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Summary Background & Aim Non‐alcoholic fatty liver disease (NAFLD), and especially fibrotic non‐alcoholic steatohepatitis, is associated with high risks of liver‐related events (LRE) and extrahepatic events (EHE). We evaluated the competitive risk occurrence of LRE and EHE in a large cohort of biopsy‐proven NAFLD stratified according to baseline severity of fibrosis. Methods Two thousand one hundred thirty‐five patients with biopsy‐proven NAFLD were enrolled. Observed cumulative incidence functions (CIFs) were used to evaluate the risk of LRE and EHE; cause‐specific Cox model and predicted CIFs were fitted to identify predictors of LRE and EHE. A replication cohort of NAFLD patients with liver fibrosis severity estimated by liver stiffness measurement by transient elastography was also enrolled. Results Observed CIFs indicated that the 60‐month probabilities of LRE and EHE were 0.2% and 3% in F0‐F1, 2% and 3.8% in F2 and 9.7% and 6.4% in F3‐F4 patients, respectively. The cause‐specific Cox model indicated that in F0‐F1 and F2 patients, age > 50 years (HR 2.7) was the only predictor of LRE, while age > 50 years (HR 2.96), previous cardiovascular events (CVE, HR 2.07), and previous extra‐hepatic cancer (HR 2.36) were independent risk factors for EHE. In F3‐F4 patients, age > 55 years (HR 1.73), obesity (HR 1.52), PLT < 150 000/mmc (HR 3.66) and log(GGT) (HR 1.77) were associated with LRE, while age > 55 years (HR 1.74) and previous CVE (HR 2.51) were independent predictors of EHE. Predicted CIFs for HE and EHE in F0‐F1, F2 and F3‐F4 patients stratified the risk of events. The results were externally replicated. Conclusion The likelihood of EHE in NAFLD patients is relevant and increases according to the severity of liver fibrosis, while the risk of LRE is negligible in F0‐F1, low but clinically relevant in F2 and high in F3‐F4 patients.

Nonalcoholic fatty liver disease (NAFLD), affecting about 25% of general population and more than 50% of dysmetabolic patients, is an emerging cause of chronic liver disease and its complications. Recently, an international consensus of experts proposed to rename this disease as ‘Metabolic dysfunction-Associated Fatty Liver Disease’ (MAFLD) to focus on the bidirectional interplay between fatty liver and metabolic alterations and to stress the need of assessing fatty liver independently from alcohol consumption and other coexisting causes of liver disease. The peculiarity of NAFLD/MAFLD lies in the presence of a higher risk of not only – as expected – liver-related events but also of extrahepatic events, mostly cardiovascular and cancers. Available evidence suggests that these associations are not only the expression of sharing the same risk factors but shed light about the ability of NAFLD/MAFLD and particularly of its progressive form – nonalcoholic/metabolic dysfunction-associated steatohepatitis – to act as an independent risk factor via promotion of atherogenic dyslipidemia and a proinflammatory, profibrogenic, and procoagulant systemic environment. The present review summarizes available epidemiological and clinical evidence supporting the concept of NAFLD/MAFLD as a multisystemic disease, and highlights potential explanatory mechanisms underlying the association between NAFLD/MAFLD and extrahepatic disorders.

Hepatitis C virus infection has a substantial effect on morbidity and mortality worldwide because it is a cause of cirrhosis, hepatocellular carcinoma, liver transplantation, and liver-related death. Direct acting antiviral drugs available today have high efficacy and excellent safety and can be used in all patients with clinically evident chronic liver disease and in groups that demonstrate risk behaviors to reduce the spread of infection. The Global Health Strategy of WHO to eliminate hepatitis infection by 2030 assumes “a 90% reduction in new cases of chronic hepatitis C, a 65% reduction in hepatitis C deaths, and treatment of 80% of eligible people with HCV infections”. In this review effective models and strategies for achieving the global elimination of HCV infection are analyzed. The screening strategies must be simple and equally effective in high-risk groups and in the general population; fast and effective models for appropriate diagnosis of liver disease are needed; strategies for direct acting antiviral drug selection must be cost-effective; linkage to care models in populations at risk and in marginalized social classes must be specifically designed and applied; strategies for obtaining an effective vaccine against HCV infection have yet to be developed.

Methylmalonic acidemia can be secondary to a deficiency of methylmalonyl CoA mutase or to a defect of cobalamin metabolism that is classified by complementation group. We report on a new patient with cblF complementation group that is associated with an elevation of both methylmalonic acid and homocysteine, and her outcome in response to routine therapy and a dietary restriction.