GUT Feel

By: Rogelio C. Umil, MD

FATTY LIVER AND THE METABOLIC SYNDROME

Obesity is now recognized as a major challenge to health, quality of life and longevity in the developed world. The adverse impact of overweight and obesity on the risks for cardiovascular disease, cancer and musculoskeletal disorders is well documented, especially when coupled with components of the metabolic syndrome. More recently recognized is the risk of developing end stage liver disease and hepatocellular cancer as a consequence of nonalcoholic fatty liver disease (NAFLD), the primary hepatic complication of obesity and insulin resistance. NAFLD is the most common cause of liver dysfunction and affects 10% to 24% of the general population. Although NAFLD has not been included as a component of the metabolic syndrome as it has been defined, available data indicate that the onset of NAFLD is an early event in the development of insulin resistance and might thus predict the presence or future development of the metabolic syndrome.

NAFLD is the consequence of excess triglyceride accumulation in hepatocytes in the absence of significant alcohol consumption. An exciting area of progress is in recognizing that the renin-angiotensin system (RAS) is a major modulator of insulin resistance. In one study of rats, the lower adiponectin levels and impaired insulin sensitivity appeared to be mediated by the receptor AT1 because the AT1-specific angiotensin receptor blocker (ARB) olmesartan improved NAFLD, insulin sensitivity and adiponectin levels. Moreover, a provocative study of the ARB telmisartan in fructose fed rats demonstrated that treated rats not only accumulated less fat in the liver, but that this particular ARB also increased energy expenditure and prevented weight gain. Other studies have provided new insights into mechanisms of fat accumulation in NAFLD. Resistin is an adipocyte derived peptide, or adipokine, that induces insulin resistance in all of the major targets of insulin: liver, muscle and adipose tissue. A small study of NAFLD patients treated with pioglitazone demonstrated improved insulin sensitivity and reduced resistin levels. A more recent study showed that resistin levels in humans correlate with necroinflammatory changes of NASH rather than insulin sensitivity. Another study demonstrated that circulating resistin levels in humans were elevated in patients with cirrhosis and may be a major mediator of the insulin resistance known to occur in cirrhosis. Another area of rapidly expanding knowledge is in the role of endoplasmic reticulum stress (ERS) as a cause of insulin resistance and NAFLD. The smooth endoplasmic reticulum is where proteins are processed into their final form and if the flux of proteins through the endoplasmic reticulum overwhelms its processing capacity or if defective proteins impair endoplasmic reticulum processing, a stress response can initiate the process of cellular death through apoptosis. ERS has now been implicated not only in the development of insulin resistance and diabetes, but also of various forms of liver disease including NASH. Lifestyle modifications comprising healthy eating habits and regular exercise are the primary interventions recommended to patients with NAFLD. Weight loss can be facilitated by the enteric lipase inhibitor orlistat, and a randomized clinical trial of 52 NASH patients treated for 6 months found that orlistat improved serum ALT levels and steatosis more than lifestyle modification alone. When all else fails, as it too often does, dietary portion control can be enforced by surgical alteration of the stomach (Bariatric surgery). A number of studies published just in the past year suggest that NASH improves with weight loss and improved insulin sensitivity following bariatric surgery.

Advances in our understanding of the pathogenesis of NAFLD and NASH continue to be made and give us hope that new therapeutic options will soon be available. Such options are certainly needed because of the failure or inability of many to sustain lifestyle modifications and the enormous burden of this disease in our society.

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