With the widespread use of serum TSH testing and the increased sensitivity of the test, it is common in clinical practice to see patients with serum TSH (thyroid stimulating hormone) outside the normal reference range and free thyroxine (FT4) and triiodothyronine (T3) within the normal reference range. This subclinical thyroid disorder (or mild thyroid disease) is more common in middle-aged and older patients. However, there is considerable controversy regarding the definition, clinical importance, and need for timely diagnosis and treatment of this disease.
I. Overview of subclinical thyroid disease
Essentially, subclinical thyroid disease is a laboratory diagnosis in which the patient essentially has no signs and symptoms of abnormal thyroid function. Therefore, the normal reference range of TSH must be standardized, and the laboratory should have appropriate quality control procedures to ensure the accuracy and reproducibility of its tests, which should have a sensitivity of at least 0.02 mIU/L.
Definition of subclinical hypothyroidism
Subclinical hypothyroidism (subclinical hypothyroidism) is a condition in which TSH levels exceed the upper limit of the statistical normal reference range while FT4 is within the normal reference range. The following conditions must be excluded as causes of elevated TSH levels: recent dose adjustment of levothyroxine (L-T4) that has not yet reached a steady state, temporary elevation of blood TSH levels in hospitalized patients recovering from a serious illness, and recovery from destructive thyroiditis (e.g., viral subacute thyroiditis and postpartum thyroiditis), untreated primary adrenal insufficiency, patients treated with injectable human TSH, etc.
Definition of subclinical hyperthyroidism
Subclinical hyperthyroidism (subclinical hyperthyroidism) refers to serum TSH concentrations below the lower limit of normal reference values, while blood FT4 and T3 concentrations are within their own normal reference values, and other causes of lower serum TSH should be excluded, such as incomplete recovery of pituitary TSH-secreting cell function during or after treatment of hyperthyroidism, normal pregnant women, various non-thyroidal diseases (normal thyroid-disease syndrome), and patients taking dopamine. disease syndrome), and patients taking dopamine, glucocorticoids or dobutamine. Patients with pituitary and hypothalamic dysfunction (e.g., anorexia nervosa) may also present with lower than normal serum TSH concentrations but lower than normal FT4.
Epidemiology of subclinical thyroid disease
The prevalence of subclinical hypothyroidism in adult patients without thyroid disease in the United States is 4-8.5%, and the prevalence increases with age and can be as high as 20% in women older than 60 years. Data on the prevalence in men are very inconsistent, with some reports suggesting an increased prevalence in men older than 65 years, almost as high as in women. Some factors, such as a history of hyperthyroidism or type 1 diabetes, a family history of thyroid disease, or a history of external irradiation for head and neck tumors, are associated with an increased incidence of subclinical hypothyroidism.
Approximately 2-5% of patients with subclinical hypothyroidism progress to overt hypothyroidism each year. Some patients with symptoms of hypothyroidism, TSH greater than 10 mIU/L and FT4 at low normal values are also classified as having overt hypothyroidism. The rate of progression to overt hypothyroidism is related to basal serum TSH levels and is higher in patients with positive anti-thyroid antibodies. In patients not taking thyroid hormones, serum TSH decreases to normal in 5% of patients at 1-year follow-up, while the rest remain elevated.
The incidence of subclinical hyperthyroidism is much lower than that of subclinical hypothyroidism. If the lower limit of normal TSH is 0.4 mIU/L, the prevalence of subclinical hyperthyroidism in the population is 3.2%; excluding patients with pre-existing thyroid disease, the prevalence drops to 2%. Subclinical hyperthyroidism is more common in men than in women, more common in blacks than in whites, and common in the elderly and in areas with low iodine intake. Patients with goiter, history of previous thyroid disease, atrial fibrillation, or taking iodine-containing drugs such as amiodarone are more likely to develop subclinical hyperthyroidism.
Dominant hyperthyroidism is defined as a serum TSH level below 0.1 mIU/L and FT4, T3 or FT3 above the normal reference range. Patients with serum TSH between 0.1 and 0.45 mIU/L rarely progress to overt hyperthyroidism, while 1-2% of patients with TSH below 0.1 mIU/L progress to overt hyperthyroidism each year. Patients with large thyroid nodules and lower than normal TSH are more likely to develop overt hyperthyroidism when they are in a high iodine environment.
About subclinical hypothyroidism
Consequences of untreated subclinical hypothyroidism include heart failure or adverse cardiac endpoints (e.g., atherosclerosis and cardiovascular death), elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), systemic hypothyroid symptoms, neuropsychiatric symptoms, and progression to symptomatic overt hypothyroidism
1. Heart failure and adverse cardiac events: Many small studies have found a slight reduction in cardiac contractility on echocardiography in patients with subclinical hypothyroidism. However, the design of such studies was not comprehensive enough to include patients with a history of hyperthyroidism, and serum TSH levels were not further defined, making the conclusions less credible. There is no clear conclusion as to whether untreated subclinical hypothyroidism is associated with serious cardiovascular consequences (angina and heart attack). The results of a large cross-sectional study in the Netherlands showed that subclinical hypothyroidism is a risk factor for atherosclerosis, similar to the risk of diabetes mellitus, hypercholesterolemia and smoking. Because it was a cross-sectional study, prospective findings were lacking, and the elevated risk of MI in patients with subclinical hypothyroidism could not be confirmed in some of the patients followed up. There are no data from randomized studies on the effect of L-T4 replacement on important cardiovascular endpoints. There are also a number of small clinical intervention trials confirming that L-T4 replacement therapy improves cardiac function and reduces TC and LDL-C levels, but this has not been confirmed in randomized controlled trials.
2. Systemic symptoms: The Colorado Thyroid Disease Prevalence Study, which surveyed 25,862 people, found that patients with subclinical hypothyroidism were more likely to have symptoms of thyroid insufficiency than those with normal thyroid function. However, the study was not population-based and did not distinguish between untreated subclinical hypothyroidism and overt hypothyroidism that was being treated.
One double-blind randomized controlled trial (RCT) reported that treatment with L-T4 resulted in a significant improvement in symptoms compared to placebo, but the patients studied were mostly patients with previously treated hyperthyroidism, even including those with blood TSH in the 40-50 mIU/L range. There were also 2 RCT studies that focused on patients with TSH levels below 10 mIU/L and found that L-T4 treatment failed to improve symptoms.
III. Examination and diagnosis of subclinical hypothyroidism
If the patient’s serum TSH level is elevated but FT4 is not checked, TSH should be retested at least 2 weeks later and FT4 should be checked in 3 months. if the retest confirms that TSH is elevated and FT4 is within the reference range, the patient should be asked whether he/she has signs and symptoms of hypothyroidism, whether he/she has been treated for hyperthyroidism (radioactive iodine therapy and subtotal thyroidectomy), whether he/she has goiter and family history of thyroid disease. and clarify the blood lipid profile. Special attention should be paid to women who are pregnant or planning to become pregnant.
The presence or absence of autoantibodies does not affect the diagnosis of subclinical hypothyroidism (which is based on serum TSH levels) or the expected outcome of treatment. One study found that 4.3% of anti-TPO antibody-positive patients with an autoimmune etiology progressed to overt hypothyroidism each year, compared to 2.6% of the TPO antibody-negative group. Therefore, it is not necessary to routinely check anti-TPO antibodies in patients with subclinical hypothyroidism.
IV. Benefits and risks of treating subclinical hypothyroidism
In patients with subclinical hypothyroidism, the management plan should not be based on the TSH level alone, but should pay attention to the comprehensive clinical situation. The potential risk of treatment is mainly the progression to subclinical hyperthyroidism, which occurs in 14-21% of patients treated with L-T4, because no studies have confirmed that treatment of subclinical hypothyroidism can reduce morbidity and mortality.