Individuals with extreme insulin resistance have a high prevalence of thyroid nodules that do not appear to be associated with metreleptin treatment, according to study results published in The Journal of Clinical Endocrinology & Metabolism.
Syndromes of extreme insulin resistance include generalized or partial lipodystrophy and insulin receptor gene (INSR) mutation syndromes, and high-dose insulin and metreleptin are used to treat both conditions. However, data are lacking regarding the effects of known mitogenic stimuli, including hyperinsulinemia and leptin, on thyroid proliferation in this patient population.
An association between milder forms of insulin resistance and thyroid proliferation has previously been observed, and in this study researchers hypothesized that severe hyperinsulinemia and/or leptin treatment in patients with extreme insulin resistance would lead to a higher prevalence of proliferative thyroid changes. The cohort included 81 patients with lipodystrophy and 11 with INSR mutations (5 homozygous, 6 heterozygous). Thyroid characteristics were examined by ultrasound and characterized by echogenicity, vascularity, and the presence of lesions/nodules. In the study group, 60 patients were receiving metreleptin therapy at the time of thyroid ultrasound.
In patients younger than 19 years, thyroid nodules were detected in 4 of 23 patients (17%) with lipodystrophy and 1 of 7 patients with an INSR mutation (14%); in the cohort as a whole, 29 of 80 patients (36.3%) with lipodystrophy had thyroid nodules. Patients with lipodystrophy and INSR mutations without thyroid lesions tended to be significantly younger (16.5 ± 6.4 years) when compared with patients with only colloid cysts (30.6 ± 15.4 years; P =.0002) and patients with nodules (43.4 ± 18.6 years; P <.0001). Patients who were treated with metreleptin did not have an increase in thyroid nodules, even though many had received treatment for relatively long periods of time (up to 16.7 years in patients with lipodystrophy and 6 years in patients with an INSR mutation).
There were several limitations to the study, the researchers noted, including a small sample size of patients with an INSR mutation, comparison of thyroid volume and nodularity to published controls instead of having an internal control group, and a young patient cohort.
“All nodules in our pediatric cohort of extreme insulin resistance were diagnosed after age 9 years, and  patients had papillary thyroid cancer diagnosed at age 18.4 and 18.8 years. Thus, thyroid [ultrasound] starting at a pubertal age might be considered for early detection of thyroid abnormalities in patients with extreme insulin resistance,” wrote the investigators. “Prospective, longitudinal studies are needed to clarify the effects of extreme [insulin resistance] and/or metreleptin treatment on nodules/cancer development, and mechanistic studies are needed to determine the etiology of thyroid abnormalities in patients with extreme insulin resistance.”
Kushchayeva Y, Kushchayev S, Startzell M, et al. Thyroid abnormalities in patients with extreme insulin resistance syndromes [published online January 16, 2019]. J Clin Endocrinol Metab. doi:10.1210/jc.2018-02289