Management of non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease is a very common medical condition, driven by a combination of genetic and lifestyle factors, ultimately producing a severe chronic liver disease and increased cardiovascular risk. Most people are asymptomatic for a long time, and their daily life is unaffected, leading to difficulty in identifying and managing people who slowly progress to non-alcoholic steatohepatitis (NASH), NASH-cirrhosis, and eventually hepatocellular carcinoma. Despite advances in the understanding of pathogenic mechanisms and the identification of liver fibrosis as the strongest factor in predicting disease progression, no specific treatments have been approved by regulatory agencies. Outside controlled trials, treatment is generally limited to lifestyle intervention aimed at weight loss. Pioglitazone remains the drug of choice to reduce progression of fibrosis in people with diabetes, although it is often used off-label in the absence of diabetes. Vitamin E is mainly used in children and may be considered in adults without diabetes. Several drugs are under investigation according to the agreed targets of reduced NASH activity without worsening of fibrosis or improving fibrosis without worsening of NASH. Anti-inflammatory, anti-fibrotic agents and metabolism modulators have been tested in either phase III or phase IIb randomized controlled trials; a few failed, and others have produced marginally positive results, but only a few are being tested in extension studies. The development of non-invasive, easily repeatable surrogate biomarkers and/or imaging tools is crucial to facilitate clinical studies and limit liver biopsy.

Insights into Nonalcoholic Fatty-Liver Disease Heterogeneity

“…103 Being a multisystem disease, NAFLD is commonly associated with metabolic features, with a prevalence of 80% of obesity, 72% dyslipidemia, and 44% of T2DM. 1,104 Although the combination of these features acts in an additive manner to promote NAFLD progression, T2DM is the feature most strongly and consistently associated with a more severe disease and progression. [105][106][107] Considering the ominous effect of T2DM on liver disease progression and extrahepatic complications (i.e., cardiovascular disease, cancer risk, and chronic kidney disease), most guidelines recommend patients that NAFLD need to be screened and treated for metabolic comorbidities.…”

Mitochondrial Mutations and Genetic Factors Determining NAFLD Risk

“…There are several main targets in NAFLD treatments: (1) lifestyle modification, which includes changes in feeding behavior, healthy diet, and exercise, oriented around weight loss; (2) control and management of the cardiovascular risks (the leading cause of mortality among NAFLD patients); and (3) prevention of the NAFLD progression to more severe forms and development of associated complications [ 6 ]. Ideal treatment should combine glucose and lipid-lowering drugs, metabolism modulators, antioxidants, and anti-inflammatory and anti-fibrotic agents [ 209 ]. A single substance (natural or synthetic) cannot provide such complex activities; thus, several combined approaches and drugs should be used.…”

Systematic review of existing guidelines for NAFLD assessment

“…Its global prevalence of 25% varies across different geographical areas, from 14% in Africa to 32% in the Middle East [8] . The distribution of NAFLD appears to be linked to socioeconomic status, with a higher prevalence in industrialized countries [9] , although incidence is increasing in every social and ethnic group [10] .…”