Poster The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2013

Does thyroid hormone resistance facilitate the development of Cardiomyopathy? (#352)

Walter E. Plehwe 1 , Eljas Laufer
  1. The Epworth Centre, Richmond, VIC, Australia

Thyroid Hormone Resistance (THR) is a rare autosomal dominant inherited syndrome, usually due to a single mutation in the β-isoform of the thyroid hormone receptor (TR) gene. With pituitary THR, TSH is inadequately suppressed by T4 and T3 (TH) resulting in elevated TH with normal TSH.   The TR β-isoform predominates in most tissues except the heart, where the α-isoforms occur. Subjects commonly show sinus tachycardia, which experimentally may cause cardiomyopathy (CM). Many point mutations mostly in β-TR gene exons 8-10 have been identified. In others without  β-TR mutations, THR may reflect genetic heterogeneity of coactivators and corepressors which modulate TR-dependent actions of TH1. We have identified a kindred with THR in 3 generations. Several members have developed CM.

A 63yo male presented with an 8-month history of reduced exercise tolerance. TFT were fT4:36.1 pmol/L (N 11-21), fT3:8.6 pmol/L (3.2-6.4) and TSH:2.08 mU/L (0.5-5.5) without goitre. Cardiac investigations revealed tachyarrhythmias culminating in atrial fibrillation, with global left ventricular(LV) hypokinesis (LVEF:40%), mildly dilated LV and normal coronaries. Stress echocardiography showed non-sustained multiform ventricular tachycardia. He received β-blockade and amiodarone. He had 8 first- and 20 second-degree relatives. Two brothers with elevated TH had CM. Their mother (dec.  87yr) had similar TFT on thyroxine replacement (fT4:28.1, fT3:6.3, TSH:1.45). Inheritance was autosomal dominant. βTR gene analysis was performed (Dr. R. Clifton-Bligh) showing a single point mutation in exon 8, A268G, reported previously in one family2. Others3,4 showed marked heterogeneity of cardiovascular (CV) indices with no correlation between the mutation and CV characteristics, including impaired diastolic function, high systemic vascular resistance, tachycardia and temporal variation in signs and parameters of TH action in the same individuals. Whether CM is due to variable penetrance of gene expression is unclear. THR may have a permissive effect exacerbating cardiotoxic effects of other disorders.

Further studies of affected relatives are underway to determine their risk of cardiac disease.

  1. Koenig RJ. Thyroid (1998); 8:703-13.
  2. Jézèquel P et al. Hum Mutat (1996); 8(4):396.
  3. Kahaly G et al. J Clin Endocrinol Metab (2002); 87:204-12.
  4. Pulcrano M et al. J Clin Endocrinol Metab (2009); 94:2812-16.