Introduction

Graft-versus-host disease (GvHD) has historically been categorized as either acute or chronic, based on the temporal pattern of manifestations. Acute GvHD is operationally defined as the manifestation of the disease within 100 days following transplantation, whereas chronic GvHD is characterized by its onset occurring 100 days after the commencement of the intervention. In the context of chronic GvHD, prominent involvement is often observed in vital organs such as the liver, gastrointestinal tract, skin, mucosal surfaces, lungs, and bone marrow, although their manifestations may not invariably co-occur. Among the diverse array of GvHD subtypes, chronic liver GvHD has been the subject of extensive investigation and has gained recognition for its characteristic presentation of a gradual or sudden onset of jaundice accompanied by an elevation in alkaline phosphatase (ALP) levels [1,2].

Hepatic GvHD, classified based on clinical features, can manifest in three distinct ways. The first presentation, referred to as typical acute GvHD, is characterized by elevated levels of alkaline phosphatase (ALP) and total bilirubin, along with mild increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). This type typically occurs within the initial two weeks following stem cell transplantation and is frequently accompanied by symptoms such as skin rash and diarrhea. The second presentation, known as the hepatitic variant, is defined by a notable elevation in AST and ALT levels, with a minimal rise in ALP. This variant typically arises during the period of immunosuppression tapering. Unlike typical acute GvHD, the simultaneous occurrence of skin and gastrointestinal symptoms is infrequent in this variant. The final presentation, identified as chronic GvHD, is characterized by a progressive escalation in ALP levels, followed by the onset of jaundice [2]. However, the distinct histopathological findings in hepatitic variant GvHD can occasionally resemble those observed in autoimmune hepatitis. In this report, we present a case of chronic liver GvHD that presented as acute hepatitis and exhibited a favourable response to an autoimmune hepatitis treatment regimen. This unfamiliar diagnosis presents a significant clinical challenge.

Case Report

A 31-year-old Thai male patient was diagnosed with myelodysplastic syndrome (MDS) classified as intermediate risk according to the International Prognostic Scoring System (IPSS). Initially, treatment with decitabine, a nucleic acid synthesis inhibitor, was administered but resulted in severe febrile neutropenia and bleeding as complications. Subsequently, the patient underwent peripheral hematopoietic stem cell transplantation (HSCT) with a sibling who matched in terms of human leukocyte antigen (HLA) compatibility. The allogeneic HLA-identical HSCT took place in February 2021, preceded by pre-transplant chemotherapy consisting of busulfan and cyclophosphamide. The transplantation procedure proceeded without noteworthy incidents. Both the patient and the donor tested negative for hepatitis B/C and cytomegalovirus, and their liver function tests yielded normal results. There was no family history of autoimmune disease. The initial post-transplant period was uneventful, with successful neutrophil engraftment occurring on day 20 and platelet engraftment on day 31. No infections or complications related to acute GvHD were observed. To prevent GvHD, the patient received cyclosporin A (CsA) along with a short course of methotrexate. The duration of CsA treatment spanned approximately 2 months, during which liver function tests were carefully monitored while gradually tapering off the medication. In July 2021, precisely 153 days after the HLA-identical HSCT, the patient, who was currently receiving a daily dose of 25 mg of CsA, presented with symptoms of fatigue and jaundice. The blood chemistry analysis revealed significant elevations in ALT (1,022 U/L), AST (606 U/L), ALP (198 U/L), total bilirubin (2.06 mg/dL), direct bilirubin (1.47 mg/dL), albumin (4.2 g/ dL), and globulin (3.9 g/dL). There were no indications of other chronic GvHD manifestations, such as skin rash or diarrhea. The differential diagnosis for the acute hepatocellular injury, which occurred nearly 6 months after the engraftment of the bone marrow, encompassed CsA-induced hepatotoxicity, acute viral hepatitis (HAV/HBV/HEV), reactivation of other viruses (cytomegalovirus, herpes virus, or Epstein-Barr virus), or a distinct presentation of GvHD, particularly the hepatitic variant of liver GvHD, which raised concerns. However, it appeared unlikely that CsA was the causative agent, given that the drug level fell within the normal range (168 ng/mL, range 100-450), and adverse toxicity typically presents as cholestatic hepatic injury. Serological tests, as well as tests for viral DNA and RNA (which yielded negative results for Anti-HBc IgM, Anti-HEV IgM, Anti-HAV IgM, HSV-1&2 IgM, EBV - Capsid IgM, HBV DNA, HCV RNA, and CMV RNA), ruled out viral hepatitis. An abdominal ultrasound suggested the presence of liver parenchymal disease without a definitive spaceoccupying lesion. Following inconclusive laboratory results, a liver biopsy was conducted, revealing histopathological findings indicative of moderate portal infiltration characterized by a significant presence of lymphocytes, plasma cells, and eosinophils. These cellular infiltrations were accompanied by moderate interface hepatitis and lobular inflammation, further supported by evidence of bile duct injury and endothelitis (refer to Figure 1&2). Immunostaining analysis targeting inflammatory cells exhibited positive results for CD4 and CD8 T cells, CD138 plasma cells, and a few CD20 B cells specifically localized in periportal areas (refer to Figure 1,2). These notable pathological findings led the suspicion of autoimmune hepatitis as the underlying etiology of the patient’s condition. Consequently, serum tests were performed to detect autoantibodies, yielding the following results: a positive antinuclear antibody (ANA) titer of 1:160 with a fine speckled pattern, a negative anti-smooth muscle antibody (SMA), and a positive anti-liver kidney microsomal-1 antibody (LKM-1). Furthermore, the patient’s serum immunoglobulin G (IgG) level was measured at 2,060 mg/dL, surpassing the normal range of 700-1,600 mg/dL. The histopathological findings, along with the presence of autoantibody markers, provided compelling evidence supporting a diagnosis of autoimmune hepatitis as opposed to hepatitic variant liver graft-versus-host disease (GvHD). The patient’s International Autoimmune Hepatitis Group (IAIHG) simplified score of 8, which corresponds to a classification of “definite” autoimmune hepatitis, guided the initiation of treatment with prednisolone at a dosage of 0.5 mg/kg/day. Remarkably, following a two-week course of corticosteroid therapy, there was a profound normalization observed in the levels of ALT/AST and bilirubin. Consequently, a gradual tapering of the prednisolone dosage to 10 mg/day was implemented, accompanied by the maintenance administration of azathioprine at a daily dose of 100 mg (equivalent to 1 mg/kg/day). Throughout an ensuing 6-month follow-up period, the patient’s clinical condition remained stable without any notable exacerbations or complications.

Figure 1: Histopathological Findings

Figure 2: Immunostaining Analysis

Table 1: Summary of case reports; clinical details, laboratory results, and treatment.