Elsevier Pathology

Anatomic Pathology: Liver Pathology

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333a) A 62-year-old typist had her annual health evaluation at work and was found to have elevated serum aspartate and alanine aminotransferase (AST and ALT, respectively). Her physician inquired specifically about alcohol intake, but the patient denied any alcoholic beverages or use of any medications. Since serologic tests for hepatitis B and C and for autoimmune hepatitis were negative, her physician referred the patient for a liver biopsy. Since the liver biopsy does not appear normal, in which one of the following well-recognized categories of liver disease would you place the pathologic findings in this biopsy?

• This case demonstrates a major category of clinical and pathologic liver disease in recent decades: NAFLD (nonalcoholic fatty liver disease).

• This biopsy shows one of the major complications of large droplet steatosis, namely steatohepatitis. Steatohepatitis may be due to alcohol (alcoholic steatohepatitis or ASH) or due to risk factors, such as the presence of obesity, diabetes, insulin resistance/metabolic syndrome or dyslipidemias (nonalcoholic steatohepatitis or NASH).

• NAFLD is currently the leading cause of elevated serum aminotransferases in the United States and other developed countries, largely because of the wide prevalence of obesity and diabetes.

• The features in this biopsy that constitute steatohepatitis include: large droplet (macrovesicular) steatosis within hepatocytes, ballooning of centrilobular (acinar zone 3) hepatocytes, pericellular infiltrates of inflammatory cells (lymphocytes, neutrophils), intra-hepatocellular Mallory-Denk bodies, and perivenular/perisinusoidal “chicken-wire” fibrosis.

• Portal tracts are relatively spared (or less involved by inflammation) in comparison to centrilobular regions in steatohepatitis; however, the greater the degree of steatohepatitis, the more likely there will be “more than mild” portal inflammation (i.e., inflammatory cells that mediate the centrilobular steatohepatitis must enter through the portal tract vessels, leading to greater portal tract cellularity in worse cases of steatohepatitis).

• The fibrosis associated with steatohepatitis progresses from centrilobular regions outward to bridge to adjacent central veins and/or portal tracts. This fibrosis can be seen in this case on H&E, but trichrome and reticulin stains (or, as used in some centers, Sirius red collagen stain) are extremely important for verifying the type and degree of fibrosis.

• Ubiquitin immunostain is very useful in confirming the presence of Mallory-Denk bodies.

• Hepatocytes affected by steatohepatitis are often ballooned and demonstrate loss or absence of keratins 8/18 when immunostained. Similar loss or absence may also affect centrilobular hepatocytes that are not visibly ballooned. Immunostaining with antibody to combined K8/18, therefore can be useful in cases where steatohepatitis needs very specific confirmation and distinction from another pathologic process, and K8/18 immunostaining can also be combined with ubiquitin staining for further delineation of the correct diagnosis.

• Pathologists should be aware that the major histologic spectrum of changes in alcoholic and nonalcoholic fatty liver disease (AFLD and NAFLD, respectively) includes (1) large droplet steatosis, (2) steatohepatitis, (3) cirrhosis, and (4) hepatocellular carcinoma.

Brunt EM, Kleiner DE, Wilson LA, et al: Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD. Clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network. Hepatology 2009;49: 809-820.

Yeh MM, Brunt EM: Pathology of nonalcoholic fatty liver disease. Am J Cllin Pathol 2007;128: 837-847.

Younossi ZM, Stepanova M, Rafiq N, et al: Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 2011;53: 1874-1882.

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