A 63-year-old jaundiced man presents with vague abdominal pain. Biochemical tests reveal elevated liver enzymes with an AST/ALT ratio of 2:1 and radiology reveals a vaguely nodular liver. Gross examination of the hepatectomy shows green to yellow mottled parenchyma with no gross lesions, masses, or nodules.

Master List of Diagnoses

  • Alcoholic steatohepatitis
  • Autoimmune hepatitis
  • Biliary cirrhosis with mild activity
  • Focal nodular hyperplasia
  • Hepatocellular carcinoma
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 39, and is alcoholic steatohepatitis of the liver

Criteria for Diagnosis and Comments

The histological sections demonstrate hepatic parenchyma with mild to moderate macrovesicular steatosis and diffuse mild portal and lobular, predominantly lymphocytic, inflammation. Ballooned hepatocytes with associated Mallory hyaline are present. Thin fibrous septae associated with patchy areas of ductular reaction are noted to be traversing between central veins and portal triads.

Steatohepatitis is defined by the presence of both fat and inflammation in hepatic parenchyma showing signs of active liver injury. Inflammation of the lobule with damage to hepatocytes in the form of injured cells (balloon cells) and/or individual cell necrosis (acidophil bodies) are histological manifestations of ongoing liver injury. Cytoplasmic accumulation of eosinophilic clusters of ubiquitinated cytokeratin (Mallory hyaline) is also frequently noted feature of liver injury. Steatohepatitis can be seen in both alcoholic and nonalcoholic fatty liver disease.

Alcohol-associated fatty liver disease (AFLD) is a leading cause of liver failure and liver transplantation in the United States. The presence of macrovesicular fat deposition around zone 3 is common although foci of microvesicular steatosis occasionally can be admixed with macrovesicular steatosis, especially in the setting of binge drinking and decompensated disease. Balloon cells can be differentiated from hepatocytes with steatosis by the presence in the former of a centrally placed nucleus in the background of rarefaction or vacuolization of cytoplasm. Mallory hyaline is often associated with balloon cells; both are concentrated around the central vein in AFLD. Lobular inflammation shows a prominence of neutrophils, which can form a perimeter around hepatocytes, a feature known as satellitosis. Portal inflammation is mild and comprised of mononuclear cells. The distinction between AFLD and nonalcoholic fatty liver disease is difficult to make solely on a histologic basis and incorporation of clinical history is important.

Features of hepatic injury that favor AFLD include cholestatic alcoholic steatohepatitis, which is characterized by obstructive changes (eg, cholestasis), portal tract edema, and neutrophilic infiltration of the bile ducts. Alcoholic foamy degeneration, which is the accumulation of small droplet fat in hepatocytes in a centrilobular distribution, and sclerosing hyaline necrosis, which is characterized by centrilobular hepatocyte dropout, confluent necrosis, and occlusion of the central veins are more often present in AFLD. Sclerosing hyaline necrosis is associated with poor prognosis.

Fibrosis is first noted around central veins, distributed around individual hepatocytes in a so called “chicken wire” or pericellular fashion. As the disease progresses, central-central and central-portal bridging fibrosis and eventually mixed macronodular and micronodular cirrhosis will develop. The following factors have been associated with disease progression: (a) female, (b) obesity, (c) early age at onset of drinking, (d) daily or near daily drinking, (e) concurrent liver disease, and (f) genetic susceptibility (patatin-like phospholipase domain-containing-3 (PNPLA3) gene rs738409 C>G polymorphism). Up to 15% of patients with alcoholic steatohepatitis will develop cirrhosis, of these 1% - 2% of them progress to hepatocellular carcinoma (HCC).

Hepatocellular carcinoma - HCC is a malignant hepatocellular tumor and differentiation is allotted based on how well the neoplastic cells recapitulate hepatocytes. There is variation in both architectural growth patterns and degree of cytologic atypia. Solid, trabecular, and pseudoglandular are frequently encountered growth patterns. Neoplastic cells have abundant to moderate amounts of cytoplasm; the cytoplasm can be pink with Mallory hyaline or can show fatty or clear cell change. Large round nuclei and prominent nucleoli are common. The presence of arteries unaccompanied by portal tracts is a common feature of HCCs, which is not seen in regenerative nodules. It is usually easily recognized on routine H&E stains; however, histochemical and immunostains can act as an adjunct to diagnosis.

The diffuse expansion and/or loss of reticulin staining is frequent in hepatocellular carcinoma. CAM5.2 is positive in all HCCs. CD10 and/or polyclonal carcinoembryonic antigen (pCEA) are expressed in a canalicular pattern by up to 90% of HCCs. CD34 shows a strong diffuse sinusoidal staining pattern in HCCs. HepPar1 has shown increased sensitivity for well to moderately differentiated HCCs. Glypican 3 labels up to 85% of HCCs and does not stain a noninflamed and noncirrhotic background liver. Overall, it is best to use a panel of markers when the diagnosis in in doubt.

Biliary cirrhosis with mild activity can be due to a myriad of etiologies involving both the intra- and extrahepatic biliary system. Primary sclerosing cholangitis is primarily a disease that affects the extrahepatic biliary tree. In contrast, primary biliary cirrhosis affects medium-sized intrahepatic bile ducts. Biliary cirrhosis often demonstrates a marked ductular reaction along with patchy loss of bile ducts in the portal tracts and mild inflammation. Cholestasis is common. The regenerative nodules in biliary cirrhosis tend to be jigsaw puzzle-shaped as opposed to the rounded contours in nonbiliary causes of cirrhosis. Steatosis can be patchy but is not usually a prominent feature of biliary cirrhosis.

Autoimmune hepatitis (AIH) is a relapsing and remitting immune-mediated liver disease that most commonly affects females in their 20s and 40s. The diagnosis requires the exclusion of other etiologies (eg, drug reaction, viral hepatitis). AIH can present as an acute hepatitis. The main histologic hallmark of AIH is hepatitis dominated by plasma cells and interface activity, while other features like emperipolesis and pseudorosettes could be seen but are neither specific nor sensitive. Serologic findings included elevation of immunoglobulin G, antinuclear antibodies, anti-smooth muscle antibodies, anti-liver/kidney microsomal antibodies, liver cytosol type-1 antibodies, and soluble liver antigen.

Focal nodular hyperplasia is a benign condition that develops as result of shunting of arterial blood flow, which leads to the production of fibrous bands. Histologically, the lesion is comprised of nodules of benign hepatocytes with intervening thin fibrous septae with blood vessels. The reticulin staining pattern demonstrates normal thickness (1 - 2 cells) hepatocyte trabeculae. Ductular reaction can be seen in the fibrous septae. The background liver is noncirrhotic. Glutamine synthetase demonstrates map-like staining that can help differentiate from inflammatory hepatic adenomas, which often show diffuse staining.

  1. Which of the following is true regarding alcoholic steatohepatitis

    1. Balloon cells, Mallory hyaline, and pericellular “chicken wire” fibrosis are common findings
    2. Fat accumulation is exclusively small droplet (microvesicular)
    3. Fibrosis is first noted exclusively at the portal tracts (zone 1)
    4. Inflammation is marked with a predominance of plasma cells
    5. It is histologically distinct from nonalcoholic steatohepatitis
  2. Mutation in which of the following genes has been associated with disease progression of alcohol-associated fatty liver disease?

    1. Coproporphyrinogen oxidase (CPOX)
    2. Hepatoctye nuclear factor-1 alpha (HNF1A)
    3. Patatin-like phospholipase domain-containing-3 (PNPLA3)
    4. P-type ATPase (ATP7B)
    5. Serpin peptidase inhibitor, clade A, member 1 (SERPINA1)
  3. Which of the following is a common histologic feature of biliary cirrhosis?

    1. Interface hepatitis with clusters of plasma cells
    2. Jigsaw puzzle-like shapes of regenerating hepatocyte nodules
    3. Nodules of benign hepatocytes with thin intervening fibrous septae
    4. Nuclear atypia and prominent nucleoli
    5. Scattered lymphoid aggregates within the hepatic parenchyma

References

  1. Alpert L, Hart J. The Pathology of Alcoholic Liver Disease. Clin Liver Dis. 2016(3):473-489.
  2. Altamirano J, Miquel R, Katoonizadeh A, et al. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology. 2014;146(5):1231-1239.
  3. Saberi B, Dadabhai AS, Jang YY, Gurakar A, Mezey E. Current Management of Alcoholic Hepatitis and Future Therapies. J Clin Transl Hepatol. 2016;4(2):113-122.
  4. Sakhuja P. Pathology of alcoholic liver disease, can it be differentiated from nonalcoholic steatohepatitis? World J Gastroenterol. 2014;20:16474-16479.

Author

Safia N. Salaria, MD
Surgical Pathology Committee
Vanderbilt University Medical Center
Nashville, TN


Answer Key

  1. Balloon cells, Mallory hyaline, and pericellular “chicken wire” fibrosis are common findings (a)
  2. Patatin-like phospholipase domain-containing-3 (PNPLA3) (c)
  3. Jigsaw puzzle-like shapes of regenerating hepatocyte nodules (b)