Contributed by Anthony J. Demetris, M.D.
PATIENT HISTORY: Per referral letter, the patient is a middle aged black male who underwent liver transplantation for acute fulminant liver failure due to Budd-Chiari syndrome. De novo post transplant hepatitis C was diagnosed by HCV RNA in serum and liver tissues and a consistent histopathological features. His aminotransferases and total bilirubin were persistently elevated between 1-2 times normal until early November when the total bilirubin and alkaline phosphatase were noted to be 5 times normal. Itaconazole, started about 2-3 weeks earlier for dermatophytosis, was discontinued due to presumed hepatotoxicity. His other medications were cyclosporine A, prednisone, coumadin, and axid. Subsequently, the patient developed a progressive rise in AST, ALT and total bilirubin to 700-900, 1200-2100 and 25-30 mg/dl. He has been on anticoagulant therapy and recent ultrasound with Doppler flow studies indicate that all hepatic vessels are patent. An ERCP was normal. A CT scan of the abdomen showed ascites, but no mass or lymphadenopathy. All viral studies (HAV, HBV, CMV, EBV) have been negative. Serum HCV RNA levels have not changed compared to earlier when his condition was stable. A qualitative EBV PCR was positive but EBV DNA was undetectable by a quantitative assay (done at the University of Pittsburgh). An EBER in situ hybridization study was equivocal, but since B cells were uncommon in the liver infiltrate post transplant lymphoproliferative disorder is unlikely. He has had several liver biopsies which showed chronic hepatitis, more recently with cirrhosis and features of acute hepatitis. Despite 2 weeks of interferon for possible hepatitis C and empiric ganciclovir (?EBV), his condition has not improved. The patient now has ascites, hepatic encephalopathy, hypoalbuminemia, and renal failure. Review of outside material.

Final Diagnosis (Case 10)

ALLOGRAFT LIVER, NEEDLE BIOPSY Part 1-
  1. ACTIVE HEPATITIS, VIRAL TYPE C, FEATURES OF ACUTE WITH TRANSITION TO CHRONICITY.
  2. FOCALLY BRIDGING FIBROSIS.
  3. SUPERIMPOSED ACUTE CELLULAR REJECTION, MILD, WITH DUCT DAMAGE(see microscopic description).

ALLOGRAFT LIVER, NEEDLE BIOPSY Part 2-

  1. ACTIVE HEPATITIS, VIRAL TYPE C, FEATURES OF ACUTE WITH TRANSITION TO CHRONICITY.
  2. FOCALLY BRIDGING FIBROSIS.
  3. LESS PORTAL INFLAMMATION AND LYMPHOCYTIC DUCT DAMAGE IN COMPARISON TO PREVIOUS BIOPSY, CONSISTENT WITH INCREASED IMMUNOSUPPRESSIVE THERAPY.
  4. RESDIUAL DEGENERATIVE CHANGES IN SMALL BILE DUCTS, SUGGESTIVE OF THE EARLIEST PHASES OF CHRONIC REJECTION(see microscopic description).

Previous Biopsies on this Patient:
NONE

TPIS Related Resources:
Liver Allograft Biopsy Rejection Criteria
Liver Transplant Topics

Gross Description - Case 10

The specimen consists of one (1) HE, two (2) EBER RNA and one (1) Masson's trichrome slide and three (3) HE, two (2) trichrome and one (1) UCHL immunostain.

Microscopic Description - Case 10

Part 1
The normal lobular architecture is distorted by portal expansion, because of fibrosis, cholangiolar proliferation and a mild to moderate mixed inflammatory cell infiltrate. Bile duct infiltration and damage by lymphocytes is easily seen, and there is fairly widespread atrophy and pyknosis of the biliary epithelium. However, there is also marked interface activity, including cholangiolar proliferation.

Throughout the lobules, there is moderate to severe lobular disarray, marked Kupffer cell hypertrophy, spotty acidophilic necrosis of hepatocytes and moderate to severe lymphohistiocytic lobular inflammation which is somewhat accentuated in the perivenular regions. No definite ground glass cells or other viral inclusions are detected.

Part 2
The normal lobular architecture is distorted by marked portal expansion with focal portal-to-portal and portal-to-central bridging fibrosis. There is also a mild, predominantly mononuclear inflammatory cell infiltrate which is decreased somewhat in appearance to the previously biopsy. However, there continues to be widespread bile duct atrophy and pyknosis. This should be reflected in fairly significant elevations of the gamma glutamyltranspeptidase and alkaline phosphatase. In addition, lymphocytic bile duct damage is also present.

As in the previous specimen, there is mild to moderate interface activity, including cholangiolar proliferation. Throughout the lobules, there is moderate Kupffer cell hypertrophy, spotty acidophilic necrosis of hepatocytes, hepatocellular swelling and lymphohistiocytic lobular inflammation which is somewhat accentuated in the perivenular regions.

No viral inclusions or ground glass cells are seen.

Overall, the histopathological findings in both biopsies are indicative of more than one histopathologic insult. First and foremost, the most significant insult appears to be an active hepatitis. This contention is based on the mild to moderate interface activity, cholangiolar proliferation, lobular disarray, panlobular inflammation, spotty acidophilic necrosis of hepatocytes and positive PCR for HCV. However, a significant component of rejection is also present. In the first biopsy, the lymphocytic infiltration and damage of small bile ducts is far more than one would expect for hepatitis alone. In addition, there is fairly widespread bile duct atrophy and pyknosis. The slight perivenular accentuation of the lobular inflammation along with areas of selective perivenular fibrosis are also more frequently seen with rejection.

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