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

Laura Baalmann-Mangano, MD, Elizabeth M. Brunt, MD



Introduction
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

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 parenchyma.

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 c