“Stage” is the amount of fibrosis (scaring) detectable by biopsy…from stage one (mild) to four (cirrhosis). “Grade” is the amount of inflammation, which is caused by the activity of the virus. Generally speaking, inflammation is the precursor to fibrosis.

There is some emerging research indicating that both fibrosis and inflammation can in some cases be halted and even reversed with treatment

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 “periportal”. 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 systems
for scoring liver fibrosis have been proposed, each based upon visual
assessment of portal and periportal fibrosis.

The more frequently used systems are the :

Histology Activity Index (HAI: Knodell score),

the Ishak
modification of the HAI score, and the METAVIR. The HAI scoring system
ranges from 0 to 22 and fibrosis is staged as 0, 1, 3, and 4. This
discontinous scale was developed to allow for clear separation of mild (1+)
from extensive (3+) fibrosis which has important prognostic value. The HAI
system is simple and has been widely used, particularly in the large
multicenter trials of interferon and ribavirin therapy of chronic hepatitis
C. However, the intra- and inter-observer reproducibility of the HAI is not
very good and distinction between stages 1 and 3 may be difficult. In
addition, its discontinous scale complicates statistical analysis in
clinical trials.

The modification of the HAI scoring system proposed by Ishak et al. is more
sensitive in assessing fibrosis. Fibrosis stage is scored continuously from
0 to 6, which permits a better assessment of the effect of therapy on
fibrosis. The Ishak score is better validated and gives a more accurate
assessment of fibrosis.

The METAVIR scoring system is simple; fibrosis
stages are scored continuously from 0 to 4. This system has been carefully
validated in large groups of patients with chronic hepatitis C and has shown
good intra- and inter-observer reproducibility. Important limitations of
these scoring systems should be emphasized. Hepatic fibrosis may not be
homogenous throughout the liver and the liver specimen obtained by needle
biopsy may not accurately reflect the overall average degree of fibrosis.
The reliability of the assessment of fibrosis stage increases with the size
of the liver sample. In most studies, a minimum length of 10 mm is required.
Regardless of biopsy length, however, fibrosis may be underestimated and
cirrhosis missed in some patients.

Factors Associated With the Stage of Fibrosis

Most cross-sectional studies of large numbers of liver biopsies have shown
that the stage of fibrosis is associated with patient age, the age at onset
of infection, male sex, a history of heavy alcohol consumption, and the
presence of immune deficiency, such as HIV co-infection or immunosuppressive
therapy. The mechanisms by which age and sex affect the degree of fibrosis
are not known. Alcohol, which by itself can cause liver disease and
fibrosis, may worsen fibrosis in hepatitis C at amounts that are not
injurious in non-infected persons, but the amount of alcohol beyond which
the 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 of
fibrosis. In cross-sectional studies, serum alanine and aspartate
aminotransferase (ALT and AST) levels do not correlate well with fibrosis.
However, patients with documented, persistently normal ALT levels usually
have mild degrees of hepatitis and either no or mild stages of fibrosis. The
association between fibrosis stage and the necroinflammatory activity scores
on liver biopsy is controversial. Necroinflammatory activity is a dynamic
process in chronic hepatitis C and may fluctuate over time. Therefore, the
activity score reflects the severity of necrosis and inflammation at a given
point.

Factors Associated With Progression of Fibrosis

From retrospective studies and from some prospective studies done in
patients infected by blood transfusion at a relatively older age, it is
estimated that 20 percent of patients with chronic hepatitis C develop
cirrhosis within 20 years of onset. In contrast, studies of cohorts of women
who did not drink alcohol and who were infected by Rh immune globulin at a
young age indicated that fewer than 5 percent developed cirrhosis within 20
years. These natural history studies validate the importance of age, sex,
and alcohol intake in progression of fibrosis. Cross-sectional studies using
mathematical modelling performed on cohorts of patients with a single liver
biopsy suggest that the average rate of progression of fibrosis in chronic
hepatitis C is 0.133 METAVIR points per year. Based on this rate, the
estimate is that cirrhosis develops in the average patient after 30 years.
The average delay to the development of cirrhosis ranges from 13 years in
infected men aged 40 or more years who drink more than 50 g of alcohol to 42
years in infected women under 40 years of age who do not drink alcohol.
Furthermore, the progression of fibrosis is probably not linear. For
instance, the time required to progress from stage 0 to 2 may be far longer
than the time required to progress from stage 3 to 4. Moreover, fibrosis
progression may accelerate with age (particularly after the age of 50).
Finally, fibrosismay remain mild and stable for decades and may even regress
spontaneously in some patients.

The progression of fibrosis is difficult to predict in the individual
patient particularly based upon assessment at one point in time. There are
no good clinical, biochemical, or virological tests that predict progression
of fibrosis. High serum ALT levels have been associated with more active
liver disease and more rapid progression of fibrosis in some prospective
studies, which supports the use of monitoring of ALT levels in assessing
prognosis and need for therapy. However, the validity of this approach and
the level above which the ALT elevations are predictive of more rapid
progression is not known. Virological factors such as serum HCV RNA level
and HCV genotype are not predictive of fibrosis. Genotype 3 is associated
with more liver steatosis than other genotypes, and steatosis itself, as
well as other metabolic factors (such as lipid disorders, obesity, insulin
resistance, and diabetes) may also predispose to more rapid progression of
fibrosis.

Repeat liver biopsy is the only reliable means of assessing the progression
of fibrosis and is commonly recommended every 3 to 5 years in untreated
patients. A second liver biopsy can distinguish patients with rapidly
progressive fibrosis, but may also merely indicate that the initial biopsy
underestimated the degree of fibrosis. Overall, the risk of progression of
fibrosis of more than one point in a 3 to 5 year period is low. In patients
with factors associated with a higher risk of progression such as age beyond
50 years, alcohol consumption, or high serum ALT levels, liver biopsy may be
recommended more frequently (2 to 3 years); in contrast, in the younger
patient with no other risk factors, liver biopsies may be performed less
frequently (every 5 to 6 years).

References

1. Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H,
et al. Histologic grading and staging of chronic hepatitis. J Hepatol
1995;22:696-9.

2. Bedossa P, Poynard T. The METAVIR cooperative study group. An algorithm
for the grading of activity in chronic hepatitis C. Hepatology
1996;24:289-93.

3. Tong MJ, El-Farra NS, Reijes AR, Co RL. Clinical outcomes after
transfusion-associated hepatitis C. N Engl J Med 1995; 332:1463-6.

4. Poynard T, Bedossa P, Opolon P for the OBSVIRC, METAVIR, CLINIVIR, and
DOSVIRC groups. Natural history of liver fibrosis progression in patients
with chronic hepatitis C. Lancet 1997;349:825-32.

5. Alter HJ, Seeff LB. Recovery, persistence, and sequelae in hepatitis C
virus infection: a perspective on long-term outcome. Sem Liver Dis
2000;20:17-35.