Burden of Liver Disease Among Individuals With Turner Syndrome and Klinefelter Syndrome: A Comprehensive Perspective

ABSTRACT The liver is increasingly recognized as a major regulator of systemic cardio‐renal‐metabolic health. Evidence is mounting that sex‐chromosome dosage per se itself, independent of gonadal sex hormones, modulates hepatic physiology and liver disease risk. Turner syndrome (TS; monosomy X) and Klinefelter syndrome (KS; 47, XXY and variants) are the two most common sex‐chromosome aneuploidies and carry a clinically relevant, yet often under‐appreciated, burden of liver disease. Population studies show that individuals with TS have 2‐ to sixfold higher odds of raised liver enzymes, steatotic liver disease, advanced fibrosis, and even hepatocellular malignancy compared with to sex‐ and age‐matched controls. In KS, the prevalence of metabolic dysfunction‐associated steatotic liver disease (MASLD) reaches approximately 45%, with testosterone deficiency, visceral adiposity, and systemic inflammation acting as key drivers. Pathogenetic mechanisms converge on vascular dysgenesis and estrogen deficiency in TS, and on hypogonadism‐related metabolic derangements in KS, together accelerating steatosis, inflammation, and fibrogenesis. This concise review/Comprehensive perspective reviews discusses historical background, epidemiology, hepatic phenotypes, pathophysiology, and current diagnostic and management recommendations. It also highlights critical knowledge gaps, including the need for prospective cohorts, optimized hormone‐replacement protocols, and trials of emerging pharmacological approaches anti‐MASH agents. Raising awareness among all stakeholders, endocrinologists, hepatologists, and primary‐care physicians is essential for early detection, multidisciplinary management, and improved hepatic and extra‐hepatic outcomes in these vulnerable patient populations.