EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Fibrosing cholestatic hepatitis is an aggressive and usually fatal form of viral hepatitis in immunosuppressed patients. We assessed the hepatotoxicity of methotrexate and prednisolone combination therapy in the background of hepatitis B virus infection.

Materials and Methods: We report the clinical course of 55-year-old woman who underwent a deceased-donor liver transplant for fulminant liver failure.

Results: The patient’s medical history was significant for hepatitis B virus infection and rheumatoid arthritis. Methotrexate and prednisolone combi-nation therapy were started 5 months earlier. The patient was hospitalized because of an elevation in her liver enzymes and total bilirubin. Deterioration of liver functions and encephalopathy were developed 5 weeks after hospital admission. A deceased-donor liver transplant was performed, and pathological examination of recipient liver revealed fibrosing cholestatic hepatitis. The patient was reoperated on for bile leak and discharged 40 days after the deceased-donor liver transplant.

Conclusions: The natural course of the current case was similar to previously reported cases with fibrosing cholestatic hepatitis. Clinicians should consider the potential hepatotoxicity of methotrexate and steroid therapy in hepatitis B virus infected patients.

Key words : Fibrosing cholestatic hepatitis, Hepatotoxicity, Methotrexate, Fulminant liver failure, Liver transplant

Fibrosing cholestatic hepatitis is a rapidly progressive, sometimes fatal, form of liver injury. Though originally reported in liver transplant recipients with recurrent hepatitis B, it is recognized frequently in chronic hepatitis B or C patients who are undergoing immunosuppression.¹ Low-dose, weekly methotrexate (10 to 25 mg per week) used as either monotherapy or in combination with other drugs (eg, prednisolone) has a superior effectiveness in treating rheumatoid arthritis.2 We report the clinical features and histopathologic characteristics of a woman with fibrosing cholestatic hepatitis after methotrexate and prednisolone therapy for rheumatoid arthritis.

After 5 months of methotrexate (15 mg/wk) and prednisolone (10 mg/d) therapy for rheumatoid arthritis, jaundice and weakness developed in 55-year-old woman. The patient’s medical history was significant for hepatitis B virus infection. Hepatitis B virus reactivation was detected (hepatitis B virus DNA count; 2.41 × 10⁷ IU/mL). Elevation of liver trans-aminase and bilirubin levels with normal bleeding tests were determined (aspartate transaminase; 1323 U/L, alanine transaminase; 2272 U/L, total bilirubin; 342 μmol/L). Lamivudine therapy was started with the cessation of methotrexate and prednisolone. The clinical course progressed to acute hepatic failure. After 6 cycles of plasmapheresis therapy, a slight improvement in liver function tests was seen. Ultrasonography revealed abdominal ascites without splenomegaly or hepatomegaly. Moderate encephalopathy was developed, and a deceased-donor liver transplant was done 5 weeks after admission. Patient was reoperated for on a biliary anastomotic leak 18 days after the deceased-donor liver transplant, and she was discharged 40 days after the deceased-donor liver transplant.

On macroscopic examination of liver, cholestasis without nodular formation was observed (Figure 1). Microscopically, lobules were markedly disarrayed because of fibrous expansion of portal tracts, ground glass appearance of hepatocytes, and canalicular or intracytoplasmic cholestasis (Figure 2). Portal inflammation and cholangiolar proliferation were prominent.

The histopathologic alterations in fibrosing cholestatic hepatitis are characterized by marked hepatocyte ballooning (swelling), intracellular and canalicular cholestasis, and periportal and/or perisinusoidal fibrosis.^1,3 It is evident that the occurrence of fibrosing cholestatic hepatitis is underscored by the common thread of severe immunosuppression. It has been believed that uninhibited viral replication in hepatocytes is crucial for the initiation and progression of fibrosing cholestatic hepatitis.¹ The accumulation of abundant hepatitis B virus surface antigens within the endoplasmic reticulum and Golgi complex leads to stress of these organelles, resulting in apoptotic or necrotic death of hepatocytes in a relatively short time, thus causing progressive and rapid liver failure.¹

Hepatotoxicity (hepatic fibrosis and cirrhosis) associated with methotrexate is well recognized.^4,5 The frequency of transaminase elevation during methotrexate treatment is reported to be between 0.6% and 13%.⁴ Alcohol consumption, diabetes, obesity, chronic viral hepatitis, and medications such as arsenic and vitamin A have been reported as risk factors.⁶ The increased generation of reactive oxygen and nitrogen species, together with the decreased antioxidant defense, promotes the development and progression of hepatotoxicity.⁷ Increased hepatotoxicity of methotrexate has been reported during dexamethasone therapy in humans.⁸ Recent experimental study has demonstrated that corticosteroid administration produces a decrease in biliary excretion of methotrexate, which results in increased methotrexate content in liver.⁹ This effect, together with steroid-induced liver damage, may predispose to the observed acute hepatotoxicity of methotrexate.

The natural course of the current case resembled the previously reported cases of fibrosing cholestatic hepatitis. Various treatment modalities have been used to reduce hepatitis B virus effects and liver support in fibrosing cholestatic hepatitis. Liver transplant should be considered in patients with liver failure unresponsive to medical treatment. Clinicians should be mindful of potential hepatotoxicity of methotrexate and steroid therapy in hepatitis B virus infected patients.

Volume: 12 Issue: 1 March 2014 - Supplement - 1

FULL TEXT