Fatty Liver Disease -- It's More Than Alcohol and Obesity

Heiner Wedemeyer, MD, Michael P. Manns, MD


July 23, 2003

In This Article

Pathogenesis and Natural History of NAFLD and NASH

Christopher Day[12] of Newcastle upon Tyne, United Kingdom, reviewed the pathogenesis of steatohepatitis during the President's premeeting program. He proposed a modification of the classical "2-hit model" of NASH pathogenesis. This model considered steatosis as the "first hit," followed by a "second hit" leading to hepatocyte injury and inflammation. It has been shown that the severity of fat accumulation correlates with activation of hepatic stellate cells, thus, steatosis per se may activate fibrogenesis. Steatosis then "sensitizes" the liver to the second hit. Candidates for the "second hit" include oxidative stress (eg, reactive oxygen species induce the expression of proinflammatory molecules and proapoptotic molecules such as Fas ligand), several different cytokines, or endotoxins. Dr. Day summarized data suggesting that the link between obesity, insulin resistance, and the risk of NASH might be explained by increased release of free fatty acids from adipose tissue.

A number of studies have shown that the majority of NASH patients are obese and that one fourth to one half of these patients suffer from type 2 diabetes.[13,14,15] It is also widely accepted that insulin resistance is a universal finding in patients with NAFLD. During this year's EASL meeting, several studies were presented that analyzed large cohorts (involving from 270 to more than 400 patients with NASH) for characteristics and possible links to the metabolic syndrome and insulin resistance. One group from Italy confirmed that insulin resistance -- but not insulin secretion -- is associated with NAFLD.[16] In another Italian cohort from Turin and Bologna, metabolic syndrome was found to be present in a large proportion of patients with NAFLD, including nonobese, nondiabetic individuals. In turn, the presence of NASH was found to be associated with metabolic syndrome.[17] However, few patients with NASH did not show any of the characteristics of the metabolic syndrome, and only 25% of patients with metabolic syndrome have NASH; only a minority of obese patients progress to NASH. Thus, individual environmental and genetic factors are clearly important for progression to NASH. Candidate genes include genes determining the magnitude and pattern of obesity (11-beta hydroxysteroid dehydrogenase type I), genes determining insulin sensitivity (PPAR [peroxisome proliferator-activated receptor]-gamma), genes involved in hepatic lipid storage (apolipoprotein E, microsomal triglyceride transfer protein), genes involved in fatty acid oxidation (CYPs [cytochrome P450s], PPAR-alfa, acyl-CoA oxidase), cytokine genes (IL [interleukin]-4, TGF [transforming growth factor]-beta, IL-10, IFN [interferon]-gamma, TNF [tumor necrosis factor]-alpha), genes influencing oxidative stress (HFE, TNF-alpha), and genes encoding proteins involved in response to oxidative stress (MnSOD [manganese superoxide dismutase], UCP [uncoupling protein]-2).

Ghrelin is a hormone that induces release of growth hormone, adrenocorticotropic hormone, and cortisol, and thereby increases food intake and body weight. The role of ghrelin in NASH was investigated by Elisabetta Bugianesi and colleagues.[18] They found that ghrelin is elevated in patients with NAFLD -- and, interestingly, primarily in those patients with normal body weight -- but that it is not associated with insulin resistance and/or disease activity. Thus, ghrelin is not likely to be a key mediator in the pathogenesis of fatty liver disease.

Our knowledge regarding progression rates from steatosis to NASH and from NASH to cirrhosis has significantly improved.[19] It has become clear that "simple" steatosis rarely progresses to NASH unless a "second hit" occurs. However, once NASH has been established, a significant proportion of patients may develop significant fibrosis and cirrhosis (up to 25% in follow-up studies). Moreover, many cases of previously termed "cryptogenic" cirrhosis may be explained by steatohepatitis.[20] Recently published studies[21] as well as reports presented during this year's EASL meeting[22] suggest that even patients with normal aminotransferase levels and steatosis may have inflammatory activity and signs of fibrosis. This leads to the dilemma of how to proceed with patients who have signs of steatosis on ultrasound examination but normal alanine aminotransferase (ALT) values. Should we biopsy all of these patients? Of course we first have to ask whether the biopsy will have any therapeutic consequence. Asking patients to lose some weight and increase their exercise would be good advice regardless. It may then be wise to screen these individuals for insulin resistance before treatment with insulin-sensitizing agents is started.


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