Case 1 -
Fibrosing Cholestatic Hepatitis B
Beth Israel Deaconess Medical Center
Click on each slide thumbnail image for an enlarged view
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.
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.
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.
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.  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.  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.
Three main atypical patterns of re-infection
have been identified – hepatocyte ballooning, fatty change and a distinctive cholestatic syndrome.
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.
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.  The interval between the liver transplantation and
re-transplantation or death due to FCH ranged from 3 months to slightly over a year.
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
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. 
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. 
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.  A significant association between the level of hepatocyte expression of HBV RNA and the
severity of ballooning degeneration was also found.  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.
Fibrosing cholestatic hepatitis was first reported in 1994 in a renal transplant recipient who was an
HBsAg carrier at the time of transplantation.  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,  and HBV has been clearly identified as a frequent and major risk factor in the occurrence of
chronic liver diseases in renal transplant recipients.  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,  in other organ transplants, such as bone marrow transplantation, 
and cardiac transplantation,(20} and in other types of immunosuppression, such as HIV infection,
and chemotherapy. 
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
- O'Grady JG, Williams R. Liver transplantation for viral hepatitis. Br Med Bull 1990;46(2):481-91.
- Davies SE, Portmann BC, O'Grady JG, Aldis PM, Chaggar K, Alexander GJ, et al. Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. Hepatology 1991;13(1):150-7.
- Benner KG, Lee RG, Keeffe EB, Lopez RR, Sasaki AW, Pinson CW. Fibrosing cytolytic liver failure secondary to recurrent hepatitis B after liver transplantation. Gastroenterology 1992;103(4):1307-12.
- Rizzetto M, Recchia S, Salizzoni M. Liver transplantation in carriers of the HBsAg. J Hepatol 1991;13(1):5-7.
- Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP, et al. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med 1993;329(25):1842-7.
- Todo S, Demetris AJ, Van Thiel D, Teperman L, Fung JJ, Starzl TE. Orthotopic liver transplantation for patients with hepatitis B virus-related liver disease. Hepatology 1991;13(4):619-26.
- Keeffe EB. Liver transplantation: current status and novel approaches to liver replacement. Gastroenterology 2001;120(3):749-62.
- Portmann B, O'Grady JG, Williams R. Disease recurrence following orthotopic liver transplantation. Transplant Proc 1986;18(5 Suppl 4):136-141.
- Demetris AJ, Todo S, Van Thiel DH, Fung JJ, Iwaki Y, Sysyn G, et al. Evolution of hepatitis B virus liver disease after hepatic replacement. Practical and theoretical considerations. Am J Pathol 1990;137(3):667-76.
- Phillips MJ, Cameron R, Flowers MA, Blendis LM, Greig PD, Wanless I, et al. Post-transplant recurrent hepatitis B viral liver disease. Viral-burden, steatoviral, and fibroviral hepatitis B. Am J Pathol 1992;140(6):1295-308.
- O'Grady JG, Smith HM, Davies SE, Daniels HM, Donaldson PT, Tan KC, et al. Hepatitis B virus reinfection after orthotopic liver transplantation. Serological and clinical implications. J Hepatol 1992;14(1):104-11.
- Hubscher SG, Portmann BC. Transplantation pathology. In: MacSween RNM, Burt AD, Portmann BC, Ishak KG, Scheuer PJ, Anthony PP, editors. Pathology of the liver. 4th ed. London: Churchill Livingstone; 2002. p. 885-941.
- Lau JY, Bain VG, Davies SE, O'Grady JG, Alberti A, Alexander GJ, et al. High-level expression of hepatitis B viral antigens in fibrosing cholestatic hepatitis. Gastroenterology 1992;102(3):956-62.
- Mason AL, Wick M, White HM, Benner KG, Lee RG, Regenstein F, et al. Increased hepatocyte expression of hepatitis B virus transcription in patients with features of fibrosing cholestatic hepatitis. Gastroenterology 1993;105(1):237-44.
- Chen CH, Chen PJ, Chu JS, Yeh KH, Lai MY, Chen DS. Fibrosing cholestatic hepatitis in a hepatitis B surface antigen carrier after renal transplantation. Gastroenterology 1994;107(5):1514-8.
- Weir MR, Kirkman RL, Strom TB, Tilney NL. Liver disease in recipients of long-functioning renal allografts. Kidney Int 1985;28(5):839-44.
- Degos F, Lugassy C, Degott C, Debure A, Carnot F, Theirs V, et al. Hepatitis B virus and hepatitis B-related viral infection in renal transplant recipients. A prospective study of 90 patients. Gastroenterology 1988;94(1):151-6.
- Munoz De Bustillo E, Ibarrola C, Colina F, Castellano G, Fuertes A, Andres A, et al. Fibrosing cholestatic hepatitis in hepatitis C virus-infected renal transplant recipients. J Am Soc Nephrol 1998;9(6):1109-13.
- Cooksley WG, McIvor CA. Fibrosing cholestatic hepatitis and HBV after bone marrow transplantation. Biomed Pharmacother 1995;49(3):117-24.
- Delgado J, Munoz de Bustillo E, Ibarrola C, Colina F, Morales JM, Rodriguez E, et al. Hepatitis C virus-related fibrosing cholestatic hepatitis after cardiac transplantation: is azathioprine a contributory factor? J Heart Lung Transplant 1999;18(6):607-10.
- Fang JW, Wright TL, Lau JY. Fibrosing cholestatic hepatitis in patient with HIV and hepatitis B. Lancet 1993;342(8880):1175.
- Rosenberg PM, Farrell JJ, Abraczinskas DR, Graeme-Cook FM, Dienstag JL, Chung RT. Rapidly progressive fibrosing cholestatic hepatitis--hepatitis C virus in HIV coinfection. Am J Gastroenterol 2002;97(2):478-83.
- Kojima H, Abei M, Takei N, Mukai Y, Hasegawa Y, Iijima T, et al. Fatal reactivation of hepatitis B virus following cytotoxic chemotherapy for acute myelogenous leukemia: fibrosing cholestatic hepatitis. Eur J Haematol 2002;69(2):101-4.
- Jamal H, Regenstein F, Farr G, Perrillo RP. Prolonged survival in fibrosing cholestatic hepatitis with long-term ganciclovir therapy. Am J Gastroenterol 1996;91(5):1027-30.
- Toth CM, Pascual M, Chung RT, Graeme-Cook F, Dienstag JL, Bhan AK, et al. Hepatitis C virus-associated fibrosing cholestatic hepatitis after renal transplantation: response to interferon-alpha therapy. Transplantation 1998;66(9):1254-8.
- Jung S, Lee HC, Han JM, Lee YJ, Chung YH, Lee YS, et al. Four cases of hepatitis B virus-related fibrosing cholestatic hepatitis treated with lamivudine. J Gastroenterol Hepatol 2002;17(3):345-50.
- Tillmann HL, Bock CT, Bleck JS, Rosenau J, Boker KH, Barg-Hock H, et al. Successful treatment of fibrosing cholestatic hepatitis using adefovir dipivoxil in a patient with cirrhosis and renal insufficiency. Liver Transpl 2003;9(2):191-6.