Thyroid function, adipokines and mitokines in metabolic dysfunction‐associated steatohepatitis: A multi‐centre biopsy‐based observational study

Abstract

Background 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.

Resmetirom: Finally, the Light at the End of the NASH Tunnel?

“…In parallel, strong epidemiological evidence has indicated that hypothyroidism is also tightly associated with the development and fibrotic progression of NAFLD and NASH [19][20][21][22]. This association has recently been found to be sex-specific and mediated by adipokines/mitokines [23].…”