Clinical and Genetic Characteristics of Adult Nonautoimmune Hypothyroidism: A Single-Institution Study.

Purpose: Nonautoimmune hypothyroidism is characterized by hypothyroidism with negative thyroid autoantibodies with limited knowledge of its clinical and genetic characteristics. The aim was to characterize the clinical and genetic features of nonautoimmune hypothyroidism.

Methods: This retrospective study included 1,470 treatment-naive adult hypothyroid patients (serum TSH >10 mU/L) born before 1979 and were followed up at Ito Hospital, Tokyo, Japan. Of them, 220 patients were diagnosed with idiopathic nonautoimmune hypothyroidism by thyroid autoantibody measurements. Sequencing of 13 genes associated with nonautoimmune hypothyroidism was performed of 101 of the 220 patients. Clinical characteristics, including thyroid function and morphology, were systematically evaluated.

Results: The proportion of idiopathic nonautoimmune hypothyroidism among the 1,470 patients with treatment-naive non-transient hypothyroidism was 15.0%. Idiopathic nonautoimmune hypothyroidism patients had lower serum TSH (17.0 vs. 28.3 mU/L; P<0.001), higher serum fT4 (11.5 vs. 8.9 pmol/L; P<0.001), and a smaller thyroid volume (13.4 vs. 24.9 g; P<0.001) than autoimmune hypothyroidism patients. Genetic analysis showed that 5.0% of the analyzed idiopathic nonautoimmune hypothyroidism patients had a Mendelian disorder, with PAX8 being the most commonly affected gene. An additional 19% of the analyzed patients carried monoallelic variants in hypothyroidism-associated genes, such as DUOX2, DUOXA2, SLC26A4, TG, TPO, and TSHR, that cause autosomal recessive genetic defects.

Conclusions: In patients with treatment-naive adult nonautoimmune hypothyroidism, thyroid dysfunction was milder, and thyroid volume was smaller than in patients with autoimmune hypothyroidism. Mendelian forms were rare, but the unexpectedly high frequency of monoallelic variant carriers suggests that these variants may confer genetic risk for nonautoimmune hypothyroidism.