Endocrine Abstracts

A 79-year-old female was referred to our endocrinology service for evaluation of persistently discordant thyroid function tests (TFTs). She had been diagnosed with primary hypothyroidism (no thyroid antibodies were sent) in 2004 and had been treated with levothyroxine since then. On presentation, she was clinically euthyroid and there was no neck swelling. Her weight was 62 kg. TFTs showed elevated free thyroxine (FT4) (29 pmol/l (RR 11.9-21.6)), normal total triiodothyronine (FT3) (4.7 pmol/l (RR 3.1-6.8)), and elevated thyroid stimulating hormone (TSH) (6.44 mU/l (RR 0.3-4.2)), while taking levothyroxine 150 mg daily. When her levothyroxine dosage was reduced to 125 mg daily, she reported symptoms of fatigue, cold intolerance, and weight gain. Her body temperature was 35.8°C. These clinical features of hypothyroidism along with a significant rise in TSH (78 mU/l) and normal FT4 (17.9 pmol/l) prompted an increase of levothyroxine up to 200 mg daily. TFTs on levothyroxine 200 mg daily remained discordant, with elevated FT4 (35.1 pmol/l), normal FT3 (5 pmol/l) and a normalised TSH(1.47 mIU/l). Her hypothyroid symptoms resolved, but she subsequently was diagnosed with atrial fibrillation. Underlying causes of her persistently discordant TFTs were considered. Patient reported full compliance to levothyroxine and there was no concern for malabsorption or accelerated metabolism of thyroxine. Other potential causes of intercurrent illness or concurrent medication were excluded. Laboratory analyses excluded assay artefact and abnormal circulating thyroid hormone binding proteins. During this period of investigation, her 50-year-old daughter reported symptoms of thyrotoxicosis (anxiety, sweating and palpitations), and was found to have elevated FT4 (34.9 pmol/l), elevated FT3 (7.7 pmol/l) and normal range TSH (1.5 mIU/l). MRI Pituitary was normal, and dynamic testing with thyrotropin-releasing hormone (TRH) or T3 could not be performed due to her needle-phobia. Genetic analysis identified a thyroid hormone receptor beta (THRbeta) gene heterozygous mutation c.749 T>Cp.(Ile250 Thr), consistent with Resistance to Thyroid Hormone-beta (RTH-β) syndrome. Considering the index case’s need to maintain elevated FT4 levels to achieve a normal TSH level, coupled with the confirmed diagnosis of RTH-β in her daughter (who likely inherited the maternal mutation), a presumptive diagnosis of coexistent RTH-β and primary hypothyroidism was established for the index case. She remains well with long-term levothyroxine therapy, targeted to achieve normal range TSH.

Learning points: (1) The requirement for supraphysiological doses of levothyroxine (above 1.6µg/kg) to normalize TSH in primary hypothyroidism, in conjunction with raised FT4 and/or FT3 concentrations, can suggest underlying, coexistent RTHβ (2) Elevated FT4 and/or FT3 with non-suppressed (normal) TSH in relatives of an index case may indicate an inherited condition such as RTHβ. (3) Further research is needed to define the optimal TSH targets for managing hypothyroidism (of other etiologies) with concurrent RTHβ.