Clinical Thyroidology® for the Public

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Age- and sex-specific reference ranges for thyroid function tests reduce misdiagnosis of subclinical thyroid dysfunction.

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Overt thyroid disease is diagnosed when both the TSH and thyroid hormone levels (T4, T3) are abnormal. In almost all cases, overt thyroid disease is treated. In contrast, subclinical thyroid disease is described as the presence of abnormal TSH levels with normal blood levels of the thyroid hormones T4 and T3. Treatment of subclinical thyroid disease is much less clear.

TSH is very sensitive to changes in thyroid function and is the first hormone to become abnormal and used in assessing thyroid dysfunction. Subclinical hypothyroidism is diagnosed when TSH levels are increased above the normal range while subclinical hyperthyroidism is diagnosed when TSH levels are decreased below the normal range. In order for the diagnosis of subclinical thyroid disease to be accurate, it is important to describe and establish a normal range for blood TSH.

Current TSH ranges used do not account for potential differences due age and sex. As such, this can lead to misdiagnosis of thyroid disease. In addition, there is no agreement in when to start therapy in subclinical hypothyroidism. This study evaluated the influence of age and sex on thyroid function tests and rates of subclinical thyroid disease.

Yamada S et al. 2023 The impact of age- and sex-specific reference ranges for serum TSH and FT4 on the diagnosis of subclinical thyroid dysfunction: A multi-center study from Japan. Thyroid. Epub 2023 Feb 10. PMID: 36772798.

This study reviewed thyroid function tests from two hospitals in Japan using three different testing kits. At Takasaki Hidaka Hospital, 14,860 participants (8904 men and 5956 women) were assessed using Siemens kits, and 8132 (4682 men and 3450 women) were assessed using Abbott kits. Those with history of thyroid disease, liver cirrhosis, or renal failure; current use of levothyroxine, antithyroid drugs, insulin, and steroid hormones; and missing data, were not included.

At Okamoto Thyroid Clinic, 515 participants (99 men and 416 women) were assessed using Toso Kits. Serum TSH and free T4 were measured with kits from all manufacturers, while serum free T3 was measured with Abbott and Toso Kits. Those with history of thyroid disease, elevated antithyroid antibodies, and abnormal thyroid gland findings on ultrasonography were not included.

The study noted an increase in average TSH levels with the age progression in women with all the three kit manufacturers, while men had lower average TSH levels and minor increase with age when compared to women. Free T4 and T3 levels did not change with age in women across all three test manufacturers, but serum free T4 levels in men were higher than in women and slowly decreased with age. However, blood T3 levels in women did not change.

Diagnosis of subclinical hypothyroidism was high, especially in women, and increased age. Within women aged between 30 to 39 years-old, almost 50% of those participants initially categorized as having subclinical hypothyroidism based on the manufacturer’s reference range were categorized as being in the normal range when using reference ranges for age and sex. This number was even higher in women ages 60 to 69 years with up to 78%. On the other hand, there was no difference in the normal range between tests in men ages 30 to 39 and only 5% of men aged 40 to 49 tested normal when the prior tests as indicated having subclinical hypothyroidism. However, the number increased with age and up to 62% of men were categorized as being in the normal range when using reference ranges for age and sex. Interestingly, differences in the diagnosis of subclinical hyperthyroidism was very low and only seen in seen in middle-aged patients, with 0.6% in men and 1% in women categorized as being in the normal range when using reference ranges for age and sex.

This study showed that subclinical hypothyroidism is frequently over-diagnosed, especially in those over the age of 60 years, and women. Over diagnosis is much less frequent when diagnosing subclinical hyperthyroidism. This study shows that there is a need for laboratory reference ranges for age and sex when evaluating thyroid function to accurately diagnosis subclinical thyroid disease.

— Joanna Miragaya, MD


Overt Hypothyroidism: clear hypothyroidism an increased TSH and a decreased T4 level. All patients with overt hypothyroidism are usually treated with thyroid hormone pills.

Subclinical Hypothyroidism: a mild form of hypothyroidism where the only abnormal hormone level is an increased TSH. There is controversy as to whether this should be treated or not.

Subclinical Hyperthyroidism: a mild form of hyperthyroidism where the only abnormal hormone level is a decreased TSH.

Thyroxine (T4): the major hormone produced by the thyroid gland. T4 gets converted to the active hormone T3 in various tissues in the body.

Triiodothyronine (T3): the active thyroid hormone, usually produced from thyroxine.

TSH: thyroid stimulating hormone — produced by the pituitary gland that regulates thyroid function; also the best screening test to determine if the thyroid is functioning normally.