Subclinical Hypothyroidism

by Ben Best




T4 (thyroxine) T3 (triiodothyronine)
[ T<sub>4</sub> (thyroxine)  ] [ T<sub>3</sub> (triiodothyronine) ]


Thyroid hormone (T4,T3) from the thyroid gland regulates metabolic rate, growth and development (particularly brain development). T4 (thyroxine) is manufactured in the thyroid gland in response to TSH (Thyroid Stimulating Hormone, thyrotropin) from the anterior pituitary gland. T4 (an iodoamino acid hormone containing four iodine atoms) is 65% iodine by weight. Iodine deficiency leads to thyroid hormone deficiency (hypothyroidism), whereas excess dietary iodine can cause thyroid hormone excess (hyperthyroidism). In the thyroid gland iodide (I) is oxidized (electron removed) by the enzyme thyroid pyroxidase (TPO) before attachment to amino acid (tyrosine) residues of thyroglobulin (Tg). Transformation of the residues to thyroid hormones occurs on the thyroglobulin, to which the hormones remain attached until release into the bloodstream [ENDOTEXT; Rousset,B; PMID: 25905405 (2015) and ARCHIVES OF TOXICOLOGY; Huser,S; 92:2703 (2018)].

The thyroid gland typically holds enough T4 to maintain normal body hormone levels for 50 days. About 93% of thyroid hormone released from the thyroid gland is T4, while about 7% is T3 (triiodothyronine, one less iodine than T4). Nearly all of the released T4 will ultimately be converted to T3 (which is much more potent than T4) in the tissues. Thousands of times more T4 in the plasma is bound to serum proteins (mostly Thyroxine-Binding Globulin, TGB — which should not be confused with thyroglobulin) than is free, but it is the free T4 and free T3 that is able to enter tissues and be biologically active. Serum proteins bind T4 much more tightly than T3, causing the plasma half-life of T4 to be several times greater than that of T3. The heart cannot convert T4 to T3 and is thus dependent upon free T3 in the serum.

Thyroid hormones are essential for normal development, especially of the central nervous system. Thyroid hormones are regulators of metabolic rate and oxygen consumption. Stimulation of heart contractility accounts for 30 to 40 percent of a thyroid-hormone stimulated increase in oxygen consumption. Thyroid hormones increase the sensitivity of the heart to catecholamines. In hyperthyroidism heart rate & stroke volume increase, peripheral vascular resistance decreases, and there is ventricular hypertrophy, whereas opposite effects are seen in hypothyroidism.

Exposure of rats to severe cold increases TSH secretion and output of thyroid hormones, thereby increasing metabolic rate up to 50%. The size and number of mitochondria in the body increase when thyroid hormones are increased. During fasting there is a reduction in TSH secretion and reduced T4 activation in body tissues. Dieting or calorie restriction with adequate nutrition can cause a reduction in body temperature and metabolic rate associated with reduced serum T3 [AMERICAN JOURNAL OF CLINICAL NUTRITION; Karklin,A; 59(2):346-349 (1994) and TOXICOLOGICAL SCIENCES; Walford,RL; 52(Suppl):61-65 (1999)].

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Iodine deficiency during pregnancy can lead to a form of irreversible hypothyroid retardation of mental development and body growth in the infant known as cretinism.

In overt adult hypothyroidism, skin is dry and is easily bruised. Wounds heal slowly. Heart rate and stroke volume are reduced, but there is diastolic, sodium-sensitive hypertension due to increased peripheral resistance, increased arterial stiffening, and endothelial dysfunction [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Asvold,BO; 92(3):841-845 (2007)]. There is reduced exercise tolerance and increased shortness of breath on effort. Serum levels of LDL cholesterol increase and there is increased risk of atherosclerosis. There is a predisposition to ventricular irritability [CIRCULATION; Klein,I; 116(15):1725-1735 (2007)]. There is weight gain, despite a reduction in appetite. There is muscle weakness and cramping. Intellectual functions are slowed, memory defects occur and most of the day (12-14 hours) can be spent sleeping. Reduced serotonin release and decreased receptor sensitivity to serotonin in the cerebral cortex due to low thyroid levels may augment depression [MOLECULAR PSYCHIATRY; Bauer,M; 7(2):140-156 (2002)]. Increased oxidative stress (that is reversed by taurine supplementation) is seen in a rat model of hypothyroidism [CELL BIOCHEMISTRY AND FUNCTION; Tas,S; 24(2):153-158 (2006)]. The thyroid gland contains more selenium per gram than any other tissue, and selenium supplementation may prove to be of benefit for hypothyroidism [JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Duntas,LH; 95(12):5180-5188 (2010)]. In women there may be reduced libido, ovulation failure, and excessive, irregular bleeding. Body temperature drops and there is cold intolerance. Protein synthesis and degradation are both reduced.

Hypothyroid patients have been found to have reduced serum Vitamin B12 and elevated homocysteine (a cardiovascular risk factor). Treatment with thyroid hormone has lowered serum homocysteine, but also lowered serum Vitamin B12 [ENDOCRINE JOURNAL; Orzechowska-Pawilojc,A; 54(3):471-476 (2007)].

In autoimmune thyroid disorders, three types of antibodies can be found in the serum against three different thyroid-related proteins:

  1. thyroglobulin (Tg)
  2. thyroid peroxidase (TPO)
  3. TSH receptor (TSHr)

Autoimmune thyroiditis (Hashimoto's disease) is hypothyroidism associated with elevated Tg and/or TPO antibodies. Hashimoto's disease is the most common type of hypothyroidism in the absence of iodine deficiency. As with autoimmune diseases in general, autoimmune hypothyroidism is much more common in women than in men [THE AMERICAN JOURNAL OF PATHOLOGY; Fairweather,D; 173(3):600-609 (2008)]. Tg & TPO antibodies are secondary to thyroid injury, rather than primary causes of disease, but once formed they can worsen disease. Tg & TPO antibodies in disease-free persons in the United States rises from being found in 5-6% of teenagers to 20-22% of persons over 80 years of age [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Hollowell,JG; 87(10):489 (2002)]. Hypothyroidism can be induced by excessive iodine intake, a condition that is more common in Japan where consumption of iodine-rich foods is high. A Japanese study of reversible hypothyroid patients found that iodine restriction (avoiding foods such as seaweed products) led to a 50% decrease in serum TSH within one week for those who had no antithyroid antibodies, whereas the same decrease took over two weeks for those with antibodies or who had elevated TSH associated with pregnancy [CLINICAL ENDOCRINOLOGY; Sato,K; 45(5):519-528 (1996)].

Hyperthyroidism (Grave's disease) is associated with TSHr antibodies. Antibodies to TSHr are usually (80-95% of cases) found in Grave's disease patients, sometimes (10-20% of cases) found in Hashimoto's disease patients, but are not found in persons who have no thyroid abnormality. Antibodies to Tg & TPO are usually found in patients with Grave's disease (along with the more characteristic TSHr antibodies), and may be found (5-27% of cases) in persons who have no thyroid disease, including especially pregnant women. About 60% of hyperthyroid patients have anxiety disorder, and depressive disorders are frequent as well [JOURNAL OF NEUROENDOCRINOLOGY; Bauer,M; 20(10):1101-1114 (2008)].

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About 0.3% of the population of the United States is estimated to have overt hypothyroidism, whereas 4.3% are estimated to have subclinical hypothyroidism [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Hollowell,JG; 87(10):489 (2002)].

Subclinical hypothyroidism is typically defined as elevated plasma TSH while free plasma T4 and T3 remain within normal range (although low). Elevated TSH may or may not cause a corrective increase in thyroid hormone production & release. Plasma TSH above 20 milli-International Units per liter (20 microIU per milliliter, 20 μIU/mL) is associated with overt hypothyroidism, whereas TSH in the 0.4 to 4 μIU/mL range is considered normal. Median plasma TSH in the disease-free population of the United States rises with age from 0.44 μIU/mL in teenagers to 9.36 μIU/mL for those who are over age 80 [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Hollowell,JG; 87(10):489 (2002)]. Subclinical hypothyroidism in the 10 μIU/mL to 20 μIU/mL plasma TSH range is often treated with T4 (levothyroxine) replacement (25 to 75 micrograms per day), but treatment of those with plasma TSH between 4 μIU/mL to 10 μIU/mL is controversial [ENDOCRINE REVIEWS; Biondi,B; 29(1):76-131 (2008)].

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A study of over 30,000 individuals with plasma TSH in the normal range (0.5 μIU/mL to 3.5 μIU/mL) found a linear increase of both mean systolic and mean diastolic blood pressure with increasing plasma TSH, amounting to a 3−5 mmHg increase in systolic and 2−4 mmHg increase in diastolic blood pressure [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Asvold,BO; 92(3):841-845 (2007)]. Another study of over 30,000 individuals with plasma TSH in the normal range (0.5 μIU/mL to 3.5 μIU/mL) found a linear increase in serum LDL cholesterol & triglycerides as well as a linear decrease in serum HDL cholesterol with increasing plasma TSH [ EUROPEAN JOURNAL OF ENDOCRINOLOGY; Asvold,BO; 156(2):181-186 (2007)]. A study of 25,000 Norwegians (about one-third men) over age 20 with mean follow-up of 8.3 years found a positive correlation for women (but not men) between coronary heart disease and TSH within the 0.5 to 3.5 μIU/mL range [ARCHIVES OF INTERNAL MEDICINE; Asvold,BO; 168(8):855-860 (2008)]. A study of over 3,000 Americans over age 65 (mean follow-up 12.5 years) found no association between subclinical hypothyroidism (7μIU/mL ± 3μIU/mL) and cardiovascular disorder or mortality [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Cappola,AR; 295(9):1033-1041 (2006)]. An Australian study of over 2,000 subjects (mean age 50 years, age range 17-89 years) found 5.6% to have subclinical hypothyroidism. Over a 20-year period those with subclinical hypothyroidism having plasma TSH greater than 10 μIU/mL were more than twice as likely to have a coronary heart disease event (fatal or nonfatal) as normals. Those with subclinical hypothyroidism having plasma TSH less than 10 μIU/mL were more than one-and-a-half times as likely to have a coronary heart disease event as those with normal TSH [ARCHIVES OF INTERNAL MEDICINE; Walsh,JP; 165(21):2467-2472 (2005)]. Commenting on studies that had not shown a significant increase in cardiovascular disease for subclinical hypothyroidism the authors of the Australian study noted that the other studies were for shorter periods and that the divergence from disease-free survival curves is most obvious after ten years. It may be significant, however, that the Norwegian & Australian subjects were younger than the American subject if high TSH is more of a risk factor when it occurs at a younger age.

A small study of 24 patients with subclinical hypothyroidism having mean serum TSH of 5.3 μIU/mL found decreased intramyocardial contractility that impaired both active and passive phases of diastole [EUROPEAN JOURNAL OF ENDOCRINOLOGY; Fabrizio,A; 155(1):3-9 (2006)]. A study of 225 healthy men showed a negative linear relationship (that extended into the normal TSH range) for serum TSH and both insulin sensitivity & endothelial function [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Fernandez-Real,J; 91(9):3337-3343 (2006)]. Reduced endothelial function contributes to atherosclerosis through increased adhesion of leucocytes to blood vessel walls [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Kubes,P; 88(11):4651-4655 (1991)]. Increasing coronary artery intima media thickness (strongly associated with atherosclerosis) is seen with decreasing serum free thyroxine (T4) even in subjects with serum levels of thyroxine in the normal range [CLINICAL ENDOCRINOLOGY;Dullaart,RPF; 67(5):668-673 (2007)].

Subclinical hypothyroid patients receiving thyroxine sometimes exhibit subclinical hyperthyroidism, defined as low serum TSH, but normal T4 and T3. A study of nearly 6,000 subjects over age 65 found increasing incidence of atrial fibrillation with increasing levels of plasma thyroxine (T4) in the range from hypothyroid to subclinical hyperthyroid [ARCHIVES OF INTERNAL MEDICINE; Gammage,MD; 167(9):928-934 (2007)]. A study of older women showed that nearly half of those with subclinical hyperthyroidism developed overt hyperthyroidism within five years [THE AMERICAN JOURNAL OF MEDICAL SCIENCES; Diez,JJ; 337(4):225-232 (2009)]. Whether subclinical hyperthyroidism leads to increased mortality is controversial [ JOURNAL OF THE CARDIOMETABOLIC SYNDROME; Duggal,J; 2(3):198-206 (2007) and CLINCIAL CHEMISTRY; Goichot,B; 55(3):420-424 (2009)].

A healthy ventricle will have a short Pre-Ejection Period (PEP, the interval between ventricular contraction and the opening of the semilunar valves to eject blood) and a long ejection time (LVET, Left Ventricular Ejection Time). PEP/VLET ratio is therefore sometimes uses as an index of cardiac contractility [EUROPEAN HEART JOURNAL; Gillebert,TC; 25(24):2185-2186 (2004)]. A small study (40 middle-aged females) comparing 20 patients having autoimmune subclinical hypothyroidism (10.6 μIU/mL ± 4 μIU/mL) with controls found prolonged PEP and an increased PEP/LVET ratio in the subclinical hypothyroid patients (although LVET was not significantly different between the groups) [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Vitale,G; 87(9):4350-4355 (2002)]. Other studies of subclinical hypothyroidism and myocardial contractility have had variable results [THYROID; Kahaly,GJ; 10(8):665-679 (2000)]. Thyroid hormone increases myocardial contractility through calcium transport and myosin ATPase activation.

Unlike overt hypothyroidism, in which levothyroxine therapy has normalized high plasma homocysteine level [ANNALS OF INTERNAL MEDICINE; Hussein,WI; 131(5):348-351 (1999)], plasma homocysteine level has not been shown to be associated with subclinical hypothyroidism [THYROID; Deicher,R; 12(8):733-736 (2002)]. Subclinical hypothyroid impairment of left ventricular diastolic function that is corrected by levothyroxine therapy has been a common finding in several studies [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Monzani,F; 86(3):1110-1115 (2001), AMERICAN JOURNAL OF CARDIOLOGY; Brenta,A; 91(11):1327-1330 (2003), JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY; Ripoli,A; 45(3):439-445 (2005), and INTERNATIONAL JOURNAL OF CARDIOLOGY; Yazici,M; 95(2-3):135-143 (2004)].

Nonetheless, elderly persons with high TDH show no increased risk of mortality, and show a decreased risk of disability [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Pearce,S; 101(11):4385-4394 (2016)

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A study of subclinical hypothyroid patients (plasma TSH averaging 15 μIU/mL ± 7 μIU/mL) showed impaired working memory (but not other memory functions). But after six months of levothyroxine (T4) treatment to return TSH to normal, working memory became normal [BRAIN; Zhu,D; 129(11):2923-2930 (2006)]. A small randomized double-blind study of women having subclinical hypothyroidism (TSH 5 μIU/mL to 10 μIU/mL) given thyroxine (50 μgrams) or placebo daily for 6 months showed no clinically relevant benefits, but there was a worsening of anxiety in the thyroxine group [AMERICAN JOURNAL OF MEDICINE; Kong,WM; 112(5):348-354 (2002)].

A randomized clinical trial of one hundred subclinical hypothyroid subjects (mean plasma TSH 6.6 μIU/mL) given 100 micrograms per day levothyroxine (T4) or placebo for 12 weeks (24 weeks total, 12 weeks each on either placebo or T4) showed self-reported tiredness dropped from 89% to 78% and central adiposity (hip-to-waist ratio) dropped from 0.83 to 0.81 [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Razvi,S; 92(5):1715-1723 (2007)]. About 20% of subclinically hypothyroid postmenopausal women being given thyroid therapy have been made subclinically hyperthyroid — contributing to osteoporosis [ANNALS OF THE NEW YORK ACADEMY OF SCIENCES; Abe,E; 1116:383-391 (2007)]. Subclinical hypothyroid patients given enough levothyroxine to induce subclinical hyperthyroidism showed slightly impaired physical health, but improved mood and motor learning ability [JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; Samuels,MH; 93(5):1730-1736)].

In contrast to studies of middle-aged men which have shown higher rates of mortality with subclinical hypothyroidism, a cohort of individuals aged 85 showed increased survival with increasing levels of TSH and decreasing levels of free T4 [JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION; Gussekloo,J; 292(21):2591-2599 (2004)]. In a study of rats made hypothyroid during the first ten days of life, the mortality rate was the same as control until 24 months, but declined thereafter — with a significant increase in both average lifespan and maximum lifespan (maximum lifespan increased from 31 months to 35 months) [MECHANISMS OF AGING AND DEVELOPMENT; Ooka,H; 22(2):113-120 (1983)].

Mice subjected to chronic psychological stress show impaired T-cell mediated immunity due to decreased thyroid hormone [BIOLOGICAL PSYCHIATRY; Frick,LR; 65(11):935-942 (2009)].

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Proponents of treating subclinical hypothyroidism point to discomforting symptoms that can be relieved by thyroxine therapy, including symptoms related to cardiovascular disease risk. Proponents also claim that a significant portion of untreated patients progress to overt hypothyroidism [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; McDermott,MT; 86(10):4585-4590 (2001)].

Opponents of treating subclinical hypothyroidism warn of the problems & dangers of having to continuously be treated & monitored, especially the risk of induced hyperthyroidism and associated atrial fibrillation [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Chu,JW; 86(10):4591-4599 (2001) and EUROPEAN JOURNAL OF ENDOCRINOLOGY; Brabant,G; 154(5):633-637 (2006)].

Progression from subclinical to overt hypothyroidism is more likely when serum TSH and markers of thyroid antibodies are high [THYROID; Kahaly,GJ; 10(8):665-679 (2000)].

Treatment with levothyroxine has only been shown to reduce mortality in persons under age 65. [PLOS ONE; Andersen,M; 10(6):e0129793 (2015)

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