Affiliation:
1. Department of Medicine, Beth Israel Deaconess Medical Center Harvard Medical School Boston Massachusetts USA
2. Università Cattolica del Sacro Cuore Rome Italy
3. Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens General Hospital of Athens “Laiko” Athens Greece
4. Storr Liver Centre, Westmead Institute for Medical Research Westmead Hospital and University of Sydney Sydney New South Wales Australia
5. Department of Medicine Boston VA Healthcare System Boston Massachusetts USA
Abstract
AbstractBackground and AimsThyroid axis is currently under investigation as a therapeutic target in metabolic dysfunction‐associated steatotic liver disease (MASLD). Thyroid function was examined herein in the full spectrum of disease.MethodsSubjects were recruited and had liver biopsies in two Gastroenterology‐Hepatology Clinics (Greece and Australia) and one Bariatric‐Metabolic Surgery Clinic (Italy). The main working sample was n = 677 subjects with MASLD after excluding subjects with abnormal free thyroxine levels. Participants were classified according to thyroid‐stimulating hormone (TSH) standard criteria: Subclinical hyperthyroidism (<0.4 uIU/mL); Euthyroidism with relatively low (0.4 to <2.5 uIU/mL); euthyroidism with relatively high (2.5–4.0 uIU/mL); subclinical hypothyroidism (>4 uIU/mL).ResultsTSH as a continuous variable was positively associated with significant fibrosis (F ≥ 2), metabolic dysfunction‐associated steatohepatitis (MASH) and at‐risk MASH. Subclinical hypothyroidism was associated with fibrosis F ≥ 2 (odds ratio [OR] = 3.47, 95% confident interval [CI] [1.50, 8.05], p = .02), MASH (OR = 3.44, 95% CI [1.48, 7.98] p = .001) and at‐risk MASH (OR = 3.88, 95% CI [1.76, 8.55], p = .001), before and after controlling for adiposity, central obesity, and insulin resistance. When leptin, adiponectin, or growth differentiation factor‐15 were examined as moderators, significance was lost. Sex‐specific analysis revealed a strong association between TSH and the presence of significant fibrosis among women, eliminated only when adipokines/mitokines were adjusted for. Restricted cubic spline analysis revealed associations between TSH and liver outcomes (p‐values < .01) with inflection points for fibrosis F ≥ 2 being 2.49, for MASH being 2.67 and for at‐risk MASH being 6.96.ConclusionsThese observations provide support for studies on the administration of thyroid hormone in MASLD therapeutics for subclinical hypothyroidism and liver‐specific thyroid receptor agonists for subjects across the TSH continuum.