Antimullerian Hormone, a Marker of Ovarian Reserve, Is Protective Against Presence and Severity of NASH in Premenopausal Women.

BACKGROUND & AIMS: Antimüllerian hormone (AMH) is a marker of ovarian reserve with emerging data linking lower levels to some metabolic and inflammatory diseases in women. Whether AMH levels influence nonalcoholic fatty liver disease (NAFLD) is unknown. METHODS: Leveraging the NASH Clinical Research Network we determined the association of AMH levels within 6 months of liver biopsy with presence and severity of histologic measures of NAFLD in premenopausal women. Outcomes included presence of nonalcoholic steatohepatitis (NASH), presence and severity of fibrosis, and NAFLD Activity Score and its components. Logistic and ordinal logistic regression models were adjusted for age, race/ethnicity, homeostatic model assessment for insulin resistance, body mass index, dyslipidemia, polycystic ovary syndrome, estrogen-progestin use, and menstrual cyclicity. RESULTS: Median cohort age was 35 years; 73% were white and 24% Hispanic. Thirty-three percent had diabetes, 81% had obesity, and 95% had dyslipidemia. On biopsy 71% had NASH, 68% had any fibrosis, and 15% had advanced fibrosis. On adjusted analysis (n = 205), higher AMH quartiles were inversely associated with NAFLD histology including prevalent NASH (adjusted odds ratio [AOR], 0.64; 95% confidence interval [CI], 0.41-1.00), NAFLD Activity Score ≥5 (AOR, 0.52; 95% CI, 0.35-0.77), Mallory hyaline (AOR, 0.54; 95% CI, 0.35-0.82), and higher fibrosis stage (AOR, 0.70; 95% CI, 0.51-0.98). The protective effects of AMH were more pronounced among women without polycystic ovary syndrome (n = 164), including lower odds of NASH (AOR, 0.53; 95% CI, 0.32-0.90) and any NASH fibrosis (AOR, 0.54; 95% CI, 0.32-0.93). CONCLUSIONS: AMH may reflect a unique biomarker of NASH in premenopausal women and findings suggest a novel link between reproductive aging and histologic severity of NAFLD in women.

Polycystic ovary syndrome is associated with nonalcoholic steatohepatitis in women of reproductive age.

Polycystic ovary syndrome (PCOS) occurs in approximately 10% of all reproductive-age women, with over 50% of these patients having imaging-confirmed nonalcoholic fatty liver disease (NAFLD). Whether PCOS increases the risk for more clinically relevant disease, such as nonalcoholic steatohepatitis (NASH), is unclear. Such findings are relevant to prognosticating risk of progressive liver disease in the growing population of young adults with NAFLD. Using weighted discharge data from the United States National Inpatient Sample from 2016 to 2018, we evaluated the association of PCOS with the presence of NASH among reproductive-age women with NAFLD. The association of PCOS with NASH was assessed by logistic regression, adjusting for demographic and comprehensive metabolic comorbidities. Other causes of hepatic steatosis and chronic liver diseases were excluded. Our analysis included 189,440 reproductive-age women with NAFLD, 9415 of whom had PCOS. Of those with PCOS, 1390 (15%) had a distinct code for NASH. Women with PCOS were younger (median age, 33 vs. 40 years; p < 0.001) and more likely to have diabetes (37.0% vs. 34.0%), obesity (83.0% vs. 58.0%), dyslipidemia (26.0% vs. 21.0%), and hypertension (38.0% vs. 35.0%) (all p ≤ 0.01). On adjusted analysis accounting for these metabolic comorbidities, PCOS remained independently associated with an increased prevalence of NASH (adjusted odds ratio, 1.22; 95% confidence interval, 1.05-1.42; p = 0.008). Conclusions: Among reproductive-age women with NAFLD, metabolic risk factors were more common in those with PCOS. Despite adjustment for these metabolic comorbidities, PCOS remained associated with a 22% higher odds of having NASH. These findings support efforts to increase NAFLD screening in young women with PCOS and highlight the potential "head start" in progressive liver disease among young women with PCOS.

Mechanisms of MAFG Dysregulation in Cholestatic Liver Injury and Development of Liver Cancer.

BACKGROUND & AIMS: MAF bZIP transcription factor G (MAFG) is activated by the farnesoid X receptor to repress bile acid synthesis. However, expression of MAFG increases during cholestatic liver injury in mice and in cholangiocarcinomas. MAFG interacts directly with methionine adenosyltransferase α1 (MATα1) and other transcription factors at the E-box element to repress transcription. We studied mechanisms of MAFG up-regulation in cholestatic tissues and the pathways by which S-adenosylmethionine (SAMe) and ursodeoxycholic acid (UDCA) prevent the increase in MAFG expression. We also investigated whether obeticholic acid (OCA), an farnesoid X receptor agonist, affects MAFG expression and how it contributes to tumor growth in mice. METHODS: We obtained 7 human cholangiocarcinoma specimens and adjacent non-tumor tissues from patients that underwent surgical resection in California and 113 hepatocellular carcinoma (HCC) specimens and adjacent non-tumor tissues from China, along with clinical data from patients. Tissues were analyzed by immunohistochemistry. MAT1A, MAT2A, c-MYC, and MAFG were overexpressed or knocked down with small interfering RNAs in MzChA-1, KMCH, Hep3B, and HepG2 cells; some cells were incubated with lithocholic acid (LCA, which causes the same changes in gene expression observed during chronic cholestatic liver injury in mice), SAMe, UDCA (100 µM), or farnesoid X receptor agonists. MAFG expression and promoter activity were measured using real-time polymerase chain reaction, immunoblot, and transient transfection. We performed electrophoretic mobility shift, and chromatin immunoprecipitation assays to study proteins that occupy promoter regions. We studied mice with bile-duct ligation, orthotopic cholangiocarcinomas, cholestasis-induced cholangiocarcinoma, diethylnitrosamine-induced liver tumors, and xenograft tumors. RESULTS: LCA activated expression of MAFG in HepG2 and MzChA-1 cells, which required the activator protein-1, nuclear factor-κB, and E-box sites in the MAFG promoter. LCA reduced expression of MAT1A but increased expression of MAT2A in cells. Overexpression of MAT2A increased activity of the MAFG promoter, whereas knockdown of MAT2A reduced it. MAT1A and MAT2A had opposite effects on the activator protein-1, nuclear factor-κB, and E-box-mediated promoter activity. Expression of MAFG and MAT2A increased, and expression of MAT1A decreased, in diethylnitrosamine-induced liver tumors in mice. SAMe and UDCA had shared and distinct mechanisms of preventing LCA-mediated increased expression of MAFG. OCA increased expression of MAFG, MAT2A, and c-MYC, but reduced expression of MAT1A. Incubation of human liver and biliary cancer cells lines with OCA promoted their proliferation; in nude mice given OCA, xenograft tumors were larger than in mice given vehicle. Levels of MAFG were increased in human HCC and cholangiocarcinoma tissues compared with non-tumor tissues. High levels of MAFG in HCC samples correlated with hepatitis B, vascular invasion, and shorter survival times of patients. CONCLUSIONS: Expression of MAFG increases in cells and tissues with cholestasis, as well as in human cholangiocarcinoma and HCC specimens; high expression levels correlate with tumor progression and reduced survival time. SAMe and UDCA reduce expression of MAFG in response to cholestasis, by shared and distinct mechanisms. OCA induces MAFG expression, cancer cell proliferation, and growth of xenograft tumors in mice.