Survival After Liver Transplantation for Autoimmune Hepatitis: Are We Messing With the Immune System? (2020)

See Article on Page 866 Potential conflict of interest: Nothing to report. Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) result from the interaction between genetic and environmental factors, but they differ greatly in clinical phenotype and target of autoimmune injury. In AIH, the autoimmune damage attacks the hepatocytes, leading to a clinically evident hepatitis. The aim of treatment in AIH is to obtain complete remission and to prevent further progression. The backbone of treatment is immunosuppressive therapy, including steroids, which is required in the long term for the majority of patients. Unfortunately, there is no curative treatment for AIH, and a significant number of patients eventually progress to end‐stage liver disease and liver transplantation (LT). In the present issue, Heinemann et al.(1) provide a longterm analysis of patient and graft survival after liver transplantation for autoimmune hepatitis (AIH‐LT). Using data from the multicenter European Liver Transplant Registry (ELTR), they included 2515 AIH‐LT patients at 170 centers in 32 European countries. In this impressive cohort, overall patient survival was reduced in AIH‐LT patients compared with PBC and PSC. Interestingly, survival of AIH‐LT patients was greatly impaired by infection, mainly during the first 90 days after LT. More than 5% of those early deaths in patients with AIH‐LT were attributable to fungal infections. Current management with immunosuppressive agents after LT has greatly improved graft and patient survival but has also increased the incidence of opportunistic infections, which remain the leading causes of morbidity and mortality after LT.(2) Fortunately, because of intensive screening practices and with the implementation of appropriate prophylactic therapy in LT candidates, mortality associated with post‐LT infections is currently below 10%.(3) In the present report, infections accounted for 29.5% of all deaths in AIH patients after LT. Recently, similar data were reported in the United States using the United Network for Organ Sharing (UNOS) database.(4) Surprisingly, these data differed with the experience coming from other solid organ transplantation recipients affected by nonhepatic autoimmune diseases,(5) and they might suggest a critical role of intrahepatic immunity in dealing with systemic infections after LT. The liver has a central role in combating severe infection in nontransplanted patients, and it is extremely important for the regulation of the immune response during sepsis.(6) Defense mechanisms including bacterial clearance and acute‐phase protein or cytokine production are initiated by the liver during microbial infection, and dysregulation of this articulated balance leads to increased sepsis‐related mortality, as seen in advanced cirrhosis.(6) An important difference between AIH and the other 2 immune‐mediated diseases considered in the present report, namely, PBC and PSC, remains steroids and other immunosuppressant use. Unfortunately, strategies for the management of immunosuppressant therapy in LT candidates are limited by the lack of a full knowledge of the AIH pathogenesis in the native liver. Furthermore, AIH‐LT patients are at an increased risk for graft rejection, and it is possible that crosstalk between alloimmune and autoimmune responses influence and perpetuate each other. Prevention of bacterial and fungal infections in AIH‐LT patients is key. The guidelines from the European Association for the Study of the Liver recommend oral prophylaxis against Candida species during the first months (evidence grade 2‐3), whereas prophylaxis against Aspergillus is only recommended in high‐risk situations like prolonged use of corticosteroids before transplantation (evidence grade 2‐3).(7) In contrast, the American Association for the Study of Liver Diseases recommends reserving fungal prophylaxis only for high‐risk individuals, which does not include AIH patients.(8) Culture remains the gold standard for a definitive diagnosis; however, sample acquisition is often invasive and loaded with a high rate of false negatives. Serology is of limited utility in this setting, and therapy is often challenging and influenced by drug‐drug interactions with immunosuppressant agents. Unfortunately, the ELTR does not include complete information regarding therapies and protocols. Although impressive in number of patients and duration of follow‐up, the study is a retrospective analysis of a prospectively collected cohort. Results may potentially be biased by the heterogeneity of treatments and patient management. There are still many open questions regarding listing and early management of AIH‐LT patients: What is the best protocol for acute infections? What is the role of longterm immunosuppressants? Should antibiotics be given prophylactically? What is the best timing for listing for transplantation? So, prospective studies are required. Unfortunately, these studies have largely been hampered by the heterogeneity in presentation and the natural history of the disease itself, its relative rarity, and the varying management between centers. Further research investigating the role of the liver during microbial infection as well as modifications in this response in LT recipients are crucial to improve the outcome of these patients.