—  SPECIALTY CONFERENCE  —

Liver Pathology

Case 1 - Fibrosing Cholestatic Hepatitis B

Helen Wang
Beth Israel Deaconess Medical Center
Boston, MA


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Clinical History
A 43-year-old woman, who is status post cadaveric renal transplant eleven years before, now presents with acute liver failure. Five years after the renal transplant she was noted to have hepatitis B, but had normal liver function tests up till at least a few months before the presentation. She was in her usual state of health until two weeks prior to presentation when she developed right upper quadrant pain followed by nausea and vomiting and then jaundice. She presented to the emergency department of an outside hospital where an ultrasound revealed gallbladder edema. At that time her liver function tests and INR were noted to be elevated, and the patient was discharged home. She subsequently developed increase in abdominal girth and an increase in abdominal pain, nausea and vomiting, as well as generalized weakness. She presented to the same outside hospital again ten days later and was admitted with a diagnosis of "hepatitis". An abdominal CT revealed ascites, edema of the colon and small bowel wall. She was treated conservatively and given Unasyn for presumed cholecystitis/cholangitis. She was then transferred to the Beth Israel Deaconess Medical Center for further workup.

On presentation she complained of diarrhea or loose stool for two weeks in addition to the above symptoms. She had some shortness of breath secondary to abdominal distention. She denied any fevers, chills, bright red blood per rectum or melena. She had no recent travel or sick contact. Neither did she have unusual or undercooked food. She claimed her liver and kidney to be working normally until this acute process. She had no history of hypercoagulability in herself or her family.

In addition to the history of kidney transplant for end stage renal disease of unclear etiology and subsequent hepatitis B, her medical history was significant for hypertension and hypercholesterolemia. Her medications at home included Imuran, Sandimmune, predinisone, Lasix, Procardia, Tenormin and occasional Tylenol. She did not smoke or use alcohol or any other drugs.

Physical examination showed an overweight middle-aged woman in no acute distress with a heart rate of 105 and respiratory rate of 22. The exam was remarkable for a softly distended abdomen with tenderness in the right upper quadrant, but without guarding or rebound. Mild edema was noted on the lower extremities. Laboratory tests were remarkable for an elevated white count to 18.1 with a differential of 89 neutrophils, 9 bands, and 1 lymphocyte. Coags were notable for an elevated INR. Liver function tests were: AST 408, ALT 288, alkaline phosphatase 221, amylase 77, total bilirubin 27.9, direct bilirubin 17, indirect bilirubin 10.9, and albumin 2.5.

She was admitted to the hospital with acute liver failure. A full hepatitis panel including hepatitis A, B, C, D, and E, CMV antibody and antigen, EBV antibody panel revealed only hepatitis B surface antigen and e-antigen positivity. Right upper quadrant ultrasound revealed no bile duct dilation and no evidence of portal vein or hepatic vein thrombosis. A transjugular liver biopsy was performed.


Case 1 - Figure 1 - Extensive periportal fibrosis with canalicular and hepatocellular cholestasis
Case 1 - Figure 2 - Higher power view showing canalicular and hepatocellular cholestasis
Case 1 - Figure 3 - Relatively mild portal inflammatory infiltrate


Case 1 - Figure 4 - Ballooning degeneration of hepatocytes
Case 1 - Figure 5 - Masson stain highlights extensive fibrosis

Diagnosis:
Fibrosing Cholestatic Hepatitis B

Given the clinical history, the liver biopsy findings, and the laboratory results, the clearest explanation was that the patient had an acute fibrosing cholestatic hepatitis B with cirrhosis that is occasionally seen in the setting of chronic hepatitis B and immunosuppression. The patient was evaluated for a transplant, and during her workup she received measurement of hepatitis B DNA viral loads. The patient was begun on lamivudine to inhibit hepatitis B viral replication. A pre lamivudine viral load was greater than 56,000,000 copies per ml as was a viral load one week after beginning lamivudine. The patient had gradual improvement in her liver function over the course of her hospitalization and was discharged home two weeks later, off all immunosuppressive therapy and maintained on lamivudine treatment. Her liver function test stabilized after slight improvement and her condition remained stable except occasional episodes of nausea and vomiting. She was re-admitted one month after discharge for an orthotopic liver transplant. In spite of a difficult transplant operation and complicated post-operative course, she eventually recovered and had excellent graft function.

Fibrosing cholestatic hepatitis (FCH) was first described in liver transplant recipients who had HBV infection at the time of transplantation. [1, 2, 3] Patients with hepatitis B infection at the time of liver replacement have been known to have a high rate of re-infection that almost invariably leads to chronicity and recurrence of liver disease. [4, 5] Mortality, rate of graft loss, need for re-transplantation and incidence of abnormal liver function were significantly higher in the HBV-infected group than the HBV-immune group. [6] Recent data showed the 1-year, 4-year, and 7-year survival rates after liver transplantation for chronic HBV to be 83%, 71%, and 63%, respectively. [7] These were comparable to the rates for cryotogenic cirrhosis, alcoholic liver disease and chronic HCV, but were still less than the rates for primary sclerosing cholangitis and primary biliary cirrhosis (~ 90%, 84%, and 78%, respectively]. [7} The recurrent HBV recapitulates with variable clinical expressions the original disease, although the severity and speed of progression of disease are greater in the liver allograft than in the non-transplanted liver. [4, 6, 8, 9] Three main atypical patterns of re-infection have been identified – hepatocyte ballooning, fatty change and a distinctive cholestatic syndrome. [2, 10] These frequently occur in combination and are all associated with evidence of massive viral replication. Fibrosing cholestatic hepatitis is widely used to describe a unique combination of clinical course and histologic findings. [1, 2, 3, 9, 11] Clinically, patients with FCH had rapid deterioration of liver function with marked prolongation of prothrombin time, development of encephalopathy and liver failure over several weeks. Histologically, it is characterized by an extensive serpiginous periportal fibrosis, canalicular and cellular cholestasis, ground-glass transformation and ballooning degeneration of hepatocytes, and a rather mild inflammatory cell infiltrate. Biochemical tests showed elevated bilirubin with only a moderate rise in serum transaminases. Initially up to about 22% of the HBsAg-seropositive transplant patients who survived for more than 2 months developed this entity with almost 100% mortality within 4-6 weeks. [2] The interval between the liver transplantation and re-transplantation or death due to FCH ranged from 3 months to slightly over a year. [3, 9, 11] This lesion seems to have become less common in recurrent HBV infection, possibly as a result of immunoprophylaxis and other measures used to reduce the incidence of recurrent HBV infection. In addition, areas of overlap between fibrosing cholestatic hepatitis and other patterns of HBV infection in the liver allograft are also recognized. For example, some cases may initially present with fibrosing cholestatic features, but then revert to a more typical hepatitis following withdrawal of immunosuppression. [12]

HBV-associated nucleic acids have been identified in peripheral blood mononuclear cells and several extrahepatic sites, and these are presumed to be the source of re-infection in the liver allograft. [12] The precise mechanism of FCH is not entirely clear but has been thought to be related to the immunosuppressive therapy used to prevent graft rejection. It has been shown that the liver tissue from patients with FCH had significantly greater amounts of both HBsAg and nucleocapsid antigens than liver tissue from transplant patients without this syndrome or patients with chronic HBV infection. [13] Intrahepatic expression of pre-S1/ pre-S2 in FCH was also extensive with a distribution parallel to that of HBsAg. Furthermore, although the transplant recipients with recurrent hepatitis B infection expressed large amounts of HBV DNA in their liver grafts, irrespective of the histology, marked transcriptional activity was primarily associated with a histological diagnosis of FCH. [14] A significant association between the level of hepatocyte expression of HBV RNA and the severity of ballooning degeneration was also found. [14] These findings suggest that the excessively high levels of viral replication contribute to the pathogenesis of rapidly progressive liver disease in transplant recipients. The lack of immune response and marked accumulation of viral proteins in FCH in particular suggest a cytopathic role for the virus in this entity. [9, 13, 14]

Fibrosing cholestatic hepatitis was first reported in 1994 in a renal transplant recipient who was an HBsAg carrier at the time of transplantation. [15] In fact, liver disease has long been noted as the leading cause of death in transplant recipients whose renal allografts had functioned for more than five years, [16] and HBV has been clearly identified as a frequent and major risk factor in the occurrence of chronic liver diseases in renal transplant recipients. [17] Immunosuppressive therapy was again thought to enhance the viral replication in both HBsAg-poisitive and HBsAg-negative subjects. FCH has since been reported to be caused by HCV, [18] in other organ transplants, such as bone marrow transplantation, [19] and cardiac transplantation,(20} and in other types of immunosuppression, such as HIV infection, [21, 22] and chemotherapy. [23]

As far as treatment is concerned, FCH was initially treated with re-transplantation or transplantation of liver. More recently, treatment with antiviral agents has been reported with variable outcomes. [24, 25, 26, 27]

References

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