BACKGROUND
Metabolic dysfunction-associated steatotic liver disease (MASLD) and male hypogonadism are increasingly prevalent, metabolically interrelated conditions. Testosterone (T) deficiency has been implicated in hepatic lipid dysregulation, insulin resistance, and visceral adiposity, whereas MASLD may impair the hypothalamic-pituitary-gonadal axis. We conducted a systematic review and meta-analysis to evaluate the bidirectional association between circulating T levels and MASLD in adult men.
METHODS
Following PRISMA guidelines, a literature search was performed from inception to July 31, 2025. Twenty-eight studies met the inclusion criteria (9 comparing hypogonadal vs. eugonadal men; 19 comparing MASLD vs. non-MASLD men). Random-effects models were used to pool effect sizes for dichotomous and continuous outcomes. Meta-regression analyses assessed the influence of age, anthropometric features, glycemic markers, liver enzymes, and hormonal parameters.
RESULTS
Hypogonadal men showed a significantly higher prevalence of MASLD than eugonadal men (p = 0.001) and exhibited higher fatty liver index scores (p < 0.001). Total T concentrations were significantly lower in men with MASLD than in controls (p = 0.014). Meta-regression analyses did not identify significant effects of study-level differences in age, body mass index, or biochemical variables on the observed associations. Sex hormone-binding globulin levels were also significantly reduced in MASLD (p < 0.001), with age emerging as the only significant modifier. No significant differences were observed for luteinizing hormone, estradiol, or fibrosis-4 index. Across studies evaluating MASLD severity, moderate-to-severe disease was associated with lower T levels, particularly in analyses based on imaging.
CONCLUSIONS
This meta-analysis supports a clinically relevant association between testosterone deficiency and MASLD, although evidence for the bidirectional nature of this relationship remains asymmetric but supports a clinically relevant endocrine-hepatic axis. T deficiency appears independently linked to MASLD onset and severity beyond the effects of age and adiposity. These findings underscore the need for reciprocal screening of liver health and gonadal status in at-risk men and highlight the importance of prospective studies and randomized trials to determine whether correcting T deficiency may modify MASLD progression.
G. Spaggiari, L. Valentina, C. Felicani et al.· Andrology· 0 citations
Progressive Familial Intrahepatic Cholestasis (PFIC) is a rare liver disorder that, although typically present in childhood, can also occur in adulthood. Early diagnosis is crucial for appropriate clinical management, prognostic assessment, and therapeutic decision-making; however, it remains challenging due to phenotypic variability and the frequent identification of genetic variants of uncertain significance (VUS). Advances in next-generation sequencing (NGS) and whole-exome sequencing (WES) have improved the detection of disease-associated variants, revealing that the same genetic variants—often in a heterozygous state—may lead to adult-onset cholestatic disease, with milder or atypical presentations, while still conferring a significant risk of progressive liver injury and related complications. To assess the diagnostic yield and clinical utility of NGS panels and WES in adults with suspected PFIC or unexplained cholestatic liver disease, focusing on variant interpretation, emerging disease-associated genes, and clinical significance of VUS. A literature review was conducted to assess molecular diagnostics in adult cryptogenic cholestasis, with a focus on studies employing targeted NGS panels and WES. Selected studies were examined for diagnostic yield, variant classification, interpretive challenges, including VUS, and integration with clinical data. Data on patient demographics, sequencing techniques, and variant interpretation strategies were extracted to evaluate the current capabilities and limitations of genomic testing. From an initial search of 211 publications, 15 studies met the inclusion criteria, comprising five large adult cohorts and ten single-patient or trio-based reports. Across 72 patients, sequencing technologies identified 75 pathogenic or likely pathogenic variants, predominantly missense mutations, demonstrating high genetic heterogeneity. The most implicated genes included ABCB4, ABCB11, ATP8B1, TJP2, and USP53, with diagnostic yields ranging from 13.2% in large heterogeneous cohorts to substantially higher rates in carefully selected individual cases. VUS were identified in up to 67% of cases, highlighting the need for multidisciplinary interpretation integrating clinical, biochemical, and genetic data. Emerging evidence also implicated ciliopathy-associated genes such as DCDC2, NPHP3, PKHD1, TULP3, and TTC21B, expanding the genetic spectrum of adult cholestasis. Clinically, presentations ranged from mild biochemical abnormalities to progressive cholestasis, with pruritus being a common feature across studies. Comprehensive genetic testing significantly enhances diagnostic accuracy, informs prognosis, and guides individualized management in adults with cryptogenic cholestasis. Emerging evidence suggests that ciliopathy-associated genes may contribute to the genetic architecture of adult cholestatic disorders, further expanding the spectrum of disease-associated genes. However, the high prevalence of VUS remains a major challenge, highlighting the need for functional studies, longitudinal follow-up, and improved variant interpretation frameworks. As genomic technologies and analytical approaches continue to evolve, genetic testing is expected to play an increasingly central role in precision hepatology.
Amalia Conti, F. Gabrielli, S. Ferrari et al.· Diagnostics· 0 citations