A somatic mutation in the thyrotropin receptor gene in a patient with an autonomous nodule within a multinodular goiter

ABSTRACT Thyrotropin (TSH) is the prime regulator of thyroid cell growth and function and acts through the thyrotropin receptor (TSHR) located on the surface membrane of thyrocytes. Somatic heterozygous mutations that cause TSHR activation in the absence of TSH have been found in toxic adenomas and in hot nodules of multinodular goiters. Clinically and histologically heterogeneous nodules can share common gain-of-function mutations. Mutation prevalence varies greatly and is inversely related to iodine intake of the population. We report a Greek patient presenting with subclinical hyperthyroidism due to a fast-growing autonomous hyperplastic nodule in a long-standing multinodular goiter. Direct DNA sequencing showed that the hot nodule harbored a somatic heterozygous activating TSHR mutation: substitution of glutamine for leucine in the third transmembrane helix. This mutation (L512Q) was recently described in two solitary toxic adenomas. This report expands the spectrum of mutations shared by dissimilar hot nodules, supporting a common mechanism for nonautoimmune thyroid autonomy. The identification of the L512Q substitution demonstrates that gainof-function TSHR mutations are encountered in Greece, although iodine deficiency has been significantly corrected over the last three decades

The nonthyroidal illness syndrome in the non-critically ill patient

P>Background The nonthyroidal illness syndrome (NTIS) is a very common clinical entity among hospitalized patients and has been reported in practically every severe illness and acute or chronic stressful event. There is a large body of data associating the presence of NTIS with the severity of the underlying disease. Most of these studies concern intensive care unit (ICU) patients, whereas the non-critically ill patients outside the ICU setting are less well studied. Design We provide a review of the existing literature focusing on studies examining NTIS in non-critically ill patients and attempt to summarize the pathophysiological pathways underlying the syndrome, its prognostic role, as well as the current intervention studies mainly from a clinical standpoint. Results The aetiology of the NTIS is multifactorial and varies among different groups of patients. Experimental and clinical findings suggest that inflammatory cytokines are implicated in the pathogenesis of the syndrome, whereas recent evidence re-evaluate the role of deiodinases in thyroid hormone metabolism not only in the periphery but also in the hypothalamus and the pituitary and thus in the alterations accompanying NTIS. Clinical data examining the effectiveness of thyroid hormone supplementation in NTIS remain controversial. Conclusions As long as there is no clear evidence of benefit from thyroid hormone replacement and until well-designed studies confirm its efficacy, thyroxine supplementation should not be recommended for the treatment of NTIS