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Hepatitis in a Lung Transplant Recipient

Clinical Presentation
A 33 year-old woman with cystic fibrosis who underwent bilateral orthotopic lung transplantation twelve weeks ago presented to the emergency department complaining of increasingly severe right upper quadrant pain of one week’s duration. Physical examination was remarkable for moderate jaundice and marked right upper quadrant tenderness to palpation. Liver function testing revealed markedly elevated AST and ALT, moderate indirect and direct hyperbilirubinemia, and a moderately elevated alkaline phosphatase. Serological testing for common viral hepatitides were negative, serum PCR for cytomegalovirus DNA was negative. Hepatobiliary imaging was normal. A percutaneous liver biopsy was performed.

Pathological Findings
Microscopic examination of the liver biopsy revealed approximately five small fragments of liver tissue. There was a mild portal infiltrate of mixed inflammatory cells without evidence of limiting plate inflammation. Within the lobules, there were scattered, randomly distributed foci of hepatocyte necrosis with mixed inflammation. In a few foci, collections of epithelioid cells suggestive of poorly-formed granulomas were seen. Only rare eosinophils were present. There was one large area of inflammation and fibrosis with central necrosis.

Diagnoses
Liver tissue with microabscess formation
Mycobacterial organisms present on special stains

Discussion
In an immunosupressed patient on numerous potent medications, the differential diagnosis of multifocal lobular necrotizing granulomatous inflammation is broad. The various causes of hepatic granulomas have different histological features that help to narrow the differential diagnosis. Sarcoidosis and primary biliary cirrhosis tend to favor the portal areas, while other causes do not typically display this pattern. In granulomas caused by tuberculosis, there is often caseating necrosis, while in cat scratch disease, tularemia, and Yersinia infection, granulomas frequently have a purulent center. “Fibrin-ring” granulomas comprised of a fat vacuole surrounded by a ring of fibrin, epithelioid cells, giant cells and neutrophils may be seen Q-fever, cytomegalovirus infection, toxoplasmosis, lupus, and a few other uncommon conditions. Finally, granulomas caused by drug toxicity are sometimes associated with an eosinophilic infiltrate.¹

In this case, a broad panel of special stains for bacterial, acid-fast, and fungal organisms was ordered. In addition, less common viral causes of hepatocellular necrosis, including cytomegalovirus, adenovirus, herpes simplex virus, and varicella-zoster virus, were ruled out by immunohistochemistry. A careful search of the entire biopsy at high magnification revealed only two acid-fast organisms. Interestingly, cultures obtained from this biopsy specimen at the time of presentation were negative (though a later urine culture grew Mycobacterium tuberculosis). Based on the biopsy identification of acid-fast organisms, the patient was treated for presumptive tuberculosis and has since done well.

1. Scheuer P, Lefkowitch J. Liver Biopsy Interpretation. 7^th ed. 2006. Elsevier.

Good pick-up on that red snapper. That could easily have been missed!