Obesity and nonalcoholic fatty liver disease

Abstract

The obesity pandemic is linked to a host of metabolic, cardiovascular, respiratory and oncologic issues. A recent addition to this list is nonalcoholic fatty liver disease (NAFLD, ‘fatty liver’). NAFLD is present in over half of all obese individuals, and in almost all patients with morbid obesity. The contribution of fatty liver to overall and liver-related mortality is often underestimated. The histologic subtype of NAFLD dictates liver-related clinical outcomes. While patients with hepatic steatosis have a benign course, those with cirrhosis will eventually develop hepatic decompensation. Patients with nonalcoholic steatohepatitis (NASH) exhibit a variable course; up to one-third will develop progressive hepatic fibrosis, including 10% with cirrhosis. An emerging concern is hepatocellular carcinoma arising in cirrhotic as well as non-cirrhotic livers. NAFLD is also an independent predictor of ischaemic heart disease, even after adjustment for classical risk factors. Liver biopsy remains the gold standard but noninvasive scoring algorithms and new imaging modalities such as transient elastography (TE) can reduce the need for it. The pathogenesis of NAFLD has evolved from a two-hit model to one where multiple parallel hits are involved. Lipotoxicity, defined by cellular injury resulting from ectopic (non-adipose tissue) fat deposition, is a key player in the initiation and perpetuation of hepatocyte injury. Free fatty acid (FFA)-derived lipid intermediates such as diacylglycerol, ceramide and free cholesterol are involved in this process. The origins of lipotoxicity can be traced to obesity-related adipose tissue expansion, dysregulated adipocytokine secretion and macrophage and other inflammatory cell infiltration. The ensuing peripheral signals eventually disrupt insulin signalling in multiple tissues, promote insulin resistance and have direct pro-inflammatory effects within the liver. The hepatic adaption to this lipotoxic milieu is eventually overwhelmed, generating oxidative stress, mitochondrial injury and endoplasmic reticulum stress and culminates in hepatocyte apoptosis, hepatic stellate cell activation, progressive hepatic fibrosis and cirrhosis. Lifestyle optimisation through diet and exercise remains the cornerstone of management. Drugs such as the thiazolidinediones and vitamin E have shown benefit but questions of safety and patient selection remain. Newer therapeutic approaches involve farnesoid X receptor agonists, glucagon-like peptide-1 (GLP-1) agonists and probiotics but robust clinical data are awaited. Morbidly obese individuals with fatty liver can benefit from bariatric procedures, while liver transplantation is the only option for patients developing end-stage liver disease.