Autoimmune-Like Hepatitis Following Allogeneic Hematopietic Stem Cell Transplantation: Different Manifestation From Hepatic Graft-Versus-Host Disease

Occasional cases of post-transplant liver dysfunction which resemble autoimmune hepatitis have been reported. Although pathologically indistinguishable from ‘definite’ autoimmune hepatitis, they occur with an alloimmune etiology because the liver is of recipient origin while the immune system is of donor origin (therefore, it is autoimmune “like” hepatitis (AILH) precisely). However, the incidence and clinical features of autoimmune-like hepatitis following allogeneic stem cell transplantation (allo-HSCT) are hitherto unknown. Therefore, the aim of this study was to investigate the characteristics of AILH after allo-HSCT mainly in comparison with hepatic GVHD.

A total of 66 patients (median age=38) with malignant (n=62) and benign (n=4) hematological disorders were enrolled in this study, who underwent liver biopsy because of liver complication after allo-HSCT at the Japanese Red Cross Nagoya First Hospital between 1991 and 2010. Fifteen of the 66 patients were autopsied. Because two patients received liver biopsy twice separately, 68 specimens were investigated. The clinical course, liver function tests (T-Bil, AST, ALT, ALP, γGTP, LDH), and response to the treatment were investigated in each case. Clinical characteristics of each pathological diagnosis, especially AILH and GVHD, were studied. AILH was pathologically diagnosed according to the revised International Autoimmune Hepatitis Group diagnostic criteria (interface hepatitis, predominantly lymphoplasmacytic infiltrates and resetting of liver cells), while hepatic GVHD was based on dysmorphic or destroyed small bile dusts with infiltration of CD8+ T cells forming lymphoepithelial lesions. The onset of the hepatic complications was defined as the day when three of the liver function tests changed abnormal.

Conditioning regimes were myeloablative (n=52), and reduced intensity (n=14). Donors were HLA-matched (n=51) and mismatched (n=15), related (n=39) and unrelated (n=27). Graft sources were bone marrow (n=54), peripheral blood (n=11), and cord blood (n=1). GVHD prophylaxis consisted of a combination of short-term methotrexase and tacrolimus (n=23) or cyclosporine (n=43). Pathological diagnosis of hepatic complications included AILH (n=5), GVHD (n=23), ischemic colangiopathy (n=11), VOD/SOS (n=6), steatohepatitis (n=4), and others (n=17). Comparing AILH with GVHD, the onset of AILH (median 320, range 133–2631) was significantly later than that of GVHD (median 90, range 29–422) (p=0.005). Consequently, the day of biopsy was also delayed significantly (AIH: median 349, range 187–2647; GVHD: median 133, range 34–586) (p=0.01) in the patients of AILH. Elevation of AST (AILH: median 628, range 508–1215; GVHD: median 289, range 107–1358) was significantly higher in patients with AILH than patients with GVHD (p=0.007). T-Bil (AILH: median 9.8, range 1.2–34.9; GVHD: median 3.3, range 1.2–31.6) and ALT (AILH: median 628, range 517–1586; GVHD: median 573, range 216–2065) were relatively higher in patients with AILH. Immunologically, two of four patients tested were positive for anti-smooth muscle antibody, and one patient out of four tested had a high anti-nuclear antibody titer (1:360) in AILH group. Three of five patients (60%) with AILH and eighteen of 23 patients (78%) with GVHD received steroid therapy and other patients received only supportive care. In patients received steroid therapy, all three patients (100%) improved in AILH group, while only 12 of 18 patients (66%) improved in GVHD group. In addition, all liver function tests were normalized in three patients with AILH (60%), while in only five patients with GVHD (22%). After a median follow-up of 7.4 years, the estimated 5-year OS was 31.4% in this whole cohort. The estimated 5-year OS was 75.0% in patients with AILH and 29.8% in patients with GVHD, respectively. Conclusion: AILH was not a rare hepatic complication following allo-HSCT because five cases (8.5%) in this study were diagnosed with AILH. Compared with GVHD, AILH showed later onset, and higher elevations of transaminases. Treatment with steroids dramatically improved hepatic dysfunction in AILH. Therefore, AILH is a disease entity different from hepatic GVHD, and it should be included in the differential diagnosis of hepatic complication after allo-HSCT.

No relevant conflicts of interest to declare.