Diabetes increases the risk of liver disease progression and cirrhosis development in patients with nonalcoholic steatohepatitis (NASH). The association between diabetes and the risk of hepatocellular carcinoma (HCC) in NASH patients with cirrhosis is not well quantified. All patients with the diagnosis of NASH cirrhosis seen at Mayo Clinic Rochester between January 2006 and December 2015 were identified. All adult liver transplant registrants with NASH between 2004 and 2017 were identified using the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation registry for external validation. Cox proportional hazard analysis was performed to investigate the association between diabetes and HCC risk. Among 354 Mayo Clinic patients with NASH cirrhosis, 253 (71%) had diabetes and 145 (41%) were male. Mean age at cirrhosis evaluation was 62. During a median follow‐up of 47 months, 30 patients developed HCC. Diabetes was associated with an increased risk of developing HCC in univariate (hazard ratio [HR] = 3.6; 95% confidence interval [CI] = 1.1‐11.9; P = 0.04) and multivariable analysis (HR = 4.2; 95% CI = 1.2‐14.2; P = 0.02). In addition, age (per decade, HR = 1.8; 95% CI = 1.2‐2.6; P < 0.01) and low serum albumin (HR = 2.1; 95% CI = 1.5‐2.9; P < 0.01) were significantly associated with an increased risk of developing HCC in multivariable analysis. Other metabolic risk factors, including body mass index, hyperlipidemia, and hypertension, were not associated with HCC risk. Among UNOS NASH registrants (N = 6,630), 58% had diabetes. Diabetes was associated with an increased risk of developing HCC in univariate (HR = 1.4; 95% CI = 1.1‐1.8; P < 0.01) and multivariable (HR = 1.3; 95% CI = 1.0‐1.7; P = 0.03) analysis. Conclusion: Diabetes is associated with an increased risk of HCC in patients with NASH cirrhosis.

Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is growing in incidence but treatment options remain limited, particularly for late stage disease. As liver cirrhosis is the principal risk state for HCC development, markers to detect early HCC within this patient population are urgently needed. Perturbation of epigenetic marks, such as DNA methylation (5mC), is a hallmark of human cancers, including HCC. Identification of regions with consistently altered 5mC levels in circulating cell free DNA (cfDNA) during progression from cirrhosis to HCC could therefore serve as markers for development of minimally-invasive screens of early HCC diagnosis and surveillance.Methods: To discover DNA methylation derived biomarkers of HCC in the background of liver cirrhosis, we profiled genome-wide 5mC landscapes in patient cfDNA using the Infinium HumanMethylation450k BeadChip Array. We further linked these findings to primary tissue data available from TCGA and other public sources. Using biological and statistical frameworks, we selected CpGs that robustly differentiated cirrhosis from HCC in primary tissue and cfDNA followed by validation in an additional independent cohort.Results: We identified CpGs that segregate patients with cirrhosis, from patients with HCC within a cirrhotic liver background, through genome-wide analysis of cfDNA 5mC landscapes. Lasso regression analysis pinpointed a panel of probes in our discovery cohort that were validated in two independent datasets. A panel of five CpGs (cg04645914, cg06215569, cg23663760, cg13781744, and cg07610777) yielded area under the receiver operating characteristic (AUROC) curves of 0.9525, 0.9714, and 0.9528 in cfDNA discovery and tissue validation cohorts 1 and 2, respectively. Validation of a 5-marker panel created from combining hypermethylated and hypomethylated CpGs in an independent cfDNA set by bisulfite pyrosequencing yielded an AUROC of 0.956, compared to the discovery AUROC of 0.996.Conclusion: Our finding that 5mC markers derived from primary tissue did not perform well in cfDNA, compared to those identified directly from cfDNA, reveals potential advantages of starting with cfDNA to discover high performing markers for liquid biopsy development.

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BACKGROUND Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are known risk factors for liver disease, cirrhosis and hepatocellular carcinoma (HCC). There is substantial global variation in HBV and HCV prevalence resulting in variations in cirrhosis and HCC. We previously reported high prevalence of HBV and HCV infections in Somali immigrants seen at an academic medical center in Minnesota. AIM To determine the prevalence of chronic viral hepatitis in Somali immigrants in Minnesota through a community-based screening program. METHODS We conducted a prospective community-based participatory research study in the Somali community in Minnesota in partnership with community advisory boards, community clinics and local mosques between November 2010 and December 2015 (data was analyzed in 2020). Serum was tested for hepatitis B surface antigen, hepatitis B core antibody, hepatitis B surface antibody and anti-HCV antibody. RESULTS Of 779 participants, 15.4% tested positive for chronic HBV infection, 50.2% for prior exposure to HBV and 7.6% for chronic HCV infection. Calculated age-adjusted frequencies in males and females for chronic HBV were 12.5% and 11.6%; for prior exposure to HBV were 44.8% and 41.3%; and for chronic HCV were 6.7% and 5.7%, respectively. Seven participants developed incident HCC during follow up. CONCLUSION Chronic HBV and HCV are major risk factors for liver disease and HCC among Somali immigrants, with prevalence of both infections substantially higher than in the general United States population. Community-based screening is essential for identifying and providing health education and linkage to care for diagnosed patients.

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