Since the development of a diagnostic test to detect hepatitis C infection, it has become apparent that this infection is an increasing clinical and public health problem. The majority of these patients develop chronic hepatitis of varying degree, and it is estimated that 20 to 30% will develop cirrhosis in the long-term. Less than 5% will die from end-stage liver disease or hepatocellular carcinoma but, given the magnitude of the problem, these numbers become very significant.
Previous studies showed that important risk factors for progressive fibrosis included male gender, age of acquisition over 40, and alcohol use. These are not all amenable to treatment. More recently, in a multivariate analysis we found that the degree of steatosis correlated with fibrosis stage and that this steatosis reflected the patients’ body mass index (1). Factors such as alcohol intake, viral load, viral genotype and inflammatory activity were not significant. Steatosis has long been recognised as a common but not invariable feature of NANB (and later HCV) infection (2) but it had not been considered an important cofactor in progression. Subsequent analyses suggested that in some HCV genotypes (type 3) there may also be a viral cytopathic effect, but in most cases it was body mass index and not viral factors leading to the steatosis (3,4).
How, then, does steatosis act? Because steatohepatitis (alcoholic and non-alcoholic) causes stellate cell activation and collagen deposition in sinusoids, we analyzed this in 80 cases (5). A significant association was found between sinusoidal fibrosis, steatosis grade and overall fibrosis stage. Interestingly, there was no association with the numbers of activated sinusoidal stellate cells by a-smooth muscle actin staining, suggesting either that a-SMA expression of stellate cells is not closely linked with fibrosis temporally, or that the steatosis is contributing to fibrogenesis by some other mechanism. These possibilities are under investigation currently. In other experiments, patients unresponsive or ineligible for interferon/ribavirin therapy have been commenced on weight reduction programmes. In a pilot study there was good compliance, a reduction in steatosis and also transaminase levels that paralleled weight loss, and a somewhat surprising reduction in the mean fibrosis score on re-biopsy.
Other non-viral factors appear to play a role in fibrosis (6). Transforming growth factor b (TGF-b), an important profibrogenic cytokine, has several polymorphisms in humans that have differences in activity levels. Patients with a high producer polymorphism showed slightly elevated mean fibrosis scores when compared with the low producer group. However, analysis of similar polymorphisms of angiotensin II (which can increase TGF-b expression) showed that patients with a single high producer genotype of either gene had mild elevations in mean fibrosis scores, but if both high producer genes were present there was a highly significant increase in mean fibrosis.
These studies suggest novel interventions in patients unresponsive to interferon therapy, including weight reduction and blockade of fibrogenesis with angiotensin converting enzyme inhibitors.
References
1. Hourigan LF, Macdonald GA, Purdie D, Whitehall VH, Shorthouse C, Clouston A, Powell EE. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology. 1999;29:1215-9
2. Lefkowitch JH, et al. Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B. Gastroenterology. 1993; 104:595-603
3. Jonsson JR, Edwards-Smith CJ, Purdie D, Clouston AD, Powell EE. Body composition and hepatic steatosis as precursors of fibrosis in chronic hepatitis C patients. Reply. Hepatology 1999; 30:1531-32
4. Adinolfi LE, Utili R, Ruggiero G. Body composititon and hepatic steatosis as precursors of fibrosis in chronic hepatitis C patients. Letter. Hepatology 1999;30:1530-1.
5. Clouston AD, Jonsson JR, Purdie D, Macdonald GA, Crawford DHG, Hourigan LF, Shorthouse C, Powell EE. Steatosis and chronic hepatitis C: analysis of fibrosis and stellate cell activation. J Hepatol, 2001. (In press)
6. Powell EE, Edwards-Smith CJ, Hay JL, Clouston AD, Crawford DHG, Shorthouse C, Purdie D, Jonsson JR. Host genetic features influence disease progression in chronic hepatitis C patients. Hepatology, 31,828-833, 2000.