Subclinical thyroid disease is a common disorder encountered by primary care physicians who treat adults and the elderly. Incidence is likely to increase as the US population ages, since prevalence rises as age increases. Patients with subclinical thyroid disease have an abnormal thyroid-stimulating hormone level but a normal free thyroxine level. The classic manifestations of thyroid disorders are rarely seen, and many patients present with nonspecific symptoms. Routine screening for subclinical thyroid disorders is controversial. This article discusses recent recommendations for screening, evaluation, and treatment of patients with subclinical hyperthyroidism and hypothyroidism.

Subclinical thyroid disorders are common conditions that are typically asymptomatic and are usually seen in middle-aged and elderly patients.¹ Such disorders constitute a risk for the complications of overt thyroid disease.² Certain groups of high-risk individuals should be screened for subclinical thyroid disease. In general, treatment is not recommended when the thyroid-stimulating hormone (TSH) level is between 0.1 and 0.45 mIU/L, defined as subclinical hyperthyroidism, or between 4.5 and 10 mIU/L, defined as subclinical hypothyroidism, because of a lack of evidence of any benefit and the negligible clinical consequences. However, there is no universal agreement about the approach to the patient with subclinical thyroid disease. Some experts do recommend treating subclinical thyroid disease, despite the lack of clear evidence from clinical trials. In addition, treatment may be appropriate in patients with certain comorbid conditions (Table 1).

Subclinical Hyperthyroidism
Subclinical hyperthyroidism is defined as a drop in serum TSH concentration below the normal reference range (normal range, 0.45-4.5 mIU/L), when levels of free thyroxine (T₄) and total triiodothyronine (T₃) are within the normal range.³

It is much less common than subclinical hypothyroidism. Prevalence of subclinical hyperthyroidism is estimated to be less than 1% of the US adult population.^4,5 It is more common in women than in men, in blacks than in whites, and in older than in younger individuals.¹ The majority of patients with subclinical hyperthyroidism are either relatively healthy or have stable chronic medical conditions. They are usually clinically euthyroid and typically lack the specific signs and symptoms of overt hyperthyroidism. When symptoms are present, they are nonspecific, such as malaise, tachycardia, nervousness, or anxiety.

Subclinical hyperthyroidism can be caused by an endogenous production or an exogenous supply of thyroid hormone. Common endogenous etiologies include Graves’ disease, autonomously functioning thyroid adenomas, and multinodular goiters.⁶ Less common causes include thyroiditis, partially or inadequately treated overt hyperthyroidism, autoimmune thyroid disease, and normal pregnancy.

Exogenous subclinical hyperthyroidism can occur in patients being treated with levothyroxine sodium (eg, Levothroid, Levoxyl, Synthroid). In one study of 162 patients taking thyroxine, 23% of them had low serum TSH values.⁷ A suppressed serum TSH level may also be related to severe nonthyroid illnesses, glucocorticoid or dopamine administration, or pituitary dysfunction. It is therefore important to exclude these conditions when evaluating a patient with suspicious thyroid-related laboratory findings.

Systemic consequences
Cardiovascular. The most frequent cardiac complication is atrial fibrillation, with a 3-fold increased risk among patients aged 60 years or older.⁸ There is strong evidence supporting an increased risk of atrial fibrillation when serum TSH falls below 0.1 mIU/L.⁸ Subclinical hyperthyroidism has also been linked to a higher incidence of tachycardia, atrial arrhythmias (but not ventricular arrhythmias), left ventricular hypertrophy, diastolic dysfunction, and overall cardiovascular mortality.⁹

Skeletal. Overt hyperthyroidism is associated with osteoporosis, but the effects of subclinical hyperthyroidism on bone metabolism are less clear. For example, one study showed that bone mineral density (BMD) was not significantly decreased in postmenopausal women with endogenous subclinical hyperthyroidism, but the investigators still concluded that long-standing disease may contribute to osteoporosis in some women.¹⁰ And one meta-analysis demonstrated decreased BMD in patients with prolonged subclinical hyperthyroidism, with bone loss being greater in postmenopausal women.¹¹ The effect of exogenous subclinical hyperthyroidism on BMD remains controversial.

Natural history
Progression to overt hyperthyroidism occurs at a rate of 1% to 3% annually in patients with a serum TSH level of less than 0.1 mIU/L, whereas only a small number of patients progress to overt disease when TSH level is between 0.1 and 0.45 mIU/L.^1,12 Subclinical hyperthyroidism may persist for months to years without any overt symptoms. In many individuals, TSH levels return to normal over time. Some patients with a nodular goiter and a suppressed TSH concentration may develop overt hyperthyroidism after a radiocontrast study, resulting from the exposure to a high concentration of iodine.

Screening recommendations
A recent consensus panel consisting of representatives from the American Thyroid Association (ATA), the American Association of Clinical Endocrinologists (AACE), and the Endocrine Society recommended against routine screening for subclinical thyroid disorders, because of the absence of sufficient evidence.¹³ The US Preventive Services Task Force notes that there are insufficient data to recommend for or against routine screening for thyroid disease in adults.¹⁴ The American Academy of Family Physicians recommends screening patients older than 60 years,¹⁵ whereas the ATA advocates screening for thyroid disease, with serum TSH measurements, every 5 years in all adults aged 35 years or older.¹⁶

Evaluation
Recommendations for the evaluation of subclinical hyperthyroidism are summarized in Table 2.¹³

Management
Exogenous subclinical hyperthyroidism. The dose of levothyroxine that the patient is currently taking should be reduced to allow the TSH level to normalize. For patients taking thyroxine therapy for thyroid cancer, target TSH concentration should be reviewed with an endocrinologist. TSH level should be remeasured no earlier than 6 to 8 weeks after the dose is reduced.¹⁷

Endogenous subclinical hyperthyroidism. There is insufficient evidence to support treating patients with a TSH value between 0.1 and 0.45 mIU/L. However, elderly patients with TSH values in this range should normally be treated to decrease their risk of cardiovascular-associated mortality.¹⁸

Patients with subclinical hyperthyroidism secondary to thyroiditis should be managed symptomatically, since the condition usually resolves spontaneously. Patients with Graves’ disease who have a TSH level less than 0.1 mIU/L should be treated, as should patients with subclinical hyperthyroidism caused by nodular thyroid disease, given the expected progression to overt hyperthyroidism. In older individuals who have atrial fibrillation or osteoporosis that could have been caused or exacerbated by the mild excess of thyroid hormone, ablative therapy with radioactive iodine 131 (I131) can be considered as an initial option.

Physicians and patients should be aware that treatment with antithyroid therapy carries risks, including fever, arthralgias, agranulocytosis, fulminant hepatitis, and hypothyroidism.

Subclinical Hypothyroidism
Subclinical hypothyroidism is defined as an elevation of serum TSH above the upper limit of the reference range (4.5-10 mIU/L) in an individual with a normal serum free T4 concentration. Such patients are usually identified during routine screening or in the course of being evaluated for common nonspecific symptoms, including fatigue, weight gain, or depression.³

Subclinical hypothyroidism is much more common than subclinical hyperthyroidism, affecting about 5% to 9% of the US adult population.^4,5 The condition is associated with increasing age and is the most common thyroid abnormality in the elderly.¹⁹ One study showed that approximately 15% of men and women older than 60 years were affected,²⁰ but some investigators suggest that the prevalence may be markedly higher in elderly women (as high as 35% in one study²¹).

Subclinical hypothyroidism is more common in patients with diabetes mellitus²² or other autoimmune diseases than in the general population and is 3 times more common in whites than in blacks.⁵ About 2.5% of pregnant women with high serum antithyroid antibody concentrations develop subclinical hypothyroidism.²³

Etiology
The causes of overt and subclinical hypothyroidism are similar. The most common etiology is chronic autoimmune thyroiditis (Hashimoto’s disease). Other frequent causes include treatment with ablative therapy for Graves’ disease and inadequate thyroid-hormone replacement therapy for overt hypothyroidism.² History of neck irradiation, postpartum thyroiditis, and certain autoimmune disorders (especially type 1 diabetes) also increase risk, as does the use of lithium (Eskalith, Lithobid) or amiodarone HCl (Cordarone, Pacerone), exposure to radiographic contrast agents, and iodine deficiency.

Screening
In addition to the screening guidelines discussed earlier, screening during pregnancy has been advocated because of the adverse consequences of subclinical hypothyroidism on the developing fetus.²⁴ The consensus panel of the ATA, AACE, and the Endocrine Society recommends screening women who are pregnant or who wish to become pregnant if they have a personal or a family history of thyroid disease, suggestive symptoms or signs, type 1 diabetes, or an autoimmune disorder.¹

Systemic consequences
Serum lipids. The effect of subclinical hypothyroidism on the lipid profile is controversial. Patients with subclinical hypothyroidism have elevated levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides, but these changes are less marked than in, and not consistent with, patients who have overt hypothyroidism. Elevated levels of LDL-C and total cholesterol have been shown to decrease with levothyroxine supplementation in some studies^25,26 but not in others.²⁷

Cardiac function. Mean arterial blood pressure may be increased and cardiac output decreased in patients with subclinical hypothyroidism, but these effects can be reversed with levothyroxine therapy.²⁸ The effect of untreated subclinical hypothyroidism on cardiovascular outcomes remains uncertain, since the evidence is inconclusive.¹

Neuropsychiatric disease. Studies have linked subclinical hypothyroidism to neuropsychiatric disease and have shown it to be a risk factor for depression and mood disorders.²⁹ Panic disorders are more prevalent in depressed patients with subclinical hypothyroidism, and the response rate to antidepressants is reportedly poor compared with euthyroid patients.³⁰

Pregnancy. Subclinical hypothyroidism may adversely affect the neuropsychological development and even the survival of the fetus. It can also cause hypertension and toxemia in the mother.^29,31,32

Management
A high index of clinical suspicion should be exercised when evaluating patients with risk factors for subclinical hypothyroidism or those who have subtle features of hypothyroidism. Diagnosis is based on symptoms, an increased serum TSH concentration, and a normal serum free T₄ level.

Treatment of subclinical hypothyroidism is individualized, based on the potential benefits and risks of thyroid supplementation. Before making treatment decisions, a repeat TSH level and a free T₄ determination are recommended within 2 to 12 weeks to exclude transient forms of hypothyroidism.

When taking the history, include questions about the patient’s symptoms, past thyroid disorders, current or past medication use (including lithium and amiodarone), past thyroid surgery, and radioactive I131 therapy. A serum lipid profile and, when appropriate, a pregnancy test should be ordered. The evidence is insufficient to recommend for or against ordering a measurement of antithyroid peroxidase antibodies.¹ However, most clinical endocrinologists use antibody testing to decide whether to treat subclinical hypothyroidism, a practice endorsed by the AACE.¹³

The possible advantages of treatment are preventing progression to overt hypothyroidism and resolving the symptoms of mild hypothyroidism. There are conflicting reports on the effects of thyroid-hormone replacement therapy on neuropsychiatric symptoms, serum LDL-C concentration, and cardiac dysfunction.¹⁹ It is justifiable to treat patients with TSH levels of more than 10 mIU/L and those with positive antithyroid peroxidase antibody titers because of an increased rate of progression to overt hypothyroidism in these populations.^1,12 Routine treatment with thyroid-hormone replacement is not recommended for patients with TSH values ranging from 4.5 to 10 mIU/L, although it is reasonable to treat such patients if they are symptomatic.

Treatment is normally initiated with 25 to 50 µg/day of thyroxine and raised in increments of 25 to 50 µg/day. TSH level should be measured 6 to 8 weeks after therapy is begun. The goal is to maintain the TSH level within the normal range. Once the correct dosage of thyroxine is established, the frequency of TSH measurements may be reduced to every 6 to 12 months. Thyroxine therapy in the elderly should be initiated at lower doses and increased in smaller increments. Thyroxine overreplacement in the elderly is dangerous, because of a risk of atrial fibrillation and osteoporosis.¹⁹

Conclusion
Primary care physicians are encountering subclinical thyroid disorders with increasing frequency. Diagnosis is based on an abnormal TSH value associated with normal levels of thyroid hormones. Symptoms tend to be nonspecific, and although routine screening is not advocated, persons at risk may need to be screened. Despite a lack of sufficient data, the consensus is to treat patients with subclinical hyperthyroidism who are elderly; who are at risk for cardiac disease; who have underlying cardiac disease, osteoporosis, or osteopenia; or who have clinical features of hyperthyroidism. Treatment for subclinical hypothyroidism may be appropriate in patients with TSH levels above 10 mIU/L or with positive antithyroid peroxidase antibody titers. Such patients should be encouraged to participate in the decision-making process and should be told about the risks and benefits of antithyroid therapy versus observation.

Self-assessment test
1. Which of the following laboratory values qualifies for a diagnosis of subclinical hyperthyroidism?
A. TSH 0.4 mIU/L and elevated T₄ and normal T₃ levels
B. TSH 0.5 mIU/L and normal T₄ and T₃ levels
C. TSH 0.4 mIU/L and normal T₄ and T₃ levels
D. TSH 0.5 mIU/L and elevated T₄ and normal T₃ levels

2. All the following patient groups with subclinical hyperthyroidism should be treated with antithyroid therapy, except:
A. Elderly women with a TSH value of 0.35 mIU/L and a history of myocardial infarction
B. Middle-aged men with subclinical hyperthyroidism secondary to thyroiditis
C. 30-year-old women with a TSH value of 0.05 mIU/L and Graves’ disease
D. Elderly men with subclinical hyperthyroidism secondary to nodular thyroid disease

3. Which of these conditions is NOT a common cause of subclinical hypothyroidism?
A. Pregnancy
B. Hashimoto’s disease
C. Type 1 diabetes
D. Postpartum thyroiditis

4. All the following conditions are possible systemic effects of subclinical hypothyroidism, except:
A. Increased mean arterial blood pressure
B. Decreased cardiac output
C. Atrial fibrillation
D. Depression

5. Which of the following statements about the management of subclinical hypothyroidism is NOT true?
A. Before beginning treatment, TSH and free T₄ should be remeasured within 2 to 12 weeks
B. Treatment is appropriate for patients with TSH levels of more than 10 mIU/L
C. Treatment usually begins with 25 to 50 µg/day of thyroxine
D. TSH should be measured 6 months after therapy is initiated

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