Mild thyroid failure represents an early stage of thyroid disease that will commonly progress to overt hypothyroidism. Progression has, in fact, been reported to occur in approximately 3–18% of affected patients per year (10–17). One study evaluated the natural history of mild thyroid failure in 154 female patients over a 10-yr period; 57% of patients continued to have mild thyroid failure, 34% of patients progressed to overt hypothyroidism, and 9% of patients reverted to a normal TSH level. How many of the 9% had a transient form of thyroiditis such as silent, subacute, or postpartum thyroiditis is unclear (17). The strongest predictors of progression are the presence of antithyroid antibodies, serum TSH values greater than 20 μU/ml, a history of radioiodine ablation for Graves’ disease, a history of external radiation therapy for nonthyroid malignancies, and chronic lithium treatment (10–16).
Symptoms. Mild thyroid failure is often asymptomatic; however, nearly 30% of patients with this condition may have symptoms that are suggestive of thyroid hormone deficiency (2, 18). The Colorado Thyroid Disease Prevalence Study (2) measured serum TSH levels and conducted symptom surveys in over 25,000 state residents. Elevated serum TSH values were found in 9.5% of all subjects and in 8.9% of those who were not already on thyroid hormone therapy (Fig. 1); 75% of these individuals had serum TSH levels in the 5–10 μU/ml range. In response to a validated survey regarding symptoms of thyroid hormone deficiency, the 2,336 subjects who were identified as having mild thyroid failure significantly more often reported having dry skin (28%; P < 0.001), poor memory (24%; P < 0.001), slow thinking (22%; P < 0.001), muscle weakness (22%; P < 0.001), fatigue (18%; P < 0.01), muscle cramps (17%; P < 0.001), cold intolerance (15%; P< 0.001), puffy eyes (12%; P < 0.05), constipation (8%; P < 0.05), and hoarseness (7%; P < 0.05) than did euthyroid subjects. It is important to note that, whereas euthyroid subjects experienced a mean of 12.1% of all listed symptoms, overtly hypothyroid subjects had 16.6% of these symptoms (P < 0.05 vs. euthyroid group), and subjects with mild thyroid failure reported an intermediate 13.7% of the symptoms (P < 0.05 vs. euthyroid group) (Fig. 2). This suggests a “dosage effect” between levels of thyroid hormones and symptoms. Consistent with these findings, a Swiss study involving 332 women with hypothyroidism reported that 24% of the 93 subjects with mild thyroid failure exhibited typical symptoms of hypothyroidism (18). These studies also emphasize the difficulty in making the diagnosis of primary hypothyroidism using clinical symptoms alone; euthyroid subjects and patients with mild or overt hypothyroidism all had similar constellations of symptoms. Despite statistical significance in large groups, it can be difficult in an individual patient to distinguish a euthyroid subject from one with either mild or overt thyroid disease.
Neurobehavioral abnormalities and neuromuscular function. Other cross-sectional studies have demonstrated evidence of specific neurobehavioral and neuromuscular dysfunction in mild thyroid failure patients (19–31). Depression (19–23), memory loss (2, 19, 24), cognitive impairment (25) and a variety of neuromuscular complaints (26, 27) have all been reported to occur more frequently in patients with this condition. Objective peripheral nerve dysfunction, manifested by decreased conduction amplitude in peripheral nerves (28), and an abnormal stapedial reflex (29) have been demonstrated in these patients. Skeletal muscle abnormalities, including elevated serum creatine phosphokinase levels (30), increased circulating lactate levels during exercise (26), and repetitive discharges on surface electromyography (27), have also been reported. Finally, there is intriguing evidence that mild thyroid failure in pregnant women may result in reduced intellectual development of their euthyroid offspring (31).
Cardiac-pulmonary function. Myocardial function has been reported in multiple studies to be subtly impaired in patients with mild thyroid failure (32–41). Identified functional abnormalities include impaired myocardial contractility (32–40) and diastolic dysfunction (39–41), at rest (32, 34, 37, 39–41) or with exercise (35–39). Myocardial texture has also been shown to be abnormal by videodensitometric analysis (40). In one comprehensive study of exercise capacity (38), patients with mild thyroid failure were shown to have significant impairment of exercise-related stroke volume, cardiac index, and maximal aortic flow velocity. Pulmonary testing in these same patients revealed decreased vital capacity, reduced anaerobic thresholds, and decreased oxygen uptake at the anaerobic threshold (38). These data clearly demonstrate that cardiovascular function in mild thyroid failure is slightly impaired and not identical to that in the euthyroid state. The important question is whether these differences result in clinically significant impairment of performance in affected patients.
Cardiovascular risk factor. Mild thyroid failure has been extensively evaluated as a cardiovascular risk factor. The condition has been shown to be associated with increased serum levels of total cholesterol (Fig. 3) and low-density lipoprotein (LDL) cholesterol in most but not all studies (2, 38, 42, 43) and with reduced high-density lipoprotein cholesterol in some studies (38). Some reports have suggested that even high normal serum TSH values may adversely affect serum lipid and lipoprotein levels (44–46). It has been estimated that an increase in the serum TSH level of 1 μU/ml is associated with a rise in the serum total cholesterol concentration of 0.09 mmol/liter (3.5 mg/dl) in women and 0.16 mmol/liter (6.2 mg/dl) in men (45). The relationship between TSH and LDL cholesterol seems to be most significant in individuals who have underlying insulin resistance (46). One recent study reported that patients with mild thyroid failure, and even subjects with high normal serum TSH values, have evidence of endothelial dysfunction, manifested by impaired flow-mediated, endothelial-dependent vasodilatation (47). An association between mild thyroid failure and peripheral vascular disease was suggested by an older case-control study involving elderly women (48). A 20-yr follow-up study of the original Whickham Survey found no association between initial hypothyroidism, raised serum TSH levels, or antithyroid antibodies and the development of coronary artery disease (49). In contrast, a more recent report from the Rotterdam Study (9) concluded that patients with mild thyroid failure have a significantly increased prevalence of aortic atherosclerosis and myocardial infarctions. After adjustment for multiple known coronary artery disease risk factors, the authors found mild thyroid failure to be an independent and equivalently important risk factor for myocardial infarctions (Fig. 4).