Nearly half of Klinefelter patients had fatty liver, driven by metabolic syndrome — not low testosterone
Journal: The Journal of Clinical Endocrinology and Metabolism | Published: 2026-02-20 | Type: Cross-sectional study | PMID: 40878796 Authors: Marrone A et al. — all authors from the University of Campania Luigi Vanvitelli, Naples, Italy Funding/COI: PRIN 2022 (Italian national research grant). No conflicts of interest listed.
Klinefelter syndrome (KS) — the most common sex chromosome aneuploidy in males, 47,XXY — is already known to predispose men to hypogonadism, metabolic syndrome, and cardiovascular disease. This Italian cross-sectional study of 82 KS patients is the first to systematically characterize the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD) in this population. It found MASLD in nearly half of patients, driven primarily by metabolic syndrome rather than by testosterone deficiency or any KS-specific endocrine factor.
This is a single-center cross-sectional study — the design appropriate for a first-pass prevalence estimate in a rare disease, but incapable of establishing causation or temporal relationships. The sample of 82 patients is small overall, and the FibroScan subgroup (n=46) is smaller still, limiting the power of the correlation analyses. Use of CAP via FibroScan for steatosis quantification is a validated, objective method and a genuine strength over ultrasound alone. The multivariable logistic regression is correctly applied but underpowered with this sample size — detecting only one significant predictor may reflect low power as much as a true null result for other variables.
There is no non-KS male control group. Without age- and BMI-matched controls, it is impossible to say whether the 45.1% MASLD prevalence in KS is elevated above background, or simply reflects the general metabolic burden these men carry. The authors' framing of this as an "unmet need" unique to KS is premature without that comparison.
A useful first look at an overlooked comorbidity in Klinefelter syndrome, not a definitive answer. The finding that metabolic syndrome — not hypogonadism — drives MASLD risk in KS men is scientifically interesting and, if replicated with a control group, would clarify whether KS carries any liver-specific risk beyond its metabolic phenotype. As it stands, the absence of controls makes the headline prevalence figure hard to interpret. Worth reading for the CAP/IGF-1 correlation, which hints at a growth hormone axis contribution to hepatic steatosis in this population — but that thread needs a much larger study to pull on.