Abstract Introduction Thyroid hormone resistance (THR) is a rare disorder characterized by elevated free thyroxine (fT4) and free triiodothyronine (fT3) with nonsuppressed thyrotropin (TSH). The most common cause is mutation in the THRB gene, resulting in impaired hormone action in target tissues and disruption of the hypothalamo-pituitary-thyroid axis. A hallmark feature is the discrepancy between thyroid function tests and the clinical picture. The differential diagnosis includes TSH-secreting pituitary adenoma, assay interference, and drugs affecting thyroid hormone metabolism. Given its usual autosomal dominant inheritance, family history should be carefully evaluated. Definitive diagnosis is made through genetic testing. The increased frequency of autoimmune thyroid disease (AITD) in these patients may be related to lymphocytic activation due to chronic TSH stimulation or heightened screening. Here, we present a case of THR with dual receptor mutation, diagnosed at an advanced age in a patient long followed with AITD. Clinical Case A 70-year-old male had been followed for 20 years with a diagnosis of hypothyroidism was referred to our clinic due to discordant thyroid function tests. He had been on 100 mcg levothyroxine daily, and there were no signs of hypo- or hyperthyroidism. Laboratory tests revealed TSH: 7.1 mIU/L (0.27-4.8), fT4: 2.32 ng/dL (0.79-1.59), fT3: 3.2 ng/L (2.04-4.4). Review of past records revealed persistently elevated fT4 with nonsuppressed TSH. Anti-TG and anti-TPO antibodies were positive. In biochemical tests, SHBG, AST, ALT, CK were within normal levels, while LDL elevation (212 mg/dL) was evident. On ultrasonography, the thyroid gland dimensions were measured as 17 mm, 13 mm and 4 mm for the right lobe, left lobe and isthmus; parenchyma heterogeneity and millimetric nodules were observed. TSH and fT4 assays with polyethylene glycol precipitation excluded interference. Pituitary MRI was unremarkable, ruling out TSHoma. A family history of abnormal thyroid function tests and difficulty with dose titration was elicited. Genetic testing, ordered with a preliminary diagnosis of THR, identified the likely pathogenic variants THRB:c.749TC and TSHR:c.1582CT. Genetic counseling was recommended to family members. The patient was clinically euthyroid and current levothyroxine therapy was maintained. Conclusion Diagnosis of THR is often delayed, and typical presentations include diffuse goiter and a history of unnecessary thyroidectomy, radioactive iodine administration, or antithyroid drug use. In our case, although the age of diagnosis was much later than expected, the silent presentation may be associated with the heterogeneity in the effect of mutations or the coexistence of two mutations. Importantly, autoantibody positivity does not exclude THR, as AITD may coexist more frequently in this group. During follow-up, clinical assessment takes precedence over laboratory or even genetic findings, serving as the main guide for therapy.
Saydam et al. (Thu,) studied this question.