Thyroid disease is common in the general population, and the prevalence increases with age. The assessment of thyroid function by modern assays is both reliable and inexpensive. Screening for thyroid dysfunction is indicated in certain high-risk groups, such as neonates and the elderly.

Hypothyroidism is by far the most common thyroid disorder in the adult population and is more common in older women. It is usually autoimmune in origin, presenting as either primary atrophic hypothyroidism or Hashimoto's thyroiditis. Thyroid failure secondary to radioactive iodine therapy or thyroid surgery is also common. Rarely, pituitary or hypothalamic disorders can result in secondary hypothyroidism.

Approximately 4 million people in the United States are hypothyroid and receive thyroxine replacement therapy. By contrast, hyperthyroidism is much less common, with a female-to-male ratio of 9:1. Graves' disease is the most common cause and affects primarily young adults. Toxic multi-nodular goiters tend to affect the older age-groups.

Diabetic patients have a higher prevalence of thyroid disorders compared with the normal population (Table 1). Because patients with one organ-specific autoimmune disease are at risk of developing other autoimmune disorders, and thyroid disorders are more common in females, it is not surprising that up to 30% of female type 1 diabetic patients have thyroid disease. The rate of postpartum thyroiditis in diabetic patients is three times that in normal women. A number of reports have also indicated a higher than normal prevalence of thyroid disorders in type 2 diabetic patients, with hypothyroidism being the most common disorder.

How Thyroid Dysfunction May Affect Diabetic Patients
The presence of thyroid dysfunction may affect diabetes control. Hyperthyroidism is typically associated with worsening glycemic control and increased insulin requirements. There is underlying increased hepatic gluconeogenesis, rapid gastrointestinal glucose absorption, and probably increased insulin resistance. Indeed, thyrotoxicosis may unmask latent diabetes.

In practice, there are several implications for patients with both diabetes and hyperthyroidism. First, in hyperthyroid patients, the diagnosis of glucose intolerance needs to be considered cautiously, since the hyperglycemia may improve with treatment of thyrotoxicosis. Second, underlying hyperthyroidism should be considered in diabetic patients with unexplained worsening hyperglycemia. Third, in diabetic patients with hyperthyroidism, physicians need to anticipate possible deterioration in glycemic control and adjust treatment accordingly. Restoration of euthyroidism will lower blood glucose level.

Although wide-ranging changes in carbohydrate metabolism are seen in hypothyroidism, clinical manifestation of these abnormalities is seldom conspicuous. However, the reduced rate of insulin degradation may lower the exogenous insulin requirement. The presence of hypoglycemia is uncommon in isolated thyroid hormone deficiency and should raise the possibility of hypopituitarism in a hypothyroid patient. More importantly, hypothyroidism is accompanied by a variety of abnormalities in plasma lipid metabolism, including elevated triglyceride and low-density lipoprotein (LDL) cholesterol concentrations. Even subclinical hypothyroidism can exacerbate the coexisting dyslipidemia commonly found in type 2 diabetes and further increase the risk of cardiovascular diseases. Adequate thyroxine replacement will reverse the lipid abnormalities.

In young women with type 1 diabetes, there is a high incidence of autoimmune thyroid disorders. Transient thyroid dysfunction is common in the postpartum period and warrants routine screening with serum thyroid-stimulating hormone (TSH) 6­8 weeks after delivery. Glucose control may fluctuate during the transient hyperthyroidism followed by hypothyroidism typical of the postpartum thyroiditis. It is important to monitor thyroid function tests in these women since approximately 30% will not recover from the hypothyroid phase and will require thyroxine replacement. Recurrent thyroiditis with subsequent pregnancies is common.

Diagnosis of Thyroid Dysfunction
The diagnosis of thyroid dysfunction in diabetic patients based solely on clinical manifestations can be difficult. Poor glycemic control can produce features similar to hyperthyroidism, such as weight loss despite increased appetite and fatigue. On the other hand, severe diabetic nephropathy can be mistaken for hypothyroidism because patients with this condition may have edema, fatigue, pallor, and weight gain.

To further complicate the diagnostic process, poorly controlled diabetes, with or without its complications, may produce changes in thyroid function tests that occur in nonthyroidal illnesses. Typical changes include a low serum T3 due to impaired extrathyroidal T4-to-T3 conversion, a low serum T4 due to decreased protein binding, and an inappropriately low serum TSH concentration.

The availability of the highly sensitive immunoassay for serum TSH (with detection limit of <0.1 mU/l) provides a major advance in the diagnosis of thyroid disorders. It is the most reliable and sensitive screening test for thyroid dysfunction and allows both hypothyroidism and hyperthyroidism to be diagnosed with certainty. In addition, subclinical thyroid dysfunction can only be diagnosed by an abnormal TSH because the serum T3 and T4 are normal and, by definition, the patients are usually asymptomatic.

However, the underlying thyroid dysfunction can produce clinically important physiological effects. Subclinical hypothyroidism can elevate serum LDL cholesterol and worsen pre-existing dyslipidemia, further increasing the risk of atherosclerosis. Subclinical hyperthyroidism may increase the risk of cardiac arrhythmias and exacerbate angina. Since diabetic patients are at high risk for cardiovascular diseases, the diagnosis and treatment of subclinical thyroid diseases is important.

The presence of anti-thyroid peroxidase (TPO) antibodies is helpful in predicting the development of autoimmune thyroid disorders, especially hypothyroidism. Patients who have anti-TPO antibodies should be screened for thyroid dysfunction on a regular basis, so early detection and treatment is possible.

Management of Thyroid Dysfunction
Frank hypothyroidism should be treated with thyroid hormone therapy. L-thyroxine is the most widely used thyroid hormone replacement. Natural thyroid extracts such as desiccated thyroid should no longer be used.

The usual full replacement dose is 1.6 µg L-thyroxine per kg of body weight. Often, patients with mild thyroid failure require less than a full replacement dose initially. The dose can be adjusted by measuring TSH every 2­3 months.

Once the TSH is normalized and the patient is established on a stable dose of L-thyroxine, TSH monitoring can be done annually. With progression to complete thyroid failure, there is usually a need to increase the thyroxine dose with time. In diabetic patients with underlying coronary artery disease, L-thyroxine therapy may exacerbate angina by increasing myocardial contractility and heart rate. Therefore, it is best to start with a low dose, such as 25 µg daily, and increase slowly by monthly increments of 25 µg while monitoring the patient's clinical status and serum TSH levels.

Treatment of subclinical hypothyroidism should be considered if 1) patients have elevated serum LDL cholesterol that is worsened by the hypothyroidism, or 2) they have detectable serum anti-TPO antibodies, because the progression to frank hypothyroidism is high in this group, or 3) they are symptomatic.

Because hyperthyroidism can cause serious adverse effects on glycemic control and possibly worsen pre-existing coronary artery disease, it is desirable to consider definitive treatment with radioactive iodine therapy whenever possible. There is no contraindication to the use of antithyroid medications in diabetic patients, but the long-term remission rate of Graves' disease is <40%. Patients with toxic multi-nodular goiters or an autonomously functioning thyroid nodule should be definitively treated by radioactive iodine or surgery.

Conclusion
Thyroid dysfunction is common in diabetic patients and can produce significant metabolic disturbances. Therefore, regular screening for thyroid abnormalities in all diabetic patients will allow early treatment of subclinical thyroid dysfunction. A sensitive serum TSH assay is the screening test of choice. In type 1 diabetic patients, it is helpful to determine whether anti-TPO antibodies are present. If these are present, then annual TSH screening is warranted. Otherwise, a TSH assay should be done every 2­3 years. In type 2 diabetic patients, a TSH assay should be done at diagnosis and then repeated at least every 5 years.

Patricia Wu, MD, FACE, FRCP, is an endocrinologist with the Southern California Permanente Medical Group and an assistant clinical professor of medicine at the University of California, San Diego.