pilot study) [77] and more likelihood of common bile duct stones, thought to be secondary to sphincter of Oddi dysfunction. [78]

Another interesting finding was noted regarding replacement of iron in subclinical hypothyroid patient with coexisting iron deficiency anemia. Rise in hemoglobin was noted to be greater in patient when given both iron and thyroid hormone compared with those given iron alone. [79]

 Conclusion/Rationale for Treatment

There have been few guidelines, including one from Clinical Consensus group (comprised of representatives from the American Thyroid Association, Endocrine Society, and the American Association of Clinical Endocrinologists) to help physician choose right candidate for treatment of SCH. Following suggestions could be made based on these recommendations:

Treatment should be initiated if TSH concentration is >10 mU/L, as there is enough evidence to support the beneficial effectsTreatment of asymptomatic patient with serum TSH values between 4.5 and 10 mU/L is somewhat controversial. They need to be followed-up every 6-12 months with serum TSH and clinical evaluation. Risk of overtreatment, precipitation of angina pectoris/cardiac arrhythmia in high risk group, compliance of patients to daily medication, cost of therapy, and more so for its monitoring are major issues in treating patient who fall in this categoryPatients with serum TSH values of 4.5-10 mU/L and have symptoms suggesting hypothyroidism or have goiter, and/or high titers of antithyroid peroxidase antibodies, can benefit from treatment. Treatment can be offered and their TSH should ideally be kept < 2.5 mU/L, provided risk factors mentioned above are evaluatedTreatment should be given to pregnant women with SCH or who wish to become pregnant and patients who have ovulatory dysfunction. In pregnancy trimester-specific reference ranges for TSH should be used [80]Elderly patient experience a physiological rise in TSH. Elderly patient with SCH should be closely followed and the decision when to start treatment is still a challenge due to negative impacts of overtreatment and lack of well-organized randomized trials in this age group [34]Treatment will help in preventing progression to overt hypothyroidism especially in patients with TSH above 10, resolving symptoms with lesser TSH levels, and decreasing goiter size if it is present.


1Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev 2008;29:76-131.
2Cooper DS, Biondi B. Subclinical thyroid disease. Lancet 2012;379:1142-54.
3Cooper DS. Subclinical hypothyroidism. N Engl J Med 2001;345:260-5.
4Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The incidence of thyroid disorders in the community: A twenty year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995;43:55-68.
5Fatourechi V. Subclinical hypothyroidism: An update for primary care physicians. Mayo Clin Proc 2009;84:65-71.
6Szabolcs I, Podoba J, Feldkamp J, Dohan O, Farkas I, Sajgó M, et al. Comparative screening for thyroid disorders in old age in area of iodine deficiency, long-term iodine prophylaxis and abundant iodine intake. Clin Endocrinol (Oxf) 1997;47:87-92.
7Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al. 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. Endocr Pract 2012;18:988-1028.
8Surks 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;92:4575-82.
9Després N, Grant AM. Antibody interference in thyroid assays: A potential for clinical misinformation. Clin Chem 1998;44:440-54.
10Rix M, Laurberg P, Porzig C, Kristensen SR. Elevated thyroid-stimulating hormone level in a euthyroid neonate caused by macro thyrotropin-IgG complex. Acta Paediatr 2011;100:e135-7.
11Loh TP, Kao SL, Halsall DJ, Toh SA, Chan E, Ho SC, et al. Macro-thyrotropin: A case report and review of literature. J Clin Endocrinol Metab 2012;97:1823-8.
12Sakai H, Fukuda G, Suzuki N, Watanabe C, Odawara M. Falsely elevated thyroid stimulating hormone (TSH) level due to macro-TSH. Endocr J 2009;56:435-40.
13Azam HD, Hayat Z, Fida Z, Khan I. Subclinical hypothyroidism in patients with non specific symptoms. J Med Sci 2010;18:191-3.
14Huber G, Staub JJ, Meier C, Mitrache C, Guglielmetti M, Huber P, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: Prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metab 2002;87:3221-6.
15Kabadi UM. Subclinical hypothyroidism. Natural course of the syndrome during a prolonged follow-up study. Arch Intern Med 1993;153:957-61.
16Rosenthal MJ, Hunt WC, Garry PJ, Goodwin JS. Thyroid failure in the elderly. Microsomal antibodies as discriminant for therapy. JAMA 1987;258:209-13.
17Díez 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;89:4890-7.
18Díez JJ, Iglesias P, Burman KD. Spontaneous normalization of thyrotropin concentrations in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 2005;90:4124-7.
19Khan A, Khan MM, Akhtar S. Thyroid disorders, etiology and prevalence. Pak J Med Sci 2002;2:89-94.
20Villar HC, Saconato H, Valente O, Atalllah AN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Sys Rev 2007:CD003419.
21Herrick B. Subclinical hypothyroidism. Am Fam Physician 2008;77:953-5.
22Hari Kumar KV, Verma A, Muthukrishnan J, Modi KD. Obesity and thyrotropinemia. Indian J Pediatr 2009;76:933-5.
23Ramzan M, Ali I, Ramzan F, Ramzan MH, Ramzan F. Pprevalence of subclinical hypothyroidism in school children (6-11 years) of dera ismail khan. J Postgrad Med Inst 2013;26:22-2.
24Wu T, Flowers JW, Tudiver F, Wilson JL, Punyasavatsut N. Subclinical thyroid disorders and cognitive performance among adolescents in the United State. BMC Pediatr 2006;6:12.
25Available from: [Last accessed on 2011 Apr 2].
26Usha Menon V, Sundaram KR, Unnikrishnan AG, Jayakumar RV, Nair V, Kumar H. High prevalence of undetected thyroid disorders in an iodine sufficient adult south Indian population. J Indian Med Assoc 2009;107:72-7.
27Sarkar D. Recurrent pregnancy loss in patients with thyroid dysfunction. Indian J Endocrinol Metab 2012;16 (Suppl 2):S350-1.
28Li Y, Shan Z, Teng W, Yu X, Li Y, Fan C, et al. Abnormalities of maternal thyroid function during pregnancy affect Neuropsychological development of their children at 25-30 months. Clin Endocrinol (Oxf) 2010;72:825-9.
29Smit BJ, Kok JH, Vulsma T, Briët JM, Boer K, Wiersinga WM. Neurologic development of the newborn and young child in relation to maternal thyroid function. Acta Paediatr 2000;89:291-5.
30Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005;105:239-45.
31Menicucci D, Sebastiani L, Comparini A, Pingitore A, Ghelarducci B, L'abbate A, et al. Minimal changes of thyroid axis activity influence brain functions in young females affected by subclinical hypothyroidism. Arch Ital Biol 2013;151:1474.
32Vestergaard P, Mosekilde L. Hyperthyroidism, bone mineral, and fracture risk: A meta-analysis. Thyroid 2003;13:585-93.
33Di Mase R, Cerbone M, Improda N, Esposito A, Capalbo D, Mainolfi C, et al. Bone health in children with long-term idiopathic subclinical hypothyroidism. Ital J Pediatr 2012;38:56.
34Pasquqletti G, Tognini S, Polini A, Caraccio N, Monzani F. Is subclinical hypothyroidism a cardiovascular risk factor in the elderly? J Clin Endocrinol Metab 2013;98:2256-66.
35Gencer B, Collet TH, Virgini V, Bauer DC, Gussekloo J, Cappola AR, et al. Thyroid Studies Collaboration. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from six prospective cohorts. Circulation 2012;126:1040-9.
36Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: The Rotterdam Study. Ann Intern Med 2000;132:270-8.
37Lindeman RD, Romero LJ, Schade DS, Wayne S, Baumgartner RN, Garry PJ. Impact of subclinical hypothyroidism on serum total homocysteine concentrations, the prevalence of coronary heart disease (CHD), and CHD risk factors in the New Mexico Elder Health Survey. Thyroid 2003;13:595-600.
38Imaizumi M, Akahoshi M, Ichimaru S, Nakashima E, Hida A, Soda M, et al. Risk for ischemic heart disease and all-cause mortality in subclinical hypothyroidism. J Clin Endocrinol Metab 2004;89:3365-70.
39Walsh JP, Bremner AP, Bulsara MK, O'Leary P, Leedman PJ, Feddema P, et al. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med 2005;165:2467-72.
40Razvi 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. J Clin Endocrinol Metab 2010;95:1734-40.
41Rodondi N, Bauer DC, Cappola AR, Cornuz J, Robbins J, Fried LP, et al. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study. J Am Coll Cardiol 2008;52:1152-9.
42Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, et al. Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010;304:1365-74.
43Knapp M, Lisowska A, Sobkowicz B, Tyciñska A, Sawicki R, Musia³ W. Myocardial perfusion and intima-media thickness in patients with subclinical hypothyroidism. Adv Med Sci 2013;58:44-9.
44Monzani F, Caraccio N, KozàkowàM, Dardano A, Vittone F, Virdis A, et al. 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;89:2099-106.
45Nagasaki T, Inaba M, Kumeda Y, Hiura Y, Shirakawa K, Yamada S, et al. Increased pulse wave velocity in subclinical hypothyroidism. J Clin Endocrinol Metab 2006;91:154-8.
46Kvetny J, Heldgaard PE, Bladbjerg EM, Gram J. Subclinical hypothyroidism is associated with a low-grade inflammation, increased triglyceride levels and predicts cardiovascular disease in males below 50 years. Clin Endocrinol (Oxf) 2004;61:232-8.
47Cikim AS, Oflaz H, Ozbey N, Cikim K, Umman S, Meric M, et al. Evaluation of endothelial function in subclinical hypothyroidism and subclinical hyperthyroidism. Thyroid 2004;14:605-9.
48Owen PJ, Rajiv C, Vinereanu D, Mathew T, Fraser AG, Lazarus JH. Subclinical hypothyroidism, arterial stiffness, and myocardial reserve. J Clin Endocrinol Metab 2006;91:2126-32.
49Choi SH, Lee YJ, Park YJ, Kim KW, Lee EJ, Lim S, et al. Retinol binding protein-4 elevation is associated with serum thyroid-stimulating hormone level independently of obesity in elderly subjects with normal glucose tolerance. J Clin Endocrinol Metab 2008;93:2313-8.
50Biondi B, Fazio S, Palmieri EA, Carella C, Panza N, Cittadini A, et al. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 1999;84:2064-7.
51Iqbal A, Schirmer H, Lunde P, Figenschau Y, Rasmussen K, Jorde R. Thyroid stimulating hormone and left ventricular function. J Clin Endocrinol Metab 2007;92:3504-10.
52Iervasi G, Molinaro S, Landi P, Taddei MC, Galli E, Mariani F, et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch Intern Med 2007;167:1526-32.
53Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526-34.
54Atzmon G, Barzilai N, Surks MI, Gabriely I. Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity. J Clin Endocrinol Metab 2009;94:4768-75.
55Celik C, Abali R, Tasdemir N, Guzel S, Yuksel A, Aksu E, et al. Is subclinical hypothyroidism contributing dyslipidemia and insulin resistance in women with polycystic ovary syndrome? Gynecol Endocrinol 2012;28:615-8.
56Benetti-Pinto CL, Berini Piccolo VR, Garmes HM, Teatin Juliato CR. Subclinical hypothyroidism in young women with polycystic ovary syndrome: An analysis of clinical, hormonal, and metabolic parameters. Fertil Steril 2013;99:588-92.
57Erdogan M, Canataroglu A, Ganidagli S, Kulaksýzoglu M. Metabolic syndrome prevalence in subclinic and overt hypothyroid patients and the relation among metabolic syndrome parameters. J Endocrinol Invest 2011;34:488-92.
58McQuade C, Skugor M, Brennan DM, Hoar B, Stevenson C, Hoogwerf BJ. Hypothyroidism and moderate subclinical hypothyroidism are associated with increased all-cause mortality independent of coronary heart disease risk factors: A PreCIS database study. Thyroid 2011;21:837-43.
59Tseng FY, Lin WY, Lin CC, Lee LT, Li TC, Sung PK, et al. Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults. J Am Coll Cardiol 2012;60:730-7.
60Gussekloo 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;292:2591-9.
61Baldini IM, Vita A, Mauri MC, Amodei V, Carrisi M, Bravin S, et al. Psychopathological and cognitive features in subclinical hypothyroidism. Prog Neuropsychopharmacol Biol Psychiatry 1997;21:925-35.
62Monzani F, Del Guerra P, Caraccio N, Pruneti CA, Pucci E, Luisi M, et al. Subclinical hypothyroidism: Neurobehavioral features and beneficial effect of L-thyroxine treatment. Clin Investig 1993;71:367-71.
63Haggerty JJ Jr, Stern RA, Mason GA, Beckwith J, Morey CE, Prange AJ Jr. Subclinical hypothyroidism: A modifiable risk factor for depression? Am J Psychiatry 1993;150:508-10.
64Tappy L, Randin JP, Schwed P, Wertheimer J, Lemarchand-Béraud T. Prevalence of thyroid disorders in psychogeriatric inpatients. A possible relationship of hypothyroidism with neurotic depression but not with dementia. J Am Geriatr Soc 1987;35:526-31.
65Engum A, Bjøro T, Mykletun A, Dahl AA. An association between depression, anxiety and thyroid function--a clinical fact or an artefact? Acta Psychiatr Scand 2002;106:27-34.
66Roberts LM, Pattison H, Roalfe A, Franklyn J, Wilson S, Hobbs FD, et al. Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction? Ann Intern Med 2006;145:573-81.
67Jorde R, Waterloo K, Storhaug H, Nyrnes A, Sundsfjord J, Jenssen TG. Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab 2006;91:145-53.
68Knudsen N, Laurberg P, Rasmussen LB, Bülow I, Perrild H, Ovesen L, et al. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. J Clin Endocrinol Metab 2005;90:4019-24.
69Simonsick EM, Newman AB, Ferrucci L, Satterfield S, Harris TB, Rodondi N, et al. Health ABC Study. Subclinicalhypothyroidism and functional mobility inolder adults. Arch Intern Med 2009;169:2011-7.
70Correia N, Mullally S, Cooke G, Tun TK, Phelan N, Feeney J, et al. Evidence for a specific defect in hippocampal memory in overt and subclinical hypothyroidism. J Clin Endocrinol Metab 2009;94:3789-97.
71Tan ZS, Beiser A, Vasan RS, Au R, Auerbach S, Kiel DP, et al. Thyroid function and the risk of Alzheimer disease: The Framingham Study. Arch Intern Med 2008;168:1514-20.
72Squizzato A, Romualdi E, Piantanida E, Gerdes VE, Büller HR, Tanda M, et al. Subclinical hypothyroidism and deep venous thrombosis. A pilot cross-sectional study. Thromb Haemost 2007;97:803-6.
73Samuels MH, Schuff KG, Carlson NE, Carello P, Janowsky JS. Health status, mood, and cognition in experimentally induced subclinical hypothyroidism. J Clin Endocrinol Metab 2007;92:2545-51.
74Fox CS, Pencina MJ, D'Agostino RB, Murabito JM, Seely EW, Pearce EN, et al. Relations of thyroid function to body weight: Cross-sectional and longitudinal observations in a community-based sample. Arch Intern Med 2008;168:587-92.
75Asvold BO, Bjøro T, Vatten LJ. Association of serum TSH with high body mass differs between smokers and never-smokers. J Clin Endocrinol Metab 2009;94:5023-7.
76Monzani F, Caraccio N, Del Guerra P, Casolaro A, Ferrannini E. Neuromuscular symptoms and dysfunction in subclinical hypothyroid patients: Beneficial effect of L-T4 replacement therapy. Clin Endocrinol (Oxf) 1999;51:237-42.
77Laukkarinen J, Kiudelis G, Lempinen M, Räty S, Pelli H, Sand J, et al. Increased prevalence of subclinical hypothyroidism in common bile duct stone patients. J Clin Endocrinol Metab 2007;92:4260-4.
78Cinemre H, Bilir C, Gokosmanoglu F, Bahcebasi T. Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: A randomized, doubleblind, controlled study. J Clin Endocrinol Metab 2009;94:151-6.
79Stagnaro-Green A, Chen X, Bogden JD, Davies TF, Scholl TO. The thyroid and pregnancy: A novel risk factor for very preterm delivery. Thyroid 2005;15:351-7.
80Ross DS, Cooper DS, Mulder JE. Subclinical hypothyroidism. Up-to-date Jan 11, 2013