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Evaluating Liver Disease in Chronic Hepatitis C -- The Role of the Liver Biopsy

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    NOTE: To view the article with Web enhancements, go to: http://www.medscape.com/viewarticle/458406 MedGenMed Gastroenterology Evaluating Liver Disease in
    Message 1 of 1 , Aug 19, 2003
      NOTE: To view the article with Web enhancements, go to:

      MedGenMed Gastroenterology
      Evaluating Liver Disease in Chronic Hepatitis C -- The Role of the
      Liver Biopsy

      Laura Baalmann-Mangano, MD, Elizabeth M. Brunt, MD
      Medscape General Medicine 5(3), 2003. � 2003 Medscape

      Posted 08/08/2003
      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.[5] 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.[1] 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.[6] 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.[9]

      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
      hepatic architecture.

      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[10] 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.[11] 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.

      Concluding Remarks
      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.

      Lee RG. General principles. In: Lee RG (ed). Diagnostic Liver
      Pathology. St. Louis, Mo: Mosby; 1994: 1-21.
      Saadeh S, Cammell G, Carey W, et al. The role of the liver biopsy in
      chronic hepatitis C. Hepatology. 2001;33:196-200. Abstract
      National Institutes of Health Consensus Development Conference Panel
      Statement: Management of Hepatitis C 2002. Gastroenterology.
      2002;123:2082-2099. Abstract
      EASL International Consensus Conference on Hepatitis C Consensus
      Statement. J Hepatol. 1999;30:956-961. Abstract
      Maharaj B, Maharaj RJ, Leary WP, et al. Sampling variability and its
      influence on the diagnostic yield of percutaneous needle biopsy of
      the liver. Lancet. 1986;1:523-525. Abstract
      Brunt EM. Liver biopsy interpretation for the gastroenterologist.
      Curr Gastroenterol Rep. 2000;2:27-32. Abstract
      Rubbia-Brandt L, Leandro G, Spahr L, et al. Liver steatosis in
      chronic hepatitis C: a morphological sign suggesting infection with
      HCV genotype 3. Histopathology. 2001;39:119-124. Abstract
      Adinolfi LE, Utili R, Andreana A, et al. Relationship between
      genotypes of hepatitis C virus and histopathological manifestations
      in chronic hepatitis C patients. Eur J Gastroenterol Hepatol.
      2000;12:299-304. Abstract
      Brunt EM, Tiniakos DG. Steatosis, steatohepatitis: review of effects
      on chronic hepatitis C. Current Hepatitis Reports. 2002;1:38-44.
      Knodell RG, Ishak KG, Black WC, et al. Formulation and application of
      a numerical scoring system for assessing histologic activity in
      asymptomatic chronic active hepatitis. Hepatology. 1981;1:431-435.
      Brunt EM. Grading and staging the histopathological lesions of
      chronic hepatitis: the Knodell histopathology activity index and
      beyond. Hepatology. 2000;31:241-246. Abstract

      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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