A narrative review of factors associated with the development and progression if non‐alcoholic fatty liver disease

Abstract

Summary Background With the obesity pandemic, non‐alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease. NAFLD can progress to non‐alcoholic steatohepatitis (NASH), a potential cause of liver failure. It remains difficult to identify patients at risk for NASH, despite evolving insights in contributing factors, including genetic variance, hormones, adipokines, diet and body‐fat distribution. We aimed to present a broad perspective on these risk factors associated with NAFLD development and progression with a focus on their contribution in different age groups and susceptible high‐risk populations, hereby giving insight in the pathophysiology of NAFLD. Methods Literature was searched for relevant articles on the pathophysiology of NAFLD in different age groups. Results Our review underscores large contributions of diet, with particularly fructose promoting NASH development, and sex hormones, with oestrogens exerting protective effects and androgens negatively influencing NAFLD development. Genetic variation in corresponding pathways might further determine NAFLD progression. Conclusions Changes throughout the transition from childhood to adulthood show that variations in diet, hormone levels and metabolism are related to NAFLD progression. The human body uses different strategies to handle excessive nutrients, but each comes at a price. When corresponding pathways are strained by hormonal or genetic factors, NASH or other symptoms of the metabolic syndrome ensue. Potentially, stratification based on sex, body‐fat distribution, diet, lifestyle, microbiome, adipokines, sex hormones, blood concentrations of liver enzymes, liver histology and genetic pre‐disposition might help to identify patients at increased risk of NASH.

Non-alcoholic fatty liver disease and childhood obesity

“…Similarly, oestrogens are thought to have an anti-inflammatory and insulin sensitising role, as well as influencing body composition, favouring non-visceral rather than visceral adipose tissue distribution [31,32]. However, the persistence of pre-pubertal sex differences in NAFLD prevalence through adolescence, highlights the influence of other factors, not just pubertal factors, on pathophysiology.…”

“…Animal studies suggest that environmental exposure to endocrine disrupting chemicals (EDCs) may contribute to the development and progression of NAFLD [53]. The 'multiple hit' hypothesis describes NAFLD pathogenesis, where a number of insults are thought to act together to induce NAFLD development and progression in genetically predisposed or high-risk individuals (Figure 1) [32].…”

“…In obesity, pro-inflammatory cytokines released from hypertrophic adipose tissue, contribute to systemic insulin resistance [32]. Adipose tissue dysfunction also alters the balance of secreted adipokines, specifically the hormones leptin and adiponectin, which are thought to have pro-and anti-inflammatory roles respectively [33].…”

“…This results in a hepatic influx of free fatty acids. Hepatic de novo lipogenesis also adds to the accumulation of these free fatty acids, which undergo oxidation, storage as triglyceride or excretion via very low-density lipoprotein (VLDL) [32]. Resultant lipotoxicity occurs when hepatocellular metabolic capacity is exceeded.…”

Non‐alcoholic fatty liver disease (NAFLD)—Treat to target, but the goalposts are in the wrong place

“…Clinical trials will be necessary for the minority of patients having more advanced hepatic fibrosis but other clinical end‐points need to be part of the protocols and a comparison to the use of aspirin. The need to stratify NAFLD patients in order to identify those at highest risk has been reviewed recently …”