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发表于 2004-8-24 14:25
Hepatitis C
Chronic hepatitis C infection affects almost 3 million people in the United States. Chronic infection is generally asymptomatic and most often not progressive. Treatment for hepatitis C is long in duration, expensive, subject to side-effects, and associated with less than ideal response rates, particularly in patients with high viral load and genotype 1. Therefore, candidates for treatment need to be carefully selected. Liver biopsy helps
prognosticate which patients with hepatitis C will have progressive liver disease and are therefore more urgent candidates for treatment. Benefits from biopsy must be weighed against its risks, costs, and patient inconvenience. Non-invasive serologic tests and panels of tests are being developed with variable success to correlate with fibrosis and serve as
possible substitutes for liver biopsy.
The decision to treat hepatitis C depends on the risk for progressive liver disease in the absence of treatment. Among many natural history studies, rates of progression to cirrhosis range from 1 to 37% after variable follow-up intervals.[8] Tertiary referral centres, which are subject to selection bias, have reported the higher rates. Community-based cohorts likely give the most accurate prediction of progression to cirrhosis with a
mean cumulative incidence of cirrhosis of 7%.[8]
Key histologic predictors of progression to cirrhosis are the degrees of inflammation, fibrosis, and steatosis seen on liver biopsy. Based on retrospective data, most patients with moderate inflammation on initial liver biopsy develop cirrhosis within 20 years, and nearly all patients with severe inflammation or bridging fibrosis develop cirrhosis within 10 years. Patients with mild inflammation and/or minimal fibrosis have a low risk of progression to cirrhosis.[9] Hepatic steatosis is also emerging as a major risk factor for fibrosis progression in hepatitis C.[10]
Clinical information may help refine prognosis, but cannot substitute for the valuable information obtained from a liver biopsy. Poynard's group showed three clinical factors are independently associated with faster progression of fibrosis: age >40 at time of infection, daily alcohol consumption of 50 g or more, and male gender.[11] Indeed post-transfusion
hepatitis C patients with mean age over 40 at time of infection have a cumulative incidence of cirrhosis of over 20% after 15-20 years of follow-up.[12,13] In contrast, studies of young women infected with hepatitis C have shown development of cirrhosis in <5% after 15-20 years.[14,15] Other factors predicting progression to cirrhosis include
immunosuppression and coinfection with hepatitis B or HIV.[16,17]
Investigators have tried to identify serologic surrogates for cirrhosis and advanced fibrosis in hopes of obviating the need for liver biopsy. Serum hyaluronic acid has a 99% negative predictive value to predict the absence of cirrhosis, but only a 30% positive predictive value for cirrhosis.[18]
Other serum markers, including N-terminal propeptide of type III collagen, and YKL-40, have had variable success for predicting fibrosis and cirrhosis.[19] For the purpose of considering hepatitis C therapy, the distinction between minimal and significant fibrosis is more clinically useful than the distinction between the presence and absence of cirrhosis.
The MULTIVIRC group studied 339 patients using a panel of five non-routine serum markers (a-2 macroglobulin, haptoglobin, ?-gluatmyl transpeptidase, bilirubin and apolipoprotein A1) along with age and gender to predict significant fibrosis. Fifty percentage of the patients could be accurately stratified as having either significant or insignificant fibrosis; the other 50% had indeterminate results.[20]
Serum alanine aminotransferase (ALT) has been used to predict liver fibrosis and inflammation. At any point in time, the serum ALT shows poor correlation with liver histology.[21] Twenty-five to forty per cent of chronic hepatitis C patients have persistently normal ALT levels (usually defined as at least three normal ALTs within 6 months).[22,23] Patients with persistently normal ALTs tend to have less fibrosis and inflammation than hepatitis C patients with elevated ALTs.[24] Furthermore, in one study of 102 patients, the median progression of fibrosis was twice as fast in an elevated ALT group compared with a persistently normal ALT group (increase in Metavir fibrosis stage per year of 0.13 vs. 0.05, P < 0.001).[25] Despite these reassuring findings, patients with persistently normal ALTs may have significant inflammation (19% with moderate inflammation)[26] and even cirrhosis (6%)[27] (Table 1 and Table 2).
Other benefits from liver biopsy have been proposed. Liver biopsy may reveal unsuspected cirrhosis. Such a diagnosis is important, as surveillance for hepatocellular carcinoma as well as oesophageal varices may then be initiated. Although liver biopsy could potentially identify diseases in addition to hepatitis C, a retrospective study of 126 patients with chronic hepatitis C found that unsuspected other disorders were found in only three
patients (2%) who underwent liver biopsy.[28] Finally, liver biopsy may help predict the likelihood of response to therapy. In a study of pegylated interferon (peginterferon) a-2b with ribavirin, the absence of bridging fibrosis or cirrhosis was significantly associated with a sustained virological response (57% vs. 44%, P = 0.001).[29] However, a study of
peginterferon a-2a with ribavirin showed that cirrhosis was not an independent risk factor for predicting sustained virologic response.[30]
Although the information obtained from liver biopsy is useful, liver biopsy is not mandatory before initiating treatment for hepatitis C (Table 3). Many patients with genotype 2 or 3 are potentially candidates for therapy regardless of findings on liver biopsy because therapy is likely to succeed (80%), and duration of therapy is short (24 weeks). Liver biopsy intuitively is more useful for genotype 1 patients. Because therapy is longer (48 weeks)and less successful (<50%), many patients may desire therapy only if the chance of progressive liver disease from hepatitis C is high. Furthermore, liver biopsy may help some patients decide if they wish to continue therapy in the face of significant side-effects. For example, a patient with extensive fibrosis may decide to weather severe side-effects, possibly stopping work or making other life changes, because the risk of progressive liver disease in the absence of treatment is high. In addition, patients who
have undergone unsuccessful therapy with an earlier form of therapy (for example, interferon monotherapy) may also benefit from a liver biopsy.
Expected response to peginterferon and ribavirin in such a patient is lower than in a treatment-naïve patient. Therefore, only patients with significant disease are potential candidates for retreatment. Finally, for patients who defer therapy, many physicians would recommend a repeat liver biopsy in 3-5 years to re-evaluate the need for therapy, based on disease progression.[31]
Although histology may improve after successful hepatitis C therapy, post-treatment liver biopsy is generally not useful for guiding patient management. Patients who do not achieve a sustained virologic response after treatment may show improved histology. One study of virologic non-responders who had achieved a histologic response after 6 months of therapy randomized patients to 2 years of maintenance interferon therapy or placebo.
Maintenance therapy led to reduction of fibrosis.[32] Long-term mortality and clinical benefits from maintenance therapy are not yet known. It is still unclear what role liver biopsy should play in both identifying candidates for maintenance therapy and also following its effectiveness.
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