Mark Gurnell

A Novel Albumin Gene Mutation (R222I) in Familial Dysalbuminemic Hyperthyroxinemia

Context: Familial dysalbuminemic hyperthyroxinemia, characterized by abnormal circulating albumin with increased T4 affinity, causes artefactual elevation of free T4 concentrations in euthyroid individuals. Objective: Four unrelated index cases with discordant thyroid function tests in different assay platforms were investigated. Design and Results: Laboratory biochemical assessment, radiolabeled T4 binding studies, and ALB sequencing were undertaken. 125I-T4 binding to both serum and albumin in affected individuals was markedly increased, comparable with known familial dysalbuminemic hyperthyroxinemia cases. Sequencing showed heterozygosity for a novel ALB mutation (arginine to isoleucine at codon 222, R222I) in all four cases and segregation of the genetic defect with abnormal biochemical phenotype in one family. Molecular modeling indicates that arginine 222 is located within a high-affinity T4 binding site in albumin, with substitution by isoleucine, which has a smaller side chain predicted to reduce steric hindrance, thereby facilitating T4 and rT3 binding. When tested in current immunoassays, serum free T4 values from R222I heterozygotes were more measurably abnormal in one-step vs two-step assay architectures. Total rT3 measurements were also abnormally elevated. Conclusions: A novel mutation (R222I) in the ALB gene mediates dominantly inherited dysalbuminemic hyperthyroxinemia. Susceptibility of current free T4 immunoassays to interference by this mutant albumin suggests likely future identification of individuals with this variant binding protein.

Successful treatment of primary aldosteronism with partial adrenalectomy, facilitated by the use of 11 C-Metomidate PET/CT

Primary aldosteronism (PA) is estimated to be responsible for 5-10% of all cases of hypertension (HTN)1. The current gold standard test for determining lateralisation in PA is adrenal vein sampling (AVS). 11C-Metomidate PET/CT (MTO-PET) has recently emerged as a potential non-invasive alternative to AVS2. As 11C-Metomidate is concentrated within ‘hyper-functioning’ nodules, MTO-PET potentially not only identifies the side, but the exact site of aldosterone hypersecretion, thus raising the possibility of more targeted surgical intervention.

Pituitary Adenomas, TSH-Secreting

TSH-secreting pituitary adenomas (thyrotropinomas) are a rare but important cause of hyperthyroidism. In its most classical form (large macroadenoma with clinical and biochemical features of central hyperthyroidism) the diagnosis is relatively easily made once the failure of TSH suppression in the face of hyperthyroxinaemia is recognized. However, in recent years it has become increasingly clear that many cases are due to microadenomas, some of which are not readily visualized on conventional cross-sectional imaging, and which occur in patients with few symptoms of thyrotoxicosis. Importantly, incidental functioning (e.g., prolactinoma) or nonfunctioning pituitary adenomas are found in patients with resistance to thyroid hormone due to THRB mutations, increasing the risk of a mistaken diagnosis and inappropriate treatment/surgery. Accordingly, a systematic approach (combining clinical, biochemical, radiological and genetic investigations) is required to ensure a robust diagnosis, and thus facilitate targeted therapy (somatostatin analogue, transsphenoidal surgery and occasionally pituitary radiotherapy).