Fibrosis

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In a liver biopsy, doctors surgically remove a piece of liver tissue to examine more closely under a microscope. Usually, patients are referred for biopsy because of abnormal results on blood tests of liver function. Imaging studies may not be helpful or may show signs of diffuse liver injury, such as an enlarged liver or cirrhosis.

The biopsy is graded by two scoring systems. Both the degree of scarring (known as the "stage" of liver disease) and the degree of inflammation (known as the "grade" of disease) are noted. There are four stages. Stage 1 refers

to a minimal amount of scarring, limited to an area of the liver known as the portal triad (where the arteries, veins and bile ducts are found). Further progression of scarring outside of the portal triad and into surrounding liver cells is considered stages 2 and 3. When scarring

results in long bridges of fibrous tissue that separate nodules of normal liver tissue, it is called stage 4, or cirrhosis.

Liver disease also is graded on a scale of 1-4. In grade 1, there is minimal infiltration of inflammatory cells into the portal triad. As these cells spill over into the liver tissue from the portal triad, it is considered grades 2-3. Finally, large amounts of inflammation that involves all the liver is known as grade 4.

What is Bridging Fibrosis ?

Fibrosis is scar tissue that forms as a result of persistent inflammation in the liver. If you cut your skin, you form scar tissue which is good. However, if you inflame the liver, you can develop scar tissue or fibrosis which can be bad. If the fibrosis advances, it can start to destroy the liver. Typically fibrosis starts around the portal tract and the mildest form of fibrosis

is “periportalâ€. As the fibrosis extends, it typically extends kind of like spokes from the center of a wheel. The spokes are called fibrous septae. When the fibrous spokes from one wheel meet with the fibrous spokes form another wheel, they form a bridge and we call that bridging fibrosis. This is often called stage 3 by the Knodell classification of grading liver biopsies. If the fibrosis advances beyond this, we call it

cirrhosis or stage 4. Cirrhosis is the most advanced form of fibrosis and indicates there is substantial damage to the liver. However, a liver

can

still potentially function well with cirrhosis for many years. Patients

with hepatitis C can especially do well for many years with cirrhosis. In fact, many of these patients are appropriate candidates for treatment.

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Assessment of the Stage

of Fibrosis

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Liver biopsy remains the gold standard to assess

fibrosis. Several systemsfor scoring liver fibrosis have been proposed, each based upon visualassessment of portal and periportal fibrosis.

The more frequently used systems are the :

Histology Activity Index (HAI: Knodell score),

the Ishakmodification of the HAI score, and the METAVIR. The HAI scoring systemranges from 0 to 22 and fibrosis is staged as 0, 1, 3, and 4. Thisdiscontinous scale was developed to allow for clear separation of mild (1+)from extensive (3+) fibrosis which has important prognostic value. The HAIsystem

is simple and has been widely used, particularly in the largemulticenter

trials of interferon and ribavirin therapy of chronic hepatitisC. However, the intra- and inter-observer reproducibility of the HAI is notvery

good and distinction between stages 1 and 3 may be difficult. Inaddition,

its discontinous scale complicates statistical analysis inclinical trials.The modification of the HAI scoring system proposed by Ishak et al. is moresensitive in assessing fibrosis. Fibrosis stage is scored continuously from0 to 6, which permits a better assessment

of the effect of therapy onfibrosis. The

Ishak score is better validated and gives a more accurateassessment

of fibrosis.

The METAVIR scoring system is

simple; fibrosisstages are scored continuously from 0 to 4. This system has been carefullyvalidated in large groups of patients with chronic hepatitis C and has showngood intra- and inter-observer reproducibility. Important limitations ofthese scoring systems should be emphasized. Hepatic fibrosis may not behomogenous throughout the liver and the liver specimen obtained by needlebiopsy

may not accurately reflect the overall average degree of fibrosis.The

reliability of the assessment of fibrosis stage increases with the sizeof

the liver sample. In most studies, a minimum length of 10 mm is required.Regardless of biopsy length, however, fibrosis may be underestimated andcirrhosis missed in some patients.Factors Associated With the Stage of FibrosisMost cross-sectional studies of large numbers of liver biopsies have shownthat the stage of fibrosis is

associated with patient age, the age at onsetof infection, male sex, a history of heavy alcohol consumption, and thepresence of immune deficiency, such as HIV co-infection or immunosuppressivetherapy.

The mechanisms by which age and sex affect the degree of fibrosisare

not known. Alcohol, which by itself can cause liver disease andfibrosis,

may worsen fibrosis in hepatitis C at amounts that are notinjurious

in non-infected persons, but the amount of alcohol beyond whichthe progression of fibrosis is increased is unknown.Serum biochemical tests do not reliably predict the stage of fibrosis.Currently

available, indirect serum markers of fibrosis are not reliable,particularly

in discriminating between mild and moderate degrees offibrosis. In cross-sectional studies, serum alanine and aspartateaminotransferase

(ALT and AST) levels do not correlate well with fibrosis.However, patients with documented, persistently normal ALT levels

usuallyhave mild degrees of hepatitis and either no or mild stages of fibrosis. Theassociation between fibrosis stage and the necroinflammatory activity scoreson liver biopsy is controversial. Necroinflammatory activity is a dynamicprocess in chronic hepatitis C

and may fluctuate over time. Therefore, theactivity score reflects the severity of necrosis and inflammation at a givenpoint.Factors

Associated With Progression of FibrosisFrom retrospective studies and from some prospective studies done inpatients infected by blood transfusion at a relatively older age, it isestimated that 20 percent of patients with chronic hepatitis C developcirrhosis within 20 years of onset. In contrast, studies of cohorts of womenwho

did not drink alcohol and who were infected by Rh immune globulin at ayoung

age indicated that fewer than 5 percent developed cirrhosis within 20years.

These natural history studies validate the importance of

age, sex,and alcohol intake in progression of fibrosis. Cross-sectional studies usingmathematical modelling performed on cohorts of patients with a single liverbiopsy suggest that the average rate of progression of fibrosis in chronichepatitis C is 0.133 METAVIR points per year. Based on this rate, theestimate is that cirrhosis develops in the average patient after 30 years.The average delay to the development of cirrhosis ranges from 13 years ininfected

men aged 40 or more years who drink more than 50 g of alcohol to 42years

in infected women under 40 years of age who do not drink alcohol.Furthermore,

the progression of fibrosis is probably not linear. Forinstance, the time required to progress from stage 0 to 2 may be far longerthan

the time required to progress from stage 3 to 4. Moreover, fibrosisprogression

may accelerate with age (particularly after the age of 50).Finally,

fibrosismay remain mild and stable for decades

and may even regressspontaneously in some patients.The progression of fibrosis is difficult to predict in the individualpatient

particularly based upon assessment at one point in time. There areno

good clinical, biochemical, or virological tests that predict progressionof fibrosis. High serum ALT levels have been associated with more activeliver disease and more rapid progression of fibrosis

in some prospectivestudies, which supports the use of monitoring of

ALT levels in assessingprognosis and need for therapy. However, the

validity of this approach andthe level above which the ALT elevations are predictive of more rapidprogression is not known. Virological factors such as serum HCV RNA leveland HCV genotype are not predictive of fibrosis. Genotype 3 is associatedwith more liver steatosis than other genotypes, and steatosis itself, aswell as other metabolic factors (such as lipid disorders, obesity, insulinresistance,

and

diabetes) may also predispose to more rapid progression offibrosis.Repeat

liver biopsy is the only reliable means of assessing the progressionof

fibrosis and is commonly recommended every 3 to 5 years in untreatedpatients.

A second liver biopsy can distinguish patients with rapidlyprogressive

fibrosis, but may also merely indicate that the initial biopsyunderestimated

the degree of fibrosis. Overall, the risk of progression offibrosis

of more than one point in a 3 to 5 year period is low. In patientswith

factors associated with a higher risk of progression such as age beyond50

years, alcohol consumption, or high serum ALT levels, liver biopsy may berecommended more frequently (2 to 3 years); in contrast, in the youngerpatient with no other risk factors, liver biopsies may be performed lessfrequently (every 5 to 6 years).The problem with the gene pool? No lifeguards!