What is fibrosis?

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The progression of fibrosis in chronic hepatitis C determines theultimate

prognosis and thus the need and urgency of therapy.Fibrogenesis is a

complex dynamic process, which is mediated by necro-inflammation and activation of stellate cells.Chronic infection with hepatitis C virus (HCV) typically inducesinjury and inflammation of the liver, which appear to be responsiblefor the associated fibrogenesis. Fibrogenesis is a dynamic processcharacterized by the synthesis of constituents of the extracellularmatrix, which is a complex mixture of glycoproteins (collagen,elastin, fibronectin, laminin) and proteoglycans organized in atridimensional network.Fibrogenesis

is a non-specific mechanism, which lasts as long asinjury persists in the liver and is believed to help limit theextension of the inflammatory reaction. Fibrosis, therefore, is aphysiologic mechanism, which is at first beneficial, but which canbecome pathological if the viral infection and chronic hepatocellularinjury

persist.Fibrosis is characterized by the deposition of collagen

and otherextracellular matrix proteins and their organization in complexpolymers, which are insoluble and induce loss of the liverarchitecture.

In all forms of chronic hepatitis, including chronichepatitis C, active fibrosis begins around the portal areas(periportal or zone 1 fibrosis) and gradually extends out into thelobules towards the central veins (zone 3) with septa formation andthen bridging fibrosis.Liver BiopsyThe liver biopsy remains the gold standard to assess fibrosis.Scoring systems allow a semi-quantitative assessment and are usefulfor cross-sectional and cohort studies and in treatment trials.Several systems for scoring liver fibrosis have been proposed, eachbased on visual assessment of

collagen staining of liver biopsysamples. The more frequently used systems are the histology activityindex (HAI: Knodell score),the Ishak modification of the HAI score,and the Metavir score.The

scoring systems for hepatic fibrosis have been extremely helpfulin natural history studies and clinical trials of therapy ofhepatitis C. However, all of these systems have importantlimitations.Hepatic

fibrosis may not be homogenous throughout the liver, and theliver specimen obtained by the needle biopsy may not accuratelyreflect the

overall average degree of fibrosis. The reliability ofthe assessment of fibrosis stage increases with the size of the liversample.

The sample size is critical, a minimum length of 10 mm beingessential.Regardless

of biopsy length, however, fibrosis may be underestimatedand cirrhosis missed in some patients. In addition, scoring systemsare artificial and based on visual assessment.Fibrosis may not progress linearly in the same manner as the scoringsystems: thus, progression from stage 1 to stage 2 may be far moreimportant and require a longer period than progression from stage 3to stage 4 (or vice versa). Thus, nonparametric analysis is needed inassessing differences in fibrosis scores in clinical studies.The rate at which fibrosis progresses varies markedly betweenpatients. The major

factors known to be associated with fibrosisprogression are older age at infection, male gender, and excessivealcohol consumption.AgeAge

at onset of infection has consistently been found to be a majorfactor

influencing the rate of progression of fibrosis in hepatitisC. Thus, studies of posttransfusion hepatitis in which most patientsare

over the age of 40 at the time of onset of infection haveindicated that at least 20% of patients develop cirrhosis during thefirst 15 to 20 years of HCV infection.GenderMost studies of hepatic fibrosis have reported that male sex issignificantly associated with progression of fibrosis. The mechanismsby which sex affects fibrosis progression are unknown.In contrast, in studies

of young women infected as a result ofexposure to HCV-contamined Rh

immune globulin, less than 5% developcirrhosis within the first 15 to 20 years of infection.AlcoholIn almost all studies, a

high consumption of alcohol (more than 50g/d) has been found to be associated with higher fibrosis stage. Theeffects of a lower level of alcohol consumption, between 10 and 40g/d, have not been clearly defined.In univariate analysis, patients who drank moderate amounts ofalcohol (<50 g daily) had a slightly higher estimated rate offibrosis progression (0.143) than non-drinkers (0.125), but thedifference was not statistically significant and was confounded byother features, such as gender, body weight, and age.Alcohol,

which by itself can cause liver disease and fibrosis, mayworsen fibrosis in hepatitis C at amounts that are not injurious innon-infected

persons, but the amount of alcohol beyond which theprogression of fibrosis is increased in hepatitis C is unknown.Because of the negative influence of high alcohol consumption,abstinence or minimal

consumption are usually recommended in patientswith chronic hepatitis C.Besides its direct effects on fibrogenesis, excess alcohol intake mayhave other adverse effects on the course of hepatitis C. Thus,alcohol may affect immune responses to HCV and may

cause increases inHCV RNA levels in serum and liver, an effect that

has been reportedby some investigators, but not all.Immune Status and HCV-HIV CoinfectionImmune status probably has a major

affect on the natural history ofhepatitis C and the development of cirrhosis. Several studies haveshown that hepatitis C is more likely

to progress to cirrhosis, andthat the rate of fibrosis progression is greater in HIV-coinfectedpatients.In a study from Spain, the mean estimated time to development ofcirrhosis was 7 years in HIV-positive and 23 years in HIV-negativeinjection drug users with hepatitis C. In a study from France, theHAI score was significantly higher among 80 HIV-positive patientscompared with 80 HIV-negative injection drug users (matched for age,gender, and duration of disease). During a mean follow-up of 52 ± 30months, the incidence of

cirrhosis was significantly higher among HIV-positive than -negative patients.Viral factorsIn retrospective and cross-sectional studies, virological factors,such as serum HCV RNA levels and HCV genotype, have not beenassociated with the rate of progression of fibrosis in chronichepatitis C.Other factors,

which have been suggested to be important, includegenetic, racial/ethnic, and metabolic. The role of heterozygotemutations of HFE gene is controversial. The influence of overweighthas been emphasized recently; it is believed that steatosis relatedto overweight is responsible for the more rapid progression offibrosis.

In addition, diabetes has been shown to be associated withfibrosis.There

are no tests that reliably predict the rate of progression offibrosis

in an individual patient. High serum alanineaminotransferase (ALT) levels are associated with a higher risk offibrosis progression, and

worsening of fibrosis is uncommon inpatients with persistently normal serum aminotransferase levels.The liver biopsy remains the best method to assess fibrosis and isvaluable in determining prognosis and aiding in the decision for oragainst therapy. In untreated patients, regular ALT measurements areuseful, and repeat liver biopsy is the only reliable means ofassessing the progression of fibrosis and is commonly recommendedevery 3 to 5 years in untreated patients. A second liver biopsy candistinguish patients with rapidly progressive fibrosis, but may alsomerely indicate that the initial biopsy underestimated the degree offibrosis. Overall, the risk of progression of fibrosis of more than 1point in a 3- to 5-year period is low. In patients with factorsassociated with a higher risk of progression, such as age above 50years, excessive alcohol consumption, or high serum ALT levels, liverbiopsy may be recommended more frequently (every 2 to 3 years); incontrast, in the

younger patient with no other risk factor, the liverbiopsies may be

performed less frequently (every 5 to 10 years).The problem with the gene pool? No lifeguards!