Evaluating Liver Disease in Chronic Hepatitis C -- The Role of the Liver Biopsy
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Evaluating Liver Disease in Chronic Hepatitis C -- The Role of the
Laura Baalmann-Mangano, MD, Elizabeth M. Brunt, MD
Medscape General Medicine 5(3), 2003. � 2003 Medscape
In an era of technological advances and molecular testing, the liver
biopsy continues to be the gold standard for evaluation of most forms
of liver disease.[1,2] It is of "unquestionable value" in patients
with chronic hepatitis C. Not only does the liver biopsy confirm the
clinical diagnosis of chronic hepatitis C, but it can also reveal
unsuspected coexisting pathologic conditions, such as steatohepatitis
(alcoholic and nonalcoholic) and iron overload syndromes suggestive
of hemochromatosis, and demonstrate the presence of globules
suggestive of alpha-1-antitrypsin deficiency. Hepatocellular
dysplasia and unsuspected hepatocellular carcinoma may also be
detected on liver biopsy. Additionally, the histopathologic
alterations of the liver, namely the necroinflammatory activity
(referred to as "grade"), and the degree of fibrosis (referred to as
"stage"), can only be determined with certainty by histopathologic
evaluation. There are no currently available laboratory tests or
noninvasive procedures that reliably predict disease
necroinflammatory activity, fibrosis, or architectural remodeling.
Assessment of these parameters is important in the decision to
initiate antiviral therapy.
It is recognized that even patients with normal liver test values
(ie, "normal" alanine aminotransferase levels) do not necessarily
have inactive disease by histologic evaluation.[3,4] As such,
consensus statements regarding the management of hepatitis C from
both the National Institutes of Health and the European Association
for the Study of the Liver confirm the value of liver biopsy prior to
the initiation of antiviral therapy.[3,4] Histologic evaluation of
the liver biopsy thus allows identification of patients considered
most likely to benefit from therapy -- that is, individuals with mild
to moderate fibrosis and moderate necroinflammatory activity.
Similarly, those patients with minimal fibrosis or compensated
cirrhosis who do not need antiviral therapy or who will not benefit
from such therapy can be monitored and followed with a liver biopsy
every 3 to 5 years.[3,4]
Liver Biopsy Technique
The majority of liver core biopsies are procured with one of a number
of percutaneous aspiration or cutting needles. Diffuse parenchymal
disease processes are not always uniformly represented in the liver
parenchyma; therefore, some clinicians advocate obtaining multiple
biopsies redirected through the biopsy site in an effort to increase
the diagnostic yield. To avoid inadequate sampling, it is
generally recommended that a needle core biopsy should be at least
15-25 mm in length and 1.2-2.0 mm in diameter. Such a biopsy provides
a tissue sample that represents approximately 1/50,000 of the liver
volume. Potential clinical complications from liver biopsy are not
insignificant and can range from pain in the right upper quadrant to
more serious complications of intraperitoneal hemorrhage, with
significant blood loss or even, remotely, death. For these reasons,
consideration regarding the necessity of biopsy and the procedure
itself should be managed by experienced hepatologists.
Although there is no specific guideline, a minimum of 5 intact portal
tracts should be present for sufficient evaluation of parenchymal
disease. And finally, the subcapsular liver tissue should be
disregarded in liver biopsy interpretation for the following reasons:
The portal tracts within 2-3 mm of the capsule are often densely
fibrotic. Likewise, extensions of the fibrous capsule penetrate into
the parenchyma and can be misinterpreted as bridging fibrosis or
cirrhosis. Also, the immediate subcapsular parenchyma is the least
well-vascularized area of the liver and may show lesions of fibrosis
and extinction disproportionately to those noted in the remaining
Interpretation of the Liver Biopsy: Histologic Assessment
In chronic hepatitis C, the degree and location of inflammation, foci
of necroses and/or apoptosis, steatosis, and fibrosis are each
evaluated microscopically. It is the practice of the surgical
pathologist to interpret the various histologic findings in a
systematic fashion to ultimately derive a diagnosis and assessment of
grade and stage.
The portal tracts, which include branches of the hepatic artery,
portal vein, and interlobular bile duct within a fibrous matrix, are
assessed for the presence of chronic inflammation and for interface
activity (described below), the central features of chronic
hepatitis. The inflammatory infiltrate in chronic hepatitis C is
predominantly mononuclear, consisting mainly of lymphocytes with
occasional plasma cells and eosinophils, and will be quantified, for
example, as minimal, mild, moderate, or marked. The presence of
portal lymphoid aggregates, characteristic of hepatitis C infection,
and interface activity, previously called "piecemeal necrosis," is
also described and quantified. Interface hepatitis (activity) is
histologically noted as the presence of chronic inflammation
breaching the fibrous matrix of the portal tract (limiting plate) and
surrounding the immediately adjacent hepatocytes. Similarly, the
degree of lobular activity, that is, chronic inflammation and foci of
necrosis in the lobular parenchyma, is noted and the degree of
involvement assessed. Ongoing injury in the lobules, represented by
inflammation, apoptotic hepatocytes, or acidophil bodies, and Kupffer
cell aggregates, may be present as evidence of lobular activity.
Importantly, bridging necrosis and confluent necrosis are not
characteristically seen in hepatitis C, as they may be in other forms
of chronic liver disease.
Another feature frequently noted in many liver biopsies of chronic
hepatitis C is hepatic steatosis, or fat droplets within hepatocytes.
These are usually distributed haphazardly throughout the lobules with
no specific zonality. Many investigators have shown increased
steatosis with hepatitis C virus genotype 3[7,8] and several studies
evaluating the possible relationship of steatosis and fibrosis have
been reviewed recently.
Finally, the liver biopsy is examined for fibrosis. Fibrosis in the
liver is the wound-healing response (scar) to the underlying disease
process, and is considered the end result of ongoing injury and cell
death. The pattern of fibrosis and consequent architectural
remodeling of the liver are elucidated with the aid of the trichrome
and reticulin stains, which demonstrate various forms of collagen.
Fibrosis in chronic hepatitis of viral and autoimmune etiologies
begins in the portal region. Portal expansion, periportal fibrosis,
bridging fibrosis, or frank cirrhosis can be established
microscopically. The terms imply not only the progressive extension
of fibrous strands into the parenchyma, but also remodeling of the
Finalizing the Diagnosis
Once the histologic changes of chronic hepatitis C are documented,
the findings are summarized in the final diagnosis, which includes
not only the etiology, that is, "chronic hepatitis, hepatitis C
virus," but also the grade and stage of the disease. As briefly
mentioned previously, the grade refers to the severity of
necroinflammatory activity and is a measure of severity and ongoing
disease. The stage refers to the degree of fibrosis and architectural
remodeling; it is a measure of disease progression.
In an effort to semiquantitatively document the lesions of chronic
hepatitis to better allow comparison of serial biopsies in individual
patients, Knodell and colleagues devised a semiquantitative
scoring system of liver biopsies in 1981. The classification has
since undergone various modifications, the most popular of which are
Scheuer, Ishak, and METAVIR. Regardless of the scoring system
used, the benefit of routinely using a systematized classification
schema is 3-fold:
It promotes reporting of clinically relevant information garnered
from the biopsy.
It enables analysis of the individual histologic components allowing
the nonhepatopathologist to focus on the lesions of significance.
And finally, using a classification system allows for comparison of
biopsies in regard to interval progression and the effect of
treatment on the liver.
The importance of systematized review of liver pathology in the
assessment of chronic hepatitis C, in our experience, should not be
underestimated. The biopsy provides the clinician with diagnostic
data that in most instances cannot be gleaned from lab data or other
noninvasive procedures. Knowledge of both the limitations of the
liver biopsy and the important, albeit invaluable, information
provided about disease progression and therapeutic effect will aid
the clinician in providing optimal care of the patient.
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Laura Baalmann-Mangano, MD, Senior Resident in Pathology, Saint Louis
University School of Medicine
Elizabeth M. Brunt, MD, Associate Clinical Professor of Pathology,
Department of Anatomic Pathology, Saint Louis University Health
Sciences Center, St. Louis, Missouri
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