Official reprint from UpToDate®

www.uptodate.com

Back

Subclinical hypothyroidism

Author Douglas S Ross, MD

Section Editor David S Cooper, MD

Deputy Editors Kathryn A Martin,MD

Last literature review version 16.1: January 2008 | This Topic LastUpdated: February 4, 2008 (More)

INTRODUCTION — Subclinical hypothyroidism is defined as a normal serumfree thyroxine (T4) concentration and a slightly high serum thyrotropin (TSH)

concentration [ 1] . Patients with a basal serum TSH concentration in the

upper normal range and a greater than normal serum TSH response to theadministration of thyrotropin- releasing hormone (TRH) are also said to have

subclinical hypothyroidism by some authors [ 2] . (See "Laboratory

assessment of thyroid function" ).

Patients with subclinical hypothyroidism may have vague, non-specificsymptoms of hypothyroidism, but attempts to identify the patients on thebasis of specific, thyroid-related symptoms and signs have not been

successful [ 3] . Thus, this disorder can only be diagnosed on the basis of

laboratory test results. ( See "Laboratory assessment of thyroid function" ).

ETIOLOGY — The causes of subclinical hypothyroidism are the same as

those of overt hypothyroidism. ( See "Disorders that cause hypothyroidism" ).

Most patients have chronic autoimmune (Hashimoto's) thyroiditis with highserum concentrations of antithyroid microsomal (or antithyroid peroxidase)antibodies. In a study in the United States, for example, chronicautoimmune thyroiditis was found in 54 percent of patients with subclinical

hypothyroidism [ 4] . Similarly, in an English study 67 percent of women and

40 percent of men with subclinical hypothyroidism had high serum

antithyroid antibody concentrations [ 5] .

The other major cause is prior ablative therapy for hyperthyroidism causedby Graves' disease, accounting for up to 40 percent of the cases in the

United States [ 4] . About half of clinically euthyroid patients who received

radioiodine for Graves' hyperthyroidism and up to two-thirds of those

treated surgically have high serum TSH concentrations [ 6-8] .

Another common cause of subclinical hypothyroidism is inadequate T4replacement therapy for overt hypothyroidism, found in 37 percent of

patients in one study [ 9] . This may be intentional in patients with coexisting

heart disease, due to poor patient compliance, and/or inadequatemonitoring of therapy.

EPIDEMIOLOGY — In two population-based studies, the prevalence ofsubclinical hypothyroidism was 7.5 to 8.5 percent in women and 2.8 to 4.4

percent in men [ 5,10] . In the United States, National Health and

Examination Survey (NHANES III), which excluded subjects with knownthyroid disease, 4.3 percent of 16,533 people had subclinical hypothyroidism

[11] . The prevalence is lower in blacks than in whites in the United States

[12] .

However, serum TSH distribution shifts towards higher values with age [ 13]

. The change is independent of the presence of antithyroid antibodies,

raising uncertainty as to the upper limit of normal for serum TSH ( see

"Laboratory assessment of thyroid function" ).

Subclinical hypothyroidism occurs in about 15 percent of women over the

age of 60 years [ 5,14] and in about 8 percent of elderly men [ 14] . The

prevalence in women over age 80 years is lower (6 percent) [ 15] . The

clinical manifestations and consequences of hypothyroidism (subclinical and

overt) in the elderly are discussed in detail elsewhere. ( See "Clinical

manifestations of hypothyroidism" , section on Hypothyroidism in the elderly).

Subclinical hypothyroidism is more common in patients with type 1 diabetes

mellitus [16] , and probably also in those with other autoimmune diseases,

as compared with otherwise normal subjects. Two percent of pregnantwomen have subclinical hypothyroidism, many of whom have high serum

antithyroid antibody concentrations [ 17] .

In Europe, where iodine intake is variable, subclinical hypothyroidism is

more prevalent in areas of iodine sufficiency. In one study, the prevalence ofsubclinical hypothyroidism ranged from 4.2 percent in iodine-deficient areasto 23.9 percent in an area of abundant iodine intake, despite a similarprevalence of patients with high serum concentrations of anti-thyroid

peroxidase antibodies [ 18] .

NATURAL HISTORY — A substantial proportion of patients with subclinicalhypothyroidism eventually develop overt hypothyroidism. In a study in whichsubjects were followed for 20 years, for example, women with both highserum TSH and high thyroid antibody concentrations developed

hypothyroidism at a rate of 4.3 percent per year [ 19] .

Another study evaluated patients over age 60 years [ 20] . One-third of

those with subclinical hypothyroidism developed overt hypothyroidism infour years (8 percent per year). The risk was related in part to the initiallaboratory findings. All patients with an initial serum TSH concentration >20mU/L, 80 percent of those with serum antithyroid microsomal antibody titersof 1:1600 or higher, but no one with titers of less than 1:1600 developedovert hypothyroidism. Only 5 to 6 percent of patients had normal serum TSH

concentrations during follow up [ 15] .

In a prospective study of 82 women, overt hypothyroidism developed in nowoman who had a serum TSH concentration <6 mU/L, 43 percent of womenwith serum TSH concentrations of 6 to 12 mU/L, and 77 percent of womenwith serum TSH concentration >12 mU/L after 10 years; overthypothyroidism was more likely in women with high serum antithyroid

peroxidase concentrations [ 21] . Another study of 107 subjects found that

serum TSH concentration was the only significant predictor of progression toovert hypothyroidism: patients with serum TSH concentrations under 10, orbetween 15 and 19 mU/L were associated with 1.76 and 73.47 cases of

overt hypothyroidism per 100 patient years, respectively [ 22] .

Spontaneous recovery has also been described in patients with subclinicalhypothyroidism, although the frequency of this phenomenon is unclear

[21,22] . In one study, 37 percent of patients normalized their serum TSH

levels over a mean follow-up time of 31.7 months [ 22] . Normalization of

serum TSH concentrations were more likely to occur in patients withnegative antithyroid antibodies and serum TSH levels <10 mU/I, and within

the first two years after diagnosis [ 23] .

The underlying disease also may be a determinant of the risk of overt

hypothyroidism [ 24] . Patients who have autoimmune thyroid disease or

received radioiodine therapy or high-dose external radiotherapy are likely toprogress to overt hypothyroidism. In contrast, subclinical hypothyroidism islikely to persist in those who have had thyroid surgery for indications otherthan hyperthyroidism, or in those who received external radiotherapy duringchildhood. In an analysis of a primary care network, which included 422,242persons without known thyroid disease, 62 percent who had had a TSHmeasurement between 5.5 to 10 mIU/L had a normal TSH subsequently in

the absence of treatment [ 25] .

EFFECTS OF THYROID HORMONE REPLACEMENT — The fundamentalclinical question regarding patients with subclinical hypothyroidism iswhether they should be treated with thyroid hormone. Based upon the

natural history alone, one might argue that treatment should be started toprevent progression to overt hypothyroidism. Many randomized trials andother studies suggest additional benefits from treatment.

Hypothyroid symptoms and psychometric outcomes — Thyroid hormonereplacement has resulted in improved hypothyroid symptoms andpsychometric outcomes in some, but not all trials. Benefit appears to belimited to patients with baseline serum TSH concentration ≥ 10 mU/L.

One double-blind trial randomly assigned patients with subclinicalhypothyroidism, including some patients with TSH values as high as55 mU/L, some of whom had symptoms such as dry skin, low energyand cold intolerance, to treatment with T4 or placebo for one year

[26] . The dose of T4 was adjusted to normalize the serum TSH

concentration. During treatment, one-half of the patients in the T4group, but none in the placebo group, had fewer symptoms, asassessed by a standardized hypothyroidism diagnostic index.

Another trial was a double-blind cross-over study in which patients

received either T4 (0.15 mg/day) or placebo, each for six months [ 27]

. The T4 dose was somewhat high; as a result, some patients mayhave had subclinical hyperthyroidism. Hypothyroid symptom scoresand psychometric test results improved during the T4-treatmentperiod, and about one-half of the patients felt better during thisperiod, as compared with the placebo period.

A third 10-month double-blind trial found a significant improvement inpsychometric test scores, but no improvement in quality of life, during

treatment with T4 [ 28] ; some TSH values were as high as 32 mU/L.

In an additional trial, hypothyroid symptom scores also improved [ 29] .

In a double blind randomized cross-over trial of 100 patients withserum TSH between 3.7 and 15.8 mU/L, fatigue improved with a fixed

dose of levothyroxine 0.100 mg daily [30] .

In a trial of hypothyroid patients receiving T4 replacement, subclinicalhypothyroidism was induced by reducing the thyroxine dose (meanTSH 17 mU/L). The fatigue subscale of the Profile of Mood States, thegeneral health subscale of the Short Form 36, and measures ofworking memory were impaired during the subclinical hypothyroid arm

[31] .

In contrast, in two trials of patients with serum TSH concentrations ≤ 10mU/L treated with T4, no beneficial effect was seen on quality of life

measures [ 32] , cognitive function, emotional function, or hypothyroid

symptoms scores [ 33] .

Lastly, in a meta-analysis of 12 clinical trials, there were no differences inhypothyroid signs or symptoms, quality of life, and adverse effects between

levothyroxine therapy and placebo [ 34] .

Thus, improvement was seen in psychometric test scores and hypothyroidsymptoms in some, but not all, trials. No benefit was seen in trials ofpatients whose TSH values were under 10 mU/L.

Serum lipid and apoprotein concentrations — Despite a few conflicting

reports [ 35-37] , many cross-sectional studies have found that serum total

cholesterol concentrations in patients with subclinical hypothyroidism were

similar to those of normal subjects [ 1,38-46] ; these concentrations did not

consistently fall during T4 treatment [ 26,27,35-37,41,45,47-51 ] . However,

in the largest cross-sectional study to date (25,862 participants), subjectswith modest elevations of serum TSH (between 5.1 and 10 mIU/L) hadsignificantly higher mean total cholesterol concentrations than those whowere euthyroid (223 versus 216 mg/dL [5.6 versus 5.8 mmol/L], p<0.03)

[52] . It is not known whether this difference is clinically important with

regard to cardiovascular risk.

There are no consistent changes in serum low-density-lipoprotein (LDL)cholesterol, high-density lipoprotein (HDL) cholesterol, and apoproteinconcentrations. In some studies patients with subclinical hypothyroidism

had high serum LDL-cholesterol [ 35-37,39,53] and low HDL-cholesterol

concentrations [ 39,45] , but the values were normal in other studies

[43,44,46] . Serum apoprotein A1 concentrations were high in one study

[46] and low in another [ 53] , serum lipoprotein(a) concentrations were high

in another study [ 37] , and serum apoprotein B concentrations were normal

in some studies [ 38,45,46] and high in two studies [ 35,54] .

In a randomized, controlled trial in 66 women with subclinicalhypothyroidism treated with T4, serum total and LDL cholesterol, andapoprotein B-100 concentrations decreased significantly, whereas serumHDL cholesterol, triglyceride, and lipoprotein (a) concentrations did not

change [ 29] . In other studies, serum total and LDL cholesterol

concentrations [ 30,35,54] and apoprotein B [ 30,53] decreased after T4

therapy. And in two non-randomized trials serum lipoprotein (a)

concentrations were reduced by T4 [ 55,56] .

Further support for a mild increase in serum cholesterol in subclinicalhypothyroidism comes from a pooled analysis of the published literature,which revealed that T4 therapy resulted in a small decrease in mean serum

total cholesterol concentration of about 16 mg/dL (0.4 mmol/L) [ 57] . In

addition, a meta-analysis of 247 patients in 13 studies of subclinicalhypothyroidism found that T4 therapy resulted in significant reductions inserum total cholesterol (8 mg/dL [0.2 mmol/L]) and serum LDL cholesterol(10 mg/dL [0.3 mmol/L]); the mean serum HDL cholesterol and triglyceride

concentrations did not change [ 58] . In this metaanalysis, reductions in

serum cholesterol were only seen in patients with levels >240 mg/dL atbaseline. Also, only those patients who had "subclinical hypothyroidism"based on inadequately treated overt hypothyroidism had statistically

significant decreases in serum cholesterol. ( See "Lipid abnormalities in

thyroid disease" ).

Smoking may worsen subclinical hypothyroidism and increase its peripheraleffects. Among women with subclinical hypothyroidism, those who smokedtwo or more cigarettes per day had higher serum TSH concentrations andhigher serum total and LDL cholesterol concentrations than those who did

not smoke [ 59] . The effect of smoking was dose-dependent.

Cardiac function —

Diastolic blood pressure was unchanged in one study [ 60] , increased in two

studies [ 61,62] , and mean arterial pressure fell after T4 treatment in

another study [ 63] . Some patients with subclinical hypothyroidism have

diastolic dysfunction and increased peripheral vascular resistance, as noted

in patients with overt hypothyroidism [ 64] , and cardiac output increases

and systemic vascular resistance decreases after T4 treatment [ 63] . Right

ventricular systolic and diastolic function were abnormal in one study and

improved with T4 treatment [ 65] . Systolic time intervals usually do not

change [ 26,66] , unless they were initially prolonged [ 26] . The left

ventricular ejection fraction at rest [ 47,67] or during moderate exercise

does not change, but may increase during maximal exercise [ 67] .

Myocardial contractility during maximal exercise also may increase [ 67] .

In contrast, one observational study found no abnormalities in leftventricular mass or function in patients with serum TSH concentrations

between 3.5 and 10 mU/l compared to those with normal TSH [ 68] . (See

"Cardiovascular effects of hypothyroidism" ).

One randomized trial assessed only myocardial structure and contractility.Isovolumetric relaxation time and preejection/ejection ratio were increasedand the cyclic variation index was decreased in patients with subclinicalhypothyroidism. These alterations returned to normal with T4, but not with

placebo [ 69] .

Finally, one trial demonstrated an 11 percent improvement in carotid

intima-media thickness with treatment of subclinical hypothyroidism [ 54] .

Cardiovascular disease — Overt hypothyroidism may be associated with an

increased risk of cardiovascular disease. ( See "Cardiovascular effects of

hypothyroidism" ). Subclinical hypothyroidism may also be associated with an

increased risk of cardiovascular disease, coronary heart disease, and

possibly, all-cause mortality [ 70-77] . This was illustrated by the following

studies:

Flow-mediated dilatation, a measure of vascular endothelial responseand an early marker for atherosclerosis, was impaired in across-sectional study of patients with subclinical hypothyroidism

(mean TSH 8.85) compared with matched euthyroid controls [ 74] , and

was improved with thyroxine treatment in two trials [ 30,75] . The

brachial-ankle pulse wave velocity, a parameter of arterial stiffeningand a predictor of coronary atherosclerosis, was significantlyincreased in a cross-sectional study of patients with subclinical

hypothyroidism (mean TSH 6.89) [ 62] . Central aortic pressure and

arterial stiffness was increased in patients with subclinical

hypothyroidism (mean TSH 8.8) and was reduced by treatment [ 78] .

Serum C-reactive protein and plasma asymmetric dimethylarginine (an

endogenous nitric oxide synthase inhibitor) concentrations, appear to

be high in patients with subclinical hypothyroidism, and are

normalized by levothyroxine administration [ 76] .

Platelet-activating factor (PAF) is a proinflammatory lipid mediator thathas been implicated in atherogenesis. In plasma, PAF is inactivated byplatelet-activating factor acetylhydrolase (PAF-AH). HDL-associatedplasma PAF-AH activity is low in patients with subclinicalhypothyroidism (mean TSH 9.9), and increases to control values with

levothyroxine therapy [ 79] .

A number of observational studies have reported that, in general,older subjects with subclinical hypothyroidism are at increased risk for

coronary heart disease [ 70-72,80] . In one of these reports, the

increased risk was seen in men, but not women [ 72] , while in

another, older subjects with subclinical hypothyroidism were at

increased risk for developing heart failure, but not CHD [ 81] .

A meta-analysis of 14 observational studies of subclinicalhypothyroidism calculated an overall increased risk of CHD (OR 1. 65)

[82] .

In summary, subclinical hypothyroidism may be associated with an increasedrisk of CHD. However, clinical trials are needed to assess whether thyroidhormone replacement reduces the risk of CHD in these patients.

Mortality — An English study of mortality in patients treated forhyperthyroidism found that patients with subclinical hypothyroidismfollowing radioiodine treatment had a two-fold increased mortality from

ischemic heart disease [ 83] . (See "Radioiodine in the treatment of

hyperthyroidism" , section on Mortality).

One of the observational studies noted above reported an increase in

all-cause mortality in men, but not women [ 72] , while two others observed

an increased risk of cardiovascular mortality [ 77,80] , one of which included

3121 cardiac patients and also found an increase in all cause mortality [ 77] .

In contrast to the studies described above, the Cardiovascular Health Studyof 3233 community-dwelling subjects over age 65 years, reported thatsubclinical hypothyroidism was not associated with an increased risk of CHD,

adverse cardiovascular outcomes, or mortality [ 84] .

In addition, in a study of individuals over age 85 in the Netherlands followedfor four years, those with untreated subclinical hypothyroidism actually had

a lower rate of cardiovascular and all-cause mortality. ( See "Diagnosis of

and screening for hypothyroidism" , section on Very elderly).

Neuropsychiatric disease — Many reports of an increased prevalence ofsubclinical hypothyroidism in patients with depression or bipolar affectivedisorder need critical assessment because of confounding factors such as

inadequate control groups, coincident lithium therapy, inclusion of patients

with normal basal serum TSH concentrations but an increased response ofserum TSH to TRH administration, and/or positive tests for antithyroidmicrosomal antibodies. A 1998 study suggested that depression correlatedwith high serum anti-thyroid peroxidase antibody concentrations rather

than thyroid function [ 85] .

Despite these limitations, several reports suggest that subclinicalhypothyroidism is associated with neuropsychiatric disease. In one study,as an example, the prevalence of hypothyroidism was 14.8 percent inpatients with neurotic depression, 2.3 percent in those with senile and

multi-infarct dementia, and 1.9 percent in non-psychiatric inpatients [ 86] .

However, a large study of primary care patients in England failed todemonstrate an association of subclinical hypothyroidism with depression,

anxiety, or cognitive function [ 87] .

The following additional findings have been noted:

Patients with depression and subclinical hypothyroidism have a higherprevalence of associated panic disorder, and a poorer response to

antidepressant drugs than euthyroid depressed patients [ 88] .

Patients with subclinical hypothyroidism have a higher lifetime

frequency of depression than euthyroid subjects [ 89] .

Women with subclinical hypothyroidism who presented to a clinic forassessment of goiter were found to have increased rates offree-flowing anxiety, somatic complaints, depressive features,hysteria, and abnormal psychometric testing as compared with

euthyroid patients with goiter [ 90] . These problems improved with T4

treatment.

Pregnancy — Undetected subclinical hypothyroidism in pregnancy is a riskfactor for poor developmental outcome in the offspring, as shown in a studyof 62 children whose mothers had high serum TSH (48 of whom were not

treated) and low serum T4 concentrations during the second trimester [ 91] .

At age seven to nine years, these children had slightly lower IQ scores thandid 124 children of mothers whose serum TSH concentrations were normal(IQ score 103 versus 107, p=0.06); 15 percent of the former group but only5 percent of the latter group had scores of 85 or less.

Other findings — The following findings have also been described inpatients with subclinical hypothyroidism:

In one study, serum TSH concentrations greater than 3.6 mU/I (and anormal free T4) were associated with modest weight gain when

compared to those with serum TSH 0.4 to 0.99 mU/I [ 92] . However,

another study in children found that obese subjects had a higherserum TSH which fell to normal levels with weight loss, suggesting

that the higher TSH was a result of obesity and not the cause [ 93] .

(See "Etiology and natural history of obesity" , section on

Hypothyroidism)

An increase in C-reactive protein [ 73]

An increase in erythrocyte Na/K-ATPase [ 94]

A high frequency of neuromuscular symptoms (weakness, fatigue,paresthesias, cramps), as compared with normal subjects; in onestudy 21 of 33 patients (64 percent) had two or more of thesesymptoms, as compared with 6 of 44 normal subjects (14 percent)

[95]

A prolonged Achilles reflex time that became normal during treatment

with triiodothyronine [ 46,96]

Muscle dysfunction characterized by excessive release of lactate

during exercise [ 97]

Altered response to exercise in terms of tolerance and pattern ofsubstrate utilization; one year of thyroid hormone therapy and

restoration of euthyroidism did not correct this defect [ 98]

Electromyographic evidence of peripheral neuropathy [ 99]

Elevated basal prolactin (in 19 percent of patients), and elevated

prolactin response to TRH administration, which falls with T4 treatment

[100]

Elevated intraocular pressure, which falls with T4 treatment [ 101]

In one study, bone density was not reduced in patients with

subclinical hypothyroidism after 14 months of treatment with T4 [ 102]

; however, another study documented increased parameters of bone

turnover. (See "Bone disease with hyperthyroidism and thyroid

hormone therapy" )

Patients with unprovoked deep venous thrombosis are more likely to

have subclinical hypothyroidism [ 103] .

Patients with subclinical hypothyroidism are more likely to havecommon bile duct stones, thought to be secondary to sphincter of

Oddi dysfunction [ 104] .

Patients with type 2 diabetes and subclinical hypothyroidism have a

greater prevalence of diabetic nephropathy [ 105] .

Hypothyroid symptoms with normal thyroid function tests — Anecdotalreports suggest that T4 therapy may be beneficial in patients withsymptoms of hypothyroidism but normal thyroid function tests. However, ina randomized, crossover trial of 22 such patients, T4 was no more effectivethan placebo in increasing cognitive function and psychologic well-being

[106] .

Thus, T4 should not be prescribed for patients with hypothyroid symptomsbut normal thyroid function.

SERUM TSH ELEVATIONS NOT ASSOCIATED WITH SUBCLINICALHYPOTHYROIDISM — There are several causes of high serum TSHconcentrations that do not properly fit the definition of subclinicalhypothyroidism. These include:

During the period of recovery from nonthyroidal illnessAn unusually large pulse of TSH secretion, especially late in theeveningAssay variabilityAdrenal insufficiency

During treatment with metoclopramide or domperidone

TSH-producing pituitary adenomas and resistance to thyroid hormone,and rare mutations of the TSH receptor

All patients who have high serum TSH concentrations due to these causesare either hyperthyroid or euthyroid. Thus, minimal elevations in serum TSHconcentrations must be confirmed by repeat testing before the diagnosis ofsubclinical hypothyroidism can be accepted.

RECOMMENDATIONS — A 1998 American College of Physicians positionpaper questioned whether sufficient data existed to recommend treatment

for patients with subclinical hypothyroidism [ 107] . However, others have

recommended treatment for most patients, in large part becauseunrecognized symptoms may improve and correction of abnormal serum lipid

concentrations may be cardioprotective [ 108-110] . In view of data linking

subclinical hypothyroidism with atherosclerosis and myocardial infarction

[70] , I recommend that most patients with subclinical hypothyroidism and

TSH levels greater than 10 mU/L be treated with T4. This recommendation isconsistent with that of a clinical consensus group (comprised ofrepresentatives from the Endocrine Society, American Thyroid Association,

and the American Association of Clinical Endocrinologists) [ 111] .

Treatment will prevent progression to overt hypothyroidism, especially inthose with serum TSH concentrations greater than 10 to 15 mU/L and highserum antithyroid peroxidase antibody concentrations. Treatment inpatients with lesser elevations in serum TSH concentrations will preventgrowth of a goiter or possibly ameliorate nonspecific symptoms ofhypothyroidism such as fatigue, constipation or depression. The majorbenefit of therapy, based upon two randomized studies, is an improvement

in symptoms [26,27] . Goiter, if present, decreases in size in about 80

percent of patients [ 112] . Treatment may also improve cardiac contractility

and serum lipid concentrations in some patients and secondarily reduce therisk of atherosclerosis. The goal of therapy should be to reduce the patient'sserum TSH concentration to normal. The initial dose can be the fullanticipated dose in young, healthy patients, but older patients should be

started on a lower dose ( See "Treatment of hypothyroidism" ).

Arguments against T4 treatment include its cost, for both the hormone andfor monitoring its efficacy, the lifelong commitment to daily medication inasymptomatic patients, and the possible induction or exacerbation of angina

pectoris or cardiac arrhythmia in susceptible patients [ 113] . Although these

concerns are not usually sufficient to counterbalance the benefits oftherapy, we do recommend a higher threshold for treating elderly patientswith cardiovascular disease. If the patient is not treated, regular follow up is

indicated.

Recommendations for routine screening are discussed elsewhere. ( See

"Diagnosis of and screening for hypothyroidism" , section on Screening at

the periodic health examination).

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES1. Evered, DC, Ormston, BJ, Smith, PA, et al. Grades of hypothyroidism. Br

Med J 1973; 1:657.

2. Haggerty, JJ Jr, Garbutt, JC, Evans, DL, et al. Subclinical hypothyroidism:

a review of neuropsychiatric aspects. Int J Psychiatry Med 1990;

20:193.

3. Bemben, DA, Hamm, RM, Morgan, L, et al. Thyroid disease in the

elderly. Part 2. Predictability of subclinical hypothyroidism. J Fam Pract

1994; 38:583.

4. Hamburger, JI, Meier, DA, Szpunar, WE. Factitious elevation ofthyrotropin in euthyroid patients [letter]. N Engl J Med 1985; 313:267.

5. Tunbridge, WM, Evered, DC, Hall, R, et al. The spectrum of thyroiddisease in a community: the Whickham survey. Clin Endocrinol (Oxf)1977; 7:481.

6. Tunbridge, WM, Harsoulis, P, Goolden, AW. Thyroid function in patientstreated with radioactive iodine for thyrotoxicosis. Br Med J 1974; 3:89.

7. Toft, AD, Irvine, WJ, Hunter, WM, Seth, J. Plasma TSH and serum T-4levels in long-term follow-up of patients treated with 131-I forthyrotoxicosis. Br Med J 1974; 3:152.

8. Evered, D, Young, ET, Tunbridge, WMG, et al. Thyroid function after

subtotal thyroidectomy for hyperthyroidism. BMJ 1975; 1:25.

9. Sawin, CT, Geller, A, Hershman, JM, et al. The aging thyroid. The use of

thyroid hormone in older persons. JAMA 1989; 261:2653.

10. Bagchi, N, Brown, TR, Parish, RF. Thyroid dysfunction in adults over age

55 years. A study in an urban US community. Arch Intern Med 1990;

150:785.

11. Hollowell, JG, Staehling, NW, Flanders, WD, et al. Serum TSH, T4 and

thyroid antibodies in the United States population (1988 to 1994):

National Health and Examination Survey (NHANES III). J Clin Endocrinol

Metab 2002; 87:489.

12. Kanaya, AM, Harris, F, Volpato, S, et al. Association between thyroid

dysfunction and total cholesterol level in an older biracial population:

the health, aging and body composition study. Arch Intern Med 2002;

162:773.

13. Surks, MI, Hollowell, JG. Age-specific distribution of serum thyrotropin

and antithyroid antibodies in the U.S. population: Implications for the

prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab 2007;

92:4575.

14. Sawin, CT, Chopra, D, Azizi, F, et al. The aging thyroid. Increased

prevalence of elevated serum thyrotropin levels in the elderly. JAMA

1979; 242:247.

15. Parle, JV, Franklyn, JA, Cross, KW, et al. Prevalence and follow-up of

abnormal thyrotrophin (TSH) concentrations in the elderly in the United

Kingdom. Clin Endocrinol (Oxf) 1991; 34:77.

16. Gray, RS, Borsey, DQ, Seth, J, et al. Prevalence of subclinical thyroid

failure in insulin-dependent diabetes. J Clin Endocrinol Metab 1980;

50:1034.

17. Klein, RZ, Haddow, JE, Faix, JD, et al. Prevalence of thyroid deficiency in

pregnant women. Clin Endocrinol (Oxf) 1991; 35:41.

18. Szabolcs, I, Podoba, J, Feldkamp, J, et al. Comparative screening for

thyroid disorders in old age in areas of iodine deficiency, long term

iodine prophylaxis and abundant iodine intake. Clin Endocrinol 1997;

47:87.

19. Vanderpump, MP, Turnbridge, WM, French, JM, et al. The incidence of

thyroid disorders in the community: a twenty-year follow-up of the

Whickham survey. Clin Endocrinol 1995; 43:55.

20. Rosenthal, MJ, Hunt, WC, Garry, PJ, Goodwin, JS. Thyroid failure in the

elderly. Microsomal antibodies as discriminant for therapy. JAMA 1987;

258:209.

21. Huber, G, Staub, JJ, Meier, C, 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.

22. Diez, JJ, Iglesias, P. Spontaneous subclinical hypothyroidism in patients

older than 55 years: an analysis of natural course and risk factors for

the development of overt thyroid failure. J Clin Endocrinol Metab 2004;

89:4890.

23. Diez, JJ, Iglesias, P, Burman, KD. Spontaneous normalization of

thyrotropin concentrations in patients with subclinical hypothyroidism. J

Clin Endocrinol Metab 2005; 90:4124.

24. Kabadi, UM. Subclinical hypothyroidism. Natural course of the syndrome

during a prolonged follow-up study. Arch Intern Med 1993; 153:957.

25. Meyerovitch, J, Rotman-Pikielny, P, Sherf, M, et al. Serum thyrotropin

measurements in the community: five-year follow-up in a large network

of primary care physicians. Arch Intern Med 2007; 167:1533.

26. Cooper, DS, Halpern, R, Wood, LC, et al. L-thyroxine therapy in

subclinical hypothyroidism. A double-blind, placebo-controlled trial. Ann

Intern Med 1984; 101:18.

27. Nyström, E, Caidahl, K, Fager, G, et al. A double-blind cross-over

12-month study of L-thyroxine treatment of women with 'subclinical'

hypothyroidism. Clin Endocrinol 1988; 29:63.

28. Jaeschke, R, Foyatt, G, Gerstein, H, et al. Does treatment with

L-thyroxine influence health status in middle-aged and older adults

with subclinical hypothyroidism? J Gen Intern Med 1996; 11:744.

29. Meier, C, Staub, JJ, Roth, CB, et al. 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 Metab 2001; 86:4860.

30. Razvi, S, Ingoe, L, Keeka, G, et al. The beneficial effect of L-thyroxine

on cardiovascular risk factors, endothelial function, and quality of life in

subclinical hypothyroidism: randomized, crossover trial. J Clin

Endocrinol Metab 2007; 92:1715.

31. Samuels, MH, Schuff, KG, Carlson, NE, et al. Health status, mood, and

cognition in experimentally induced subclinical hypothyroidism. J Clin

Endocrinol Metab 2007; 92:2545.

32. Kong, WM, Sheikh, MH, Lumb, PJ, et al. A 6-month randomized trial of

thyroxine treatment in women with mild subclinical hypothyroidism. Am

J Med 2002; 112:348.

33. Jorde, R, Waterloo, K, Storhaug, H, et al. Neuropsychological function

and symptoms in subjects with subclinical hypothyroidism and the

effect of thyroxine treatment. J Clin Endocrinol Metab 2006; 91:145.

34. Villar, HC, Saconato, H, Valente, O, Atallah, AN. Thyroid hormone

replacement for subclinical hypothyroidism. Cochrane Database Syst

Rev 2007; :CD003419.

35. Caraccio, N, Ferrannini, E, Manzoni, R. Lipoprotein profile in subclinical

hypothyroidism: response to levothyroxine replacement, a randomized

placebo-controlled study. J Clin Endocrinol Metab 2002; 87:1533.

36. Arem, R, Escalante, DA, Arem, N, et al. Effect of l-thyroxine therapy on

lipoprotein fractions in overt and subclinical hypothyroidism with special

reference to lipoprotein a. Metabolism 1995; 44:1559.

37. Kung, AW, Pang, RW, Janus, ED. Elevated serum lipoprotein in

subclinical hypothyroidism. Clin Endocrinol 1995; 43:445.

38. Geul, KW, van Sluisveld, IL, Grobbee, DE, et al. The importance of

thyroid microsomal antibodies in the development of elevated serum

TSH in middle-aged women: associations with serum lipids. Clin

Endocrinol (Oxf) 1993; 39:275.

39. Althaus, BU, Staub, JJ, Ryff-de Lèche, A, et al. LDL/HDL-changes in

subclinical hypothyroidism: Possible risk factors for coronary artery

disease. Clin Endocrinol 1988; 28:157.

40. Bigos, ST, Ridgway, EC, Kourides, IA, Maloof, F. Spectrum of pituitaryalterations with mild and severe thyroid impairment. J Clin EndocrinolMetab 1978; 46:317.

41. Kutty, KM, Bryant, DG, Farid, NR. Serum lipids in hypothyroidism--a

re-evaluation. J Clin Endocrinol Metab 1978; 46:55.

42. Tunbridge, WM, Evered, DC, Hall, R, et al. Lipid profiles andcardiovascular disease in the Whickham area with particular referenceto thyroid failure. Clin Endocrinol (Oxf) 1977; 7:495.

43. Parle, JV, Franklyn, JA, Cross, KW, et al. Circulating lipids and minor

abnormalities of thyroid function. Clin Endocrinol 1992; 37:411.

44. Bogner, U, Arntz, H-R, Peters, H, Schleusener, H. Subclinical

hypothyroidism and hyperlipoproteinaemia: indiscriminate L-thyroxine

treatment not justified. Acta Endocrinol 1993; 128:202.

45. Caron, PH, Calazel, C, Parra, HJ, et al. Decreased HDL cholesterol in

subclinical hypothyroidism: the effect of L-thyroxine therapy. Clin

Endocrinol 1990; 33:519.

46. Staub, J-J, Althaus, BU, Engler, H, et al. Spectrum of subclinical and

overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid

reserve, and metabolic impact on peripheral target tissues. Am J Med

1992; 92:631.

47. Bell, GM, Todd, WTA, Forfar, JC, et al. End-organ responses to thyroxine

therapy in subclinical hypothyroidism. Clin Endocrinol 1985; 22:83.

48. Lithell, H, Boberg, J, Hellsing, K, et al. Serum lipoprotein andapolipoprotein concentrations and tissue lipoprotein lipase activity inovert and subclinical hypothyroidism: the effect of substitution therapy.Eur J Clin Invest 1981; 11:3.

49. Nilsson, G, Norlander, S, Levin, K. Studies on subclinical hypothyroidism

with special reference to the serum lipid pattern. Acta Med Scand 1976;

200:63.

50. Arem, R, Patsch, W. Lipoprotein and apolipoprotein levels in subclinical

hypothyroidism. Effect of levothyroxine therapy. Arch Intern Med 1990;

150:2097.

51. Franklyn, JA, Daykin, J, Betteridge, J, et al. Thyroxine replacement

therapy and circulating lipid concentrations. Clin Endocrinol (Oxf) 1993;

38:453.

52. Canaris, GJ, Manowitz, NR, Mayor, G, Ridgway, EC. The Colorado

thyroid disease prevalence study. Arch Intern Med 2000; 160:526.

53. Iqbal, A, Jorde, R, Figenschau, Y. Serum lipid levels in relation to serum

thyroid-stimulating hormone and the effect of thyroxine treatment on

serum lipid levels in subjects with subclinical hypothyroidism: the

Tromso Study. J Intern Med 2006; 260:53.

54. Monzani, F, Caraccio, N, Kozakowa, M, 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.

55. Milionis, HJ, Efstathiadou, Z, Tselepis, AD, et al. Lipoprotein (a) levels

and apolipoprotein (a) isoform size in patients with subclinical

hypothyroidism: Effect of treatment with levothyroxine. Thyroid 2003;

13:365.

56. Ganotakis, ES, Mandalaki K, Tampakaki M, et al Subclinical

hypothyroidism and lipid abnormalities in older women attending a

vascular disease prevention clinic: effect of thyroid replacement

therapy. Angiology 2003; 54:569.

57. Tanis, BC, Westendorp, RGJ, Smelt, AHM. Effect of thyroid substitution

on hypercholesterolaemia in patients with subclinical hypothyroidism: a

reanalysis of intervention studies. Clin Endocrinol 1996; 44:643.

58. Danese MD, Ladenson PW, Meinert CL, Powe NR. Effect of thyroxine

therapy on serum lipoproteins in patients with mild thyroid failure: a

quantitative review of the literature. J Clin Endocrinol Metab 2000;

85:2993.

59. Muller, B, Zulewski, H, Huber, P, et al. Impaired action of thyroid

hormone associated with smoking in women with hypothyroidism. N

Engl J Med 1995; 333:964.

60. Walsh, JP, Bremner, AP, Bulsara, MK, et al. Subclinical thyroid

dysfunction and blood pressure: a community-based study. Clin

Endocrinol (Oxf) 2006; 65:486.

61. Luboshitzky, R, Aviv, A, Herer, P, Lavie, L. Risk factors for cardiovascular

disease in women with subclinical hypothyroidism. Thyroid 2002;

12:421.

62. Nagasaki, T, Inaba, M, Kumeda, Y, et al. Increased pulse wave velocity

in subclinical hypothyroidism. J Clin Endocrinol Metab 2006; 91:154.

63. Faber, J, Petersen, L, Wiinberg, N, et al. Hemodynamic changes after

levothyroxine treatment in subclinical hypothyroidism. Thyroid 2002;

12:319.

64. Biondi, B, Fazio, S, Palmieri, EA, et al. Left ventricular diastolic

dysfunction in patients with subclinical hypothyroidism. J Clin Endocrinol

Metab 1999; 84:2064.

65. Turhan, S, Tulunay, C, Ozduman Cin, M, et al. Effects of thyroxine

therapy on right ventricular systolic and diastolic function in patients

with subclinical hypothyroidism: a study by pulsed wave tissue Doppler

imaging. J Clin Endocrinol Metab 2006; 91:3490.

66. Bough, EW, Crowley, WF, Ridgway, EC, et al. Myocardial function in

hypothyroidism. Relation to disease severity and response to

treatment. Arch Intern Med 1978; 138:1476.

67. Forfar, JC, Wathen, CG, Todd, WT, et al. Left ventricular performance in

subclinical hypothyroidism. Q J Med 1985; 57:857.

68. Iqbal, A, Schirmer, H, Lunde, P, et al. Thyroid stimulating hormone and

left ventricular function. J Clin Endocrinol Metab 2007; 92:3504.

69. Monzani, F, Di Bello, V, Caraccio, N, et al. Effect of levothyroxine on

cardiac function and structure in subclinical hypothyroidism: a double

blind, placebo-controlled study. J Clin Endocrinol Metab 2001; 86:1110.

70. Hak, AE, Pols, HA, Visser, TJ, et al. Subclinical hypothyroidism is an

independent risk factor for atherosclerosis and myocardial infarction in

elderly women: the Rotterdam Study. Ann Intern Med 2000; 132:270.

71. Lindeman, RD, Romero, LJ, Schade, DS, et al. 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.

72. Imaizumi, M, Akahoshi, M, Ichimaru, S, et al. Risk for ischemic heart

disease and all-cause mortality in subclinical hypothyroidism. J Clin

Endocrinol Metab 2004; 89:3365.

73. Kvetny, 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.

74. Cikim, AS, Oflaz, H, Ozbey, N, et al. Evaluation of endothelial function in

subclinical hypothyroidism and subclinical hyperthyroidism. Thyroid

2004; 14:605.

75. Taddei, S, Caraccio N, Virdis A, et al. Impaired endothelium-dependent

vasodilatation in subclincial hypothyroidism: beneficial effect of

levothyroxine therapy. J Clin Endocrinol Metab 2003; 88:3731.

76. Ozcan, O, Cakir, E, Yaman, H, et al. The effects of thyroxine

replacement on the levels of serum asymmetric dimethylarginine

(ADMA) and other biochemical cardiovascular risk markers in patients

with subclinical hypothyroidism. Clin Endocrinol (Oxf) 2005; 63:203.

77. Iervasi, G, Molinaro, S, Landi, P, et al. Association between increased

mortality and mild thyroid dysfunction in cardiac patients. Arch Intern

Med 2007; 167:1526.

78. Owen, PJ, Rajiv, C, Vinereanu, D, et al. Subclinical hypothyroidism,

arterial stiffness, and myocardial reserve. J Clin Endocrinol Metab 2006;

91:2126.

79. Milionis, HJ, Tambaki, AP, Kanioglou, CN, et al. Thyroid substitution

therapy induces high-density lipoprotein-associated platelet-activating

factor-acetylhydrolase in patients with subclinical hypothyroidism: A

potential antiatherogenic effect. Thyroid 2005; 15:455.

80. Walsh, JP, Bremner, AP, Bulsara, MK, et al. Subclinical thyroid

dysfunction as a risk factor for cardiovascular disease. Arch Intern Med

2005; 165:2467.

81. Rodondi, N, Newman, AB, Vittinghoff, E, et al. Subclinical hypothyroidism

and the risk of heart failure, other cardiovascular events, and death.

Arch Intern Med 2005; 165:2460.

82. Rodondi, N, Aujesky, D, Vittinghoff, E, et al. Subclinical hypothyroidism

and the risk of coronary heart disease: a meta-analysis. Am J Med

2006; 119:541.

83. Franklyn, JA, Sheppard, MC, Maisonneuve, P. Thyroid function and

mortality in patients treated for hyperthyroidism. JAMA 2005; 294:71.

84. Cappola, AR, Fried, LP, Arnold, AM, et al. Thyroid status, cardiovascular

risk, and mortality in older adults. JAMA 2006; 295:1033.

85. Pop, VJ, Maartens, LH, Leusink, G, et al. Are autoimmune thyroid

dysfunction and depression related? J Clin Endocrinol Metab 1998;

83:3194.

86. Tappy, L, Randin, JP, Schwed, P, et al. 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.

87. Roberts, LM, Pattison, H, Roalfe, A, et al. Is subclinical thyroid

dysfunction in the elderly associated with depression or cognitive

dysfunction?. Ann Intern Med 2006; 145:573.

88. Joffe, RT, Levitt, AJ. Major depression and subclinical (grade 2)

hypothyroidism. Psychoneuroendocrinology 1992; 17:215.

89. Haggerty, JJ, Stern, RA, Mason, GA, et al. Subclinical hypothyroidism: a

modifiable risk factor for depression? Am J Psychiatry 1993; 150:508.

90. Monzani, F, Del Guerra, P, Caraccio, N, et al. Subclinical hypothyroidism:

neurobehavioral features and beneficial effect of L-thyroxine

treatment. Clin Invest 1993; 71:367.

91. Haddow, JE, Palomaki, GE, Allan, WC, et al. Maternal thyroid deficiency

during pregnancy and subsequent neuropsychological development of

the child. N Engl J Med 1999; 341:549.

92. Knudsen, N, Laurberg, P, Rasmussen, LB, 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.

93. Reinehr, T, de Sousa, G, Andler, W. Hyperthyrotropinemia in obese

children is reversible after weight loss and is not related to lipids. J Clin

Endocrinol Metab 2006; 91:3088.

94. Nicolini, G, Balzan, S, Colzani, R, et al. Erythrocyte Na/K-ATPase is

increased in subjects with subclinical hypothyroidism. Clin Endocrinol

(Oxf) 2004; 60:705.

95. Monzani, F, Caraccio, N, Del Guerra, P, et al. Neuromuscular symptoms

and dysfunction in subclinical hypothyroid patients: beneficial effect of

L-T4 replacement therapy. Clin Endocrinol (Oxf) 1999; 51:237.

96. Ooi, TC, Whitlock, RM, Frengley, PA, Ibbertson, HK. Systolic timeintervals and ankle reflex time in patients with minimal serum TSHelevation: response to triiodothyronine therapy. Clin Endocrinol (Oxf)1980; 13:621.

97. Monzani, F, Caraccio, N, Siciliano, G, et al. Clinical and biochemical

features of muscle dysfunction in subclinical hypothyroidism. J Clin

Endocrinol Metab 1997; 82:3315.

98. Caraccio, N, Natali, A, Sironi, A, et al. Muscle metabolism and exercise

tolerance in subclinical hypothyroidism: a controlled trial of

levothyroxine. J Clin Endocrinol Metab 2005; 90:4057.

99. Misiunas, A, Niepomniszce, H, Ravera, B, et al. Peripheral neuropathy in

subclinical hypothyroidism. Thyroid 1995; 5:283.

100. Meier, C, Christ-Crain, M, Guglielmetti, M, et al. Prolactin dysregulation

in women with subclinical hypothyroidism: effect of levothyroxine

replacement therapy. Thyroid 2003; 13:979.

101. Centanni, M, Cesareo, R, Verallo, O, et al. Reversible increase of

intraocular pressure in subclinical hypothyroid patients. Eur J Endocrinol

1997; 136:595.

102. Ross, DS. Bone density is not reduced during the short-term

administration of levothyroxine to postmenopausal women with

subclinical hypothyroidism: a randomized, prospective study. Am J Med

1993; 95:385.

103. Squizzato, A, Romualdi, E, Piantanida, E, et al. Subclinical

hypothyroidism and deep venous thrombosis. A pilot cross-sectional

study. Thromb Haemost 2007; 97:803.

104. Laukkarinen, J, Kiudelis, G, Lempinen, M, et al. Increased prevalence of

subclinical hypothyroidism in common bile duct stone patients. J Clin

Endocrinol Metab 2007; 92:4260.

105. Chen, HS, Wu, TE, Jap, TS, et al. Subclinical hypothyroidism is a risk

factor for nephropathy and cardiovascular diseases in Type 2 diabetic

patients. Diabet Med 2007; 24:1336.

106. Pollock, MA, Sturrock, A, Marshall, K, et al. Thyroxine treatment in

patients with symptoms of hypothyroidism but thyroid function tests

within the reference range: randomised double blind placebo controlled

crossover trial. BMJ 2001; 323:891.

107. Clinical guideline, part 1. Screening for thyroid disease. AmericanCollege of Physicians. Ann Intern Med 1998; 129:141.

108. Helfand, M, Redfern, CC. Screening for thyroid disease: an update. Ann

Intern Med 1998; 129:144.

109. McDermott, MT, Ridgway, EC. Subclinical hypothyroidism is mild thyroid

failure and should be treated. J Clin Endocrinol Metab 2001; 86:4585.

110. Cooper, DS. Subclinical hypothyroidism. N Engl J Med 2001; 345:260.

111. Surks, MI, Ortiz, E, Daniels, GH, et al. Subclinical thyroid disease:

scientific review and guidelines for diagnosis and management. JAMA

2004; 291:228.

112. Romaldini, JH, Biancalana, MM, Figueiredo, DI, et al. Effect of

L-thyroxine administration on antithyroid antibody levels, lipid profile,

and thyroid volume in patients with Hashimoto's thyroiditis. Thyroid

1996; 6:183.

113. Chu, JW, Crapo, LM. The treatment of subclinical hypothyroidism is

seldom necessary. J Clin Endocrinol Metab 2001; 86:4591.

© 2008 UpToDate, Inc. All rights reserved. | Subscription and License Agreement

Licensed to: Nikola Hajder