Chronic Hepatitis C body weight and disease progression

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Chronic Hepatitis C body weight and disease progression

The Skinny on Chronic Hepatitis C

No doubt, obesity is a massive public health issue here in America, as welll as rest of the developed world. We think about diabetes, heart disease, and chronic lung disease when we talk about the obesity related health complications. Now we can add chronic hepatitis C, and the increased rate of progression related to obesity. There have been numerous recent articles published regarding these two diseases. E. Everhart and colleagues published an excellent article in the journal, Gastroenterology, looking at the weight-related effects on disease progression in hepatitis C. They found the following:This study showed an association of several weight-related features to increased rates of liver disease progression among patients with advanced chronic hepatitis C. In particular, insulin resistance and histologic features of fatty liver disease at baseline were strongly associated with progressive liver disease. Of

greatest clinical significance, weight change during the trial was associated with liver disease outcomes. Although this study was performed among a selected group of patients with treatment-resistant hepatitis C, it is likely that the findings would extend to other patients with hepatitis C. In addition, the relations of weight-related features and outcomes were consistent for the 2 randomized groups, with the exception of HOMA2-IR, which was strongly associated with disease progression among untreated patients but not among patients assigned to treatment.Several large cross-sectional studies, including the baseline of HALT-C, have documented an association of the degree of hepatic steatosis and fibrosis severity[8], [9], [10], [11], [12] and [13] up to cirrhosis, at which point steatosis was less common.[14] and [15] At least one study did not find an association of steatosis and fibrosis.16 Such associations have generally been made among

patients without advanced liver disease. Cross-sectional studies neither offer compelling evidence of the influence of a risk factor on disease severity nor can they quantify the risk of disease progression. In contrast to the cross-sectional studies, relatively small paired biopsy studies of patients with untreated hepatitis C either did not show a relation of steatosis on first biopsy to progression of fibrosis or did not report the result.[17] and [18] Of importance, a relation of steatosis to clinical outcomes has not been reported among a large cohort of patients with chronic hepatitis C. The current study has shown a complex yet clinically significant relation of steatosis and progressive liver disease, one that differed between patients with bridging fibrosis and with cirrhosis. No other factor showed an interaction with fibrosis stratum and outcome. In addition, in a secondary analysis limited to clinical outcomes, the interaction persisted such

that the importance of the degree of steatosis on clinical progression was modulated by the severity of fibrosis. Most significantly, among patients with bridging fibrosis, steatosis was strongly associated with progression of liver disease. It is possible that greater steatosis would be a risk factor for fibrosis progression not only among patients with advanced fibrosis but also in patients with hepatitis C and a lesser degree of fibrosis.In contrast to bridging fibrosis, clinical outcomes occurred less commonly among patients with cirrhosis and greater steatosis. Although steatosis may stimulate fibrosis progression, once cirrhosis develops, lack of histologic fat might reflect greater disease severity. In a separate analysis of this cohort, a decline in steatosis was associated with progression to cirrhosis, supporting the concept that less steatosis might be a marker of more severe disease in patients with cirrhosis.19 In the current analysis,

baseline steatosis was not associated with other indicators of liver disease such as thrombocytopenia and esophageal varices (Table 4). Nevertheless, taken together, these data indicate that the failure to find fat in cirrhotic biopsies in hepatitis C appears to be an adverse prognostic sign and is quite different from patients with steatosis and less severe fibrotic liver disease. Two other markers of fatty liver disease were also evaluated. The presence of Mallory bodies was associated with disease progression for the entire cohort, but the relation was stronger among patients with bridging fibrosis. Interestingly, pericellular (zone 3) fibrosis was not associated with disease progression in either fibrosis stratum. The Ishak fibrosis scale does not consider pericellular fibrosis in its staging, which appears justified by the current study.Although commonly found in hepatitis C–related liver disease, features of fatty liver disease have not

been considered as measures of severity and are not scored in the standard grading and staging systems.7 The presence of fatty liver is not specific to hepatitis C and has not always been recognized as clinically significant. Because of their prognostic significance, histologic characteristics of fatty liver, particularly degree of steatosis and the presence of Mallory bodies, should be recorded in biopsy readings of patients with hepatitis C, and consideration should be given to their incorporation into histologic scoring systems of chronic hepatitis. Note that patients whose baseline biopsies indicated severe steatohepatitis were excluded from the trial. It is possible that patients with severe steatohepatitis (alcoholic or nonalcoholic) and chronic hepatitis C would have had an even higher rate of outcomes.Baseline median HOMA2-IR of 4.59 was much higher than norms in the general population, as was the 24.9% prevalence of diabetes.[20] and

[21] Glucose homeostasis deteriorates with development of severe liver disease, so that diabetes is common with cirrhosis.22 Therefore, associations in cross-sectional studies cannot establish that diabetes and hyperinsulinemia result in severe liver disease. An advantage of the current study is that a strong association of HOMA2-IR to the risk of progressive liver disease was established prospectively, even though HOMA2-IR is not necessarily a good measure of true insulin resistance. In the presence of steatosis, it appears that indirect measures of insulin secretion such as HOMA2-IR are strongly affected by diminished hepatic insulin clearance as well as by insulin resistance.23 Irrespective of the mechanism of its elevation, increased HOMA2-IR was associated with significant liver disease progression.Baseline BMI was associated with outcomes (at least in univariate analysis), as was weight change. Nearly half of the HALT-C cohort was obese,

which may have contributed to the severity of liver disease and resistance to standard treatment before entering the randomized trial. For a population with severe hepatitis C that is resistant to available treatment, the association of weight change with outcomes is the most immediate clinically significant finding of this analysis. Until now, there has been indirect evidence only that overweight and obesity are associated with worse outcomes in hepatitis C. Even among patients with nonviral-related steatohepatitis, evidence that weight ameliorates clinical disease has been limited.24 As previously shown, weight loss in the HALT-C cohort was associated with decline in steatosis.19 A.S. Lok, J.E. Everhart and R.T. Chung et al., Evolution of hepatic steatosis in patients with advanced hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis trial (HALT-C) trial, Hepatology 49 (2009), pp. 1828–1837.19 Of comparable

significance, the current report has shown that weight loss was associated with a decline in inflammation. The difference in the change in inflammation between patients who lost >5% of weight within a year of random assignment and those who gained >5% was comparable to the change in inflammation between treated and untreated patients.2 Such declines in both steatosis and inflammation with weight loss might slow disease progression, even in the presence of ongoing infection. It is possible that the weight-related associations with liver disease progression identified in the current study could apply to obesity-related fatty liver in the presence of other liver diseases not resulting from hepatitis C.For patients resistant to or unable to take antiviral therapy for hepatitis C, body weight appears to be a significant modifiable risk factor for disease progression. In the absence of a long-term trial of weight loss and liver disease outcomes,

the results of this study may provide the strongest evidence for a clinical benefit of weight loss among overweight or obese persons with chronic hepatitis C.In thinking about hepatitis C, and the treatments available, while we talk about all of the new results with protease inhibitors, stepping on the scale seems just as important in the comprehensive approach the treatment of hepatitis C requires.Posted by ph S. Galati, M.D.

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