Treatment of Subclinical Thyroid Disease Subclinical thyroid disease is defined as a condition in which serum TSH is abnormally elevated (subclinical hypothyroidism) or lowered (subclinical hyperthyroidism) while the peripheral thyroid hormone concentration is still within the laboratory reference range. This abnormality in thyroid function tests is very common in the population and has been discussed extensively in textbooks and review articles. During the period 1986-2001, 19 articles on subclinical hypothyroidism and 8 articles on subclinical hyperthyroidism were identified from the Pub Med index (limited to titles and reviews) (more articles are available, if available, throughout the field of review). This article focuses on the controversial issue of whether patients with this abnormality need treatment. FINAL CONCLUSION If a patient with subclinical thyroid disease is willing to be treated after being adequately examined and properly informed about the disease and its treatment, treatment should be given. Regardless of whether the patient chooses to be treated or not, it is important to have regular checkups in the future. Practical Steps The following points should be followed when dealing with subclinical thyroid disease. Some instructions and details of the particular points are given below. The following points should be followed when dealing with subclinical thyroid disease 1. Review in a few months (e.g., 3 months) to confirm the diagnosis. 2. Establishment of the subtype of the disease from the classification of the disease. 3. Clinical signs and symptoms of the disease. 4, The status of other risk factors and disease, whether the risk factors are long term and an estimate of prognosis. 5, Tell the patient about the disease and whether to receive treatment or follow up for observation. 6, Respect the patient’s decision. 7, Follow-up. Subclinical Thyroid Disease and Severe Disease Transient serum TSH abnormalities are common in hospitalized patients, especially in those with severe disease, and for a period of time during recovery from the disease. This may be due to the disease itself or to medication. Subclinical thyroid disease cannot be diagnosed and treatment cannot be initiated in such cases. Transient Subclinical Thyroid Disease Often the cause of subclinical thyroid disease is the same as that of overt thyroid disease, and the treatment is the same. Just as with overt thyroid disease, it is important to evaluate the likelihood of a transient state before initiating lifelong medication or giving injurious therapy. Subacute and silent thyroiditis should be ruled out, and the possibility of abnormalities due to excessive iodine intake or medication should also be evaluated. Subclinical thyroid abnormalities are common during the first year after radioactive iodine therapy and surgical treatment of the thyroid without the need for lifelong or long-term treatment. Common Causes of Subclinical Hypothyroidism Spontaneous subclinical hypothyroidism is relatively common in the population, and people with high iodine intake are more likely to develop it. Patients can be divided into two main subtypes: those with detectable antithyroid antibodies (TPO-Ab and/or Tg-Ab) in the serum and those with undetectable antibodies. Patients with positive thyroid antibodies, presumably caused by autoimmune thyroiditis, are most likely to develop progressive thyroid insufficiency, with 5-10% of patients per year progressing from a subclinical state to marked hypothyroidism. It is common to have elevated serum TSH and negative thyroid antibodies, and the mechanism by which this occurs is unknown. These patients may have different subtypes of autoimmune disease with a predominant T-cell response. The incidence of autopsy findings with histologic changes of thyroiditis is significantly higher than the incidence of positive serum specimens in the population, however, there may be other pathogenic mechanisms involved. The risk of this subtype progressing to overt thyroid disease is somewhat lower (about 2% per year). Knowing that there is a risk of progression of the disease, it is important to have regular reviews, especially in patients who have not yet been treated. On the other hand we do not believe that the risk of progression of the disease is such that treatment should be started early. The patient’s current condition should be the main basis for deciding whether or not to treat. If the current condition is not serious enough to warrant initiating treatment, then it will be initiated only when progression of the disease is detected. Follow-up is necessary whether or not treatment is carried out now. If early treatment halts the progression of thyroid decline and stabilizes some of the physiological regulation of thyroid function, this will be an important rationale for early treatment. A decrease in thyroid antibody levels is often seen with the application of T4 replacement therapy, but clinically relevant controlled studies in this area are lacking. Common Causes of Subclinical Hyperthyroidism The important and major cause of subclinical hyperthyroidism is essentially dependent on the level of iodine intake in the population. In populations with mildly to moderately low iodine intake (median urinary iodine excretion 25-120 mg/24 h) or in patients with such low iodine intake in recent decades, the main cause of subclinical hyperthyroidism is functionally autonomous thyroid nodules. In these areas subclinical hyperthyroidism occurs more frequently than subclinical hypothyroidism, with a prevalence of 5-10% in people over 60 years of age. On the other hand, spontaneous subclinical hyperthyroidism is not prevalent in areas of high iodine intake, and when it does occur, it is mainly due to high doses of T4 taken by the patient for the treatment of hypothyroidism or to reduce the size of the thyroid nodules, or to prevent the recurrence of a previous thyroid cancer. ARGUMENTS FOR AND AGAINST TREATMENT OF SUBCLINICAL THYROID DISEASE Main arguments in favor of treatment 1. In subclinical thyroid disease changes in serum TSH do not fully compensate for thyroid function, and in individual patients the action of peripheral thyroid hormones is not normal. 2. Subclinical thyroid disease can be associated with impaired function of other organs, and treatment of thyroid dysfunction can reverse the damage. 3. Subclinical thyroid disease may increase the long-term risk of serious dysfunction. 4. Treatment of subclinical thyroid disorders is generally uncomplicated and, as with observational controls, inexpensive to control the disease burden. 5, Spontaneous elimination of most types of subclinical thyroid disease is highly unlikely. 6, Impaired maternal thyroid function during pregnancy increases the risk to the fetus. Major arguments against treatment 1. A significant percentage of patients do not feel better than before despite treatment. 2. Treatment will usually involve lifelong medication (subclinical hypothyroidism). 3. Treatment can cause significant side effects (subclinical hyperthyroidism). 4. The long-term risk of subclinical thyroid disease may depend on other risk factors, and in some subtypes of patients the risk is relatively low. 5. A large number of studies are needed to clarify the importance of this disease and the associated risks as well as the benefits of long-term treatment. 6. Subclinical thyroid disease is very common, and there should be sufficient evidence of the need for treatment before treatment can be legitimized for such a prevalent dysfunction. Many of the arguments regarding subclinical hyperthyroidism and hypothyroidism are similar. It is well established that a variable serum TSH signals abnormal thyroid function even when peripheral thyroid hormone values are within the laboratory reference range. Mean concentrations of T4 and T3 were significantly altered when the patient population was compared with healthy controls, or when serum thyroid hormones were measured before and after normalization of serum TSH by treatment. The range of variation in serum thyroid hormone concentrations was significantly smaller than the laboratory reference range. Thus, within the laboratory reference range, there is a large scope for individuals to change their T3 and T4 concentration values from normal to abnormal. The time for progression from subclinical to overt hypothyroidism (T4 or T3 values outside of the reference range) varies widely among individuals, depending on how high or low each individual’s normal T4 and T3 levels are within the laboratory reference range]. Serum TSH is more sensitive (by a factor of 10) to changes in thyroid function than serum T4. Thus, TSH deviates from the reference range earlier than T4 or T3 and can indicate which type of subclinical thyroid disease it belongs to. Clinical Outcomes in Mild Thyroid Disease Mild to moderate abnormal thyroid hormone levels (for an individual) can show small alterations in peripheral thyroid hormone effects. In essence, subclinical thyroid disease is no different from overt thyroid disease, but is relatively mild. The clinical picture is therefore the same, but to a lesser extent. Careful monitoring of cardiac function reveals that both subclinical hyperthyroidism and hypothyroidism may have abnormalities of cardiac function that can be reversed with treatment. An uncontrolled study showed a high prevalence of elevated intraocular pressure in patients with subclinical hypothyroidism, which was reversible with treatment. Another important role of thyroid hormones is to affect brain and neuromuscular function. In a single-blind, placebo-controlled study Jaeschke et al. reduced mean serum TSH from 12.1 to 4.lmU/L in 15 (16 in the control group) elderly subjects taking T4 for more than 6 months.Many questionnaires and tests of cognitive functioning were applied in this study, and the results concluded that the treatment was effective, but the composite memory psychometric scores, were only statistically significant ( p=0.01). This improvement corresponded to a difference of 8.7 points on an IQ test. Those authors who favor watchful waiting for middle-aged and elderly patients with subclinical hypothyroidism see limited significance in it. Those on watchful waiting should also have the same number of controls and blood tests as the treatment group. Considering the relative underdosing of T4 in this study, the physiologic properties of T4, as well as the inexpensive T4 replacement therapy and the observed effects on memory, it is difficult to agree with the conclusions they reached. Our view is that watchful waiting should be at the discretion of the patient with a known condition rather than at the discretion of physicians and the health care system. Long-term risk factors associated with subclinical thyroid disease A major problem with subclinical hypothyroidism is the risk of atherosclerosis. Subclinical hypothyroidism is often associated with alterations in serum atherogenic lipids, and with the application of T4 replacement, there are small changes in atherogenic lipids, including small reductions in serum total cholesterol (0.2-0.4 mmol) and decreases in LDL-cholesterol. There are no large population-based intervention studies demonstrating the effect of replacement therapy on vascular disease and mortality. No significant association between cardiovascular disease and subclinical hypothyroidism was found in the Whickham 20-year follow-up study. On the other hand, in a recent Dutch study of a group of elderly women, the incidence of myocardial infarction complicated by subclinical hypothyroidism was found to be the same as that of other known risk factors such as: hypercholesterolemia, hypertension, smoking and diabetes. The major problem with subclinical hyperthyroidism is that it is a long-term risk factor for atrial fibrillation and osteoporosis. analysis of the Framing ham data showed a threefold increase in the occurrence of atrial fibrillation in participants with a serum TSH <0.1 mU/L. Thyroid hormones promote bone conversion, and many studies have evaluated the link between subclinical hyperthyroidism and osteoporosis. A translocation analysis of long-term TSH suppression by taking T4 found no effect on bone mass in premenopausal women and an additional 0.91% annual bone loss in postmenopausal women. Two controlled interventional studies have shown that in menopausal women, subclinical hyperthyroidism caused by multinodular goiter reduces mineral loss in bone with treatment, whereas untreated, there is a loss of about 2% of the mineral in bone per year. There is evidence that subclinical hyperthyroidism with a serum TSH <0.lmU/L can have deleterious effects on patients. Critical values of TSH (0.1 to 0.4 mU/L) are not. Treatment of subclinical hypothyroidism Thyroxine replacement therapy can be used in direct accordance with the rules for the treatment of overt hypothyroidism, and can normalize serum TSH by adjusting the dosage of T4. the range of TSH reference values may vary depending on the method of measurement and the population of interest. In a Danish population survey, the reference range in 95% of people with no previous history of thyroid disease and normal ultrasound and TPO-Ab tests was 0.4 to 3.6 mU/L. The laboratory reference range is usually larger and is often taken as the upper limit of 4 or 5 mU/L, above which a diagnosis of subclinical hypothyroidism can be made. During treatment, T4 is adjusted in small doses to stabilize TSH at 0.8~2.5mU/L, and then thyroid function is regulated annually for lifelong control. Treatment of subclinical hyperthyroidism For patients with multinodular goiter and single thermal adenoma, radioactive iodine therapy should be chosen. However, the risk of comorbidities is higher than with T4 for subclinical hypothyroidism. About 10-20% of patients develop hypothyroidism after 5 years of radioactive iodine therapy, and l-2% may develop Graves' disease due to activation of TSH receptor autoimmunity. An advantage of radioactive iodine therapy for goiter is that it shrinks the thyroid gland (by about 50% after 1-2 years). If low doses of antithyroid drugs are given, they must be maintained for life. CONCLUSIONS Subclinical hypothyroidism and subclinical hyperthyroidism are functional abnormalities that are not clearly defined, but there is a continuum between mild to moderate hypothyroidism or hyperfunction and overt thyroid disease. Many patients with subclinical hypothyroidism have no obvious signs or symptoms of disease and feel no difference with T4 treatment. However, in l/4 to 1/2 of patients the general state of health improves after serum TSH is regulated to normal, and objective tests show improved memory function. Risk factors for atherosclerosis also improved slightly with treatment, and recent population-based surveys of older women have shown that subclinical hypothyroidism may be an independent risk factor for myocardial infarction as severe as hypertension, hyperlipidemia, smoking, and diabetes mellitus.There are few side effects of T4 replacement therapy. Subclinical hyperthyroidism may affect health and may be seen with supraventricular premature heart beats. This may be responsible for a threefold increase in the risk of atrial fibrillation. Postmenopausal women have an increased risk of developing osteoporosis, and mineral density in bone may increase with treatment. Patients with suppressed serum TSH due to autonomous nodules should be treated with radioactive iodine. T4 replacement therapy for hypothyroidism should be performed with proper dose control to prevent overdose. T4 therapy with complete serum TSH suppression is limited to patients with thyroid cancer at high risk of recurrence. Long-term follow-up is required after treatment. Some patients are reluctant to undergo prolonged treatment, and in such cases, thyroid status and other risk factors should be monitored by biochemical tests and clinical manifestations, depending on the disease. It is recognized that compounded medications should be avoided in treatment to avoid excessive costs. However, many elderly patients (at least in Denmark) are now using a range of costly, over-the-counter natural products with unclear effects and no support in the academic literature to improve their health. If such patients have abnormally elevated serum TSH, they should undoubtedly be treated immediately with T4 replacement therapy to normalize their thyroid function.