Treatment of fulminant autoimmune hepatitis: Corticosteroid therapy or liver transplantation
Yen-Nien Lin1, Chun-Lung Feng2, Ken-Sheng Cheng2, Jen-Wei Chou2 Chang-Hu Hsu2, Cheng-Yuan Peng2, Horng-Ren Yang3,4, Long-Bin Jeng3,4
1Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
3Department of Surgery, China Medical University Hospital, Taichung, Taiwan 4 Organ transplantation center, China Medical University Hospital, Taichung, Taiwan
Corresponding author: Dr. Jen-Wei Chou, M.D.
Division of Gastroenterology and Hepatology, Department of Internal Medicine
China Medical University Hospital, No. 2, Yuh-Der Road, North District, Taichung 40447, Taiwan. E-mail: codecol@yahoo.com.tw
Telephone: + 886-4-22052121, ext. 2220; Fax: +886-4-22023119
Conflicts of interest: None to declare
Keywords: autoimmune hepatitis, fulminant hepatic failure, liver transplantation,
corticosteroid, plasma exchange
Autoimmune hepatitis initially presenting as fulminant hepatic failure is rare in clinical practice. It is known to have a rapid progressive disease course, high mortality/morbidity rate, and it mostly necessitates liver transplantation. Early definite diagnosis of this disease is of the greatest importance and prompt intervention with corticosteroid therapy is the only documented treatment. However, although corticosteroid is a good therapeutic agent, it can sometimes overlook any future treatment. It can delay the timing of liver transplantation and precipitate postoperative complications. Whether corticosteroid therapy should be administered or not is a subject of debate. Here, we report a case of a 41-year-old female who presented with severe jaundice. Her clinical and laboratory findings were consistent with fulminant hepatic failure and fulfilled the criteria of autoimmune hepatitis. Despite adequate medication and plasma exchange therapy, her symptoms and laboratory findings deteriorated. Her condition improved after receiving orthotopic liver transplantation. We also reviewed the English literature on this rare disease.
Fulminant hepatic failure is a rare complication of autoimmune hepatitis (AIH). This acute severe form of AIH can develop from de novo inflammation or by transformation from an exacerbated chronic inflammation. It usually presents with characteristic laboratory features (high serum aminotransaminase, total bilirubin, and prolonged prothrombin time) and histological findings (more frequent centrilobular zone 3 necrosis with plasmacytic infiltration and bile duct injury) [1]. Although corticosteroid therapy is effective in patients with AIH, some with fulminant hepatic failure do not respond to the therapy [2,3] and eventually require orthotopic liver transplantation (OLT). Here, we describe a case of AIH presenting as fulminant hepatic failure that finally recovered after OLT. In this report, we discuss the role of corticosteroid therapy and OLT in treating fulminant AIH. In addition, we emphasize that care should be taken that any preoperative intervention should not delay OLT or precipitate postoperative complications.
In March 2010, a 41-year-old woman visited our emergency department with a 7-day history of yellowish skin and tea-colored urine. Since a month before this presentation, she was suffering from poor appetite, malaise, and epigastralgia. She denied having fever, dyspnea, habit of alcohol consumption, and history of intravenous drug abuse or liver disease. She had taken some herbal medicines, but they did not improve her condition. Moreover, she lost 4 kg of weight within a month. At 7 days before admission at our department, she developed yellowish skin with general itching and tea-colored urine. On admission, physical examination revealed that her consciousness was clear. Her vital signs were as follows: body temperature, 36.3 °C; blood pressure, 118/82 mmHg; pulse rate, 79 beats per min; and respiration rate, 18 breaths per min. Her conjunctivae were pink, and her sclerae were icteric. The results of her heart and chest examinations were normal. Her abdomen was distended with mild tenderness. There was no palpable liver or spleen. Her limbs did not show pitting edema. Laboratory test results were as follows: serum total bilirubin, 17.4 mg/dL (reference range, 0.2–1.3), with 60% fraction of direct bilirubin; alanine aminotransferase (ALT), 1031 IU/L (0–40); aspartate aminotransferase (AST), 1261 IU/L (0–35); alkaline phosphatase, 168 IU/L (38–126); -glutamyltransferase, 118 IU/L (8–50); lactate dehydrogenase, 227 IU/L (98–192); albumin, 3.1 g/dL (3.5– 4.9); globulin, 3.8 g/dL (2.5–3.5); and prothrombin time, 19 s with an international normalized ratio of 2.12. Serum protein electrophoresis revealed increased level of polyclonal -globulin (2.5 g/dL; reference range: 0.7–1.3). Serological examinations were negative for viral and metabolic makers of liver disease. The serum levels of immunological markers were as follows: immunoglobulin (Ig) G, 2180 mg/dL (751–1560); IgA, 410 mg/dL (82–453); and IgM, 293 mg/dL (46–304). Moreover,
anti-nuclear antibodies (ANA) were positive at a titer of 1:640 with a homogenous pattern, and 1:80 with a cytoplasmic pattern. Anti-smooth muscle antibodies (ASMA) were moderately elevated at a titer of 1:80, whereas the titer of anti-mitochondrial antibodies was 1:80. Abdominal ultrasonography showed parenchymal liver disease without cirrhotic change and ascites. On the basis of the laboratory findings, the patient was diagnosed as having acute fulminant form of type I AIH. Although we prescribed a 5-day intravenous administration of stronger neo-minophagen C (60 mL/day) and daily transfusion of fresh frozen plasma, her hepatic failure progressed. She developed stage II hepatic encephalopathy, and her serum total bilirubin level peaked at 29.8 mg/dL on hospital day 13. Therefore, she was transferred to our intensive care unit for aggressive treatment. Plasma exchange (PE) therapy of 20 units/day and administration of intravenous hydrocortisone (150 mg/day) were started immediately on hospital day 14. The following day, her encephalopathy progressed to stage IV with an international normalized ratio (INR) of 4.0 despite the mild decline in serum bilirubin level. Therefore, the patient’s family was informed that OLT would be required. Preoperative abdominal computed tomography scanning revealed mild atrophy of the liver and mild ascites. Finally, on hospital day 15, the patient received a living-donor liver transplant from her younger brother. The explanted liver was shrunken, measuring 17.5 × 13.0 × 6.0 cm in size and 520 gm in weight (Figure 1). The explanted liver showed no cirrhotic changes or tumor mass on cutting. Histopathological examination of the resected liver showed massive hepatocellular necrosis with infiltration of numerous inflammatory cells (Figure 2). The encephalopathy, coagulopathy, and serum bilirubin level of the patient improved dramatically after OLT. The patient was discharged uneventfully on hospital day 31, and
the liver function of her brother returned to normal one month later (Figure 3).
Discussion
AIH is a generally progressive, chronic inflammatory liver disorder of unknown cause that fluctuates in disease activity with time. AIH has a broad spectrum of presentations ranging from asymptomatic to fulminant hepatic failure. Most patients with AIH show clinical features of chronic hepatitis, but after the 1990s, some patients were reported to have acute, rarely fulminant, hepatitis with jaundice and marked elevation of serum transaminase level [4–6]. On the basis of the pattern of circulating autoantibodies, this disease can be classified into 2 main types: Type I (ANA and ASMA) and Type II [anti-liver-kidney microsome-1 antibodies (ALKM-1) and/or anti-liver cytosol-1 antibodies (ALC-1)]. According to previous literature, type II AIH is believed to be associated more frequently with acute fulminant presentation [7,8]. In recent years, type I AIH has also been reported to frequently present with fulminant hepatic failure [2,9]. In our case, type I AIH was considered on the basis of the presence of ANA and ASMA.
Since these fulminant, acute forms of AIH respond poorly to traditional treatments and have high mortality rate, early diagnosis and close surveillance should be over-emphasized. The International Autoimmune Hepatitis Group (IAHG) established a cumulative score system to facilitate easy diagnosis [10,11]. Several parameters have also been introduced for AIH to differentiate it from acute viral hepatitis, for which corticosteroid is contraindicated. These parameters are especially useful in the cases in which liver biopsy cannot be performed due to coagulopathy, or in which serum autoantibody study cannot be performed to confirm the diagnosis. Some of the reported parameters are as follows: gender, serum γ-globulin level, and AST/ALT ratio [12]. In
our case, the patient presented with an IAHG score of 17, -globulin level of 2.5 g/dL, and an AST/ALT ratio of 1.22, which was suggestive of definite AIH with acute presentation that warranted immediate therapy and frequent scrutiny.
Corticosteroid therapy alone or in combination with azathioprine is established as an effective treatment that suppresses inflammatory activity in 36–100% of AIH patients [2,3,13]. However, the therapeutic response reduces if the diagnosis and treatment are delayed [14]. Efforts are being made to improve the results by facilitating early diagnosis and intervention; management of the adverse effects of drugs; prevention of disease relapse; and introduction of alternative medication, including cyclosporine, tacrolimus, mycophenolate mofetil, and cyclophosphamide [15–18]. In the cases of AIH presenting as fulminant hepatic failure, the role of corticosteroid remains a subject of debate. Recent researches indicated that corticosteroid therapy is of little benefit and can delay OLT [2,3]. However, this result was criticized as the uncertainty of diagnosis of reported AIH may underestimate the corticosteroid response [19]. Czaja et al. suggested a 2-week or less corticosteroid trial was beneficial, and it was also helpful in predicting the indication of OLT [20]. Because of the risk of septic complication and the high serum bilirubin level on admission, we did not prescribe corticosteroid therapy to our patient and instead administered stronger neo-minophagen C therapy. We could have started corticosteroid therapy immediately after AIH was diagnosed but we instead prepared for OLT. The entire treatment course was uneventful, and the patient remained free of septic episodes. Her encephalopathy and laboratory findings improved after the operation, and she was discharged uneventfully at 14 days after the operation. OLT is an essential option for patients with fulminant hepatic failure, but the optimal timing of transplantation is
difficult to determine. The criteria established by King’s College Hospital are the most commonly used score system for general patients [21]. In the setting of AIH with fulminant hepatic failure, the Model of End-Stage Liver disease (MELD) scoring system was introduced, according to which those patients with a score of 12 points at presentation required liver transplantation [22]. Hyperbilirubinemia that does not improve or that worsens during the treatment course has been highly predictive of early mortality (100%) and also warrants urgent OLT [20]. Miyake et al. suggested that patients whose total bilirubin levels worsen during days 8–15 after the start of therapy should be considered for OLT [2]. OLT should not be delayed if the condition of AIH patients exacerbated after 2 weeks of corticosteroid therapy or if the MELD score increased [19,23,24]. In our present case, the MELD score was 26 on admission. The patient received OLT on hospital day 17 with the preoperative MELD score of 36 and hepatic encephalopathy at stage IV. Histopathological examinations of the resected liver tissue revealed massive necrosis and loss of identifiable hepatic architecture, suggesting relatively delayed OLT.
PE therapy is an extracorporeal blood purification technique designed for the removal of large-molecular-weight substances from the plasma. It is usually performed to allow liver regeneration or in the cases awaiting liver transplantation, especially in neurologic, immunologic, or hematologic diseases [25]. The clinical application of PE therapy in acute or chronic liver failure caused by viral hepatitis, toxins, or drugs is controversial; however, it has been reported [26]. Whether recovery in these patients is related to hepatocyte repair and regeneration is uncertain. However, the mechanisms by which PE therapy contributes to recovery remain unclear. This technology may be
considered to correct coagulopathy and possibly remove various toxins from the systemic circulation. Besides its use for the treatment of AIH, PE therapy has also been used to treat other autoimmune diseases such as adult onset Still’s disease [27]. However, it has never been used for treating the fulminant form of AIH. We attempted to perform PE therapy for treating hepatic failure in our patient, but discontinued it fearing that it might delay the time of OLT.
In conclusion, fulminant hepatic failure is a rare complication of AIH. Early diagnosis, excluding fulminant viral hepatitis, is beneficial for the outcome of AIH. OLT is the most essential life-saving treatment in patients with hepatic failure. The use of corticosteroid therapy or PE therapy is still controversial in treating fulminant form of AIH. High MELD score and poor treatment response of corticosteroid therapy are indicators of poor prognosis and need of prompt OLT. Moreover, the preoperative interventions should be applied carefully ensuring that they do not delay OLT or precipitate postoperative complications such as infection, bleeding, or poor wound healing.
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Figure Legends
Figure 1. The explanted liver was shrunken, measuring 17.5 × 13.0 × 6.0 cm in size and
520 gm in weight.
Figure 2. Microscopic sections of the resected liver specimens showed massive
hepatocellular necrosis with collapse, proliferation of the bile ducts, and infiltration of numerous inflammatory cells (hematoxylin and eosin (H&E) staining; ×200).
Figure 3. The time course of changes in the serum levels of liver enzymes and total
