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Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment.

ABSTRACT: Autoimmune hepatitis (AIH) is a rare disease characterized by an immune attack of the liver. This study consists of a comprehensive analysis of immune alterations related to AIH at diagnosis, and during remission phase under treatment. A total of 37 major lymphocyte populations were analyzed from the peripheral blood of new-onset AIH patients (AIHn; n = 14), AIH patients with controlled disease (n = 11), and healthy subjects (n = 14). Liver biopsy analyses were performed to complete the blood phenotypic analysis. Four blood lymphocyte populations were significantly altered in AIHn patients at diagnosis compared with healthy subjects. Levels of mucosal-associated invariant T cells (MAIT), Type 1/Type 17 helper (Th1/ Th17) cells, clusters of differentiation (CD4) T cells, and invariant natural killer T cells were decreased, whereas MAIT granzyme B+ (GrB) cells were increased. A trend toward an increase of CD8+CD161+GrB+ cells was also observed. These alterations were not restored with standard immunosuppressive treatments. In the liver of AIHn patients, CD4, forkhead box P3 (Foxp3), and MAIT cell markers were enriched in the portal tract, and CD8, CD161, and GrB markers were enriched in the hepatic lobule. During remission, the hepatic lobule was clear of infiltrating T cells, but residual CD4 and MAIT cells were found in the portal tract, where Foxp3 was decreased, as previously described. In vitro, MAIT cells were functionally altered in AIH patients. Ex vivo MAIT cell activity (GrB) was linked to severe fibrosis. Conclusion: Our work proposes a global view of the lymphocyte alterations from diagnosis to remission phase in AIH patients. The absence of blood immune homeostasis restoration and the persistence of a CD4 infiltrate in the liver under standard immunosuppression could form the basis of the high risk of relapse observed in AIH. (Hepatology Communications 2018; 00:000-000).

SUBMITTER: Renand A

PROVIDER: S-EPMC6078209 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment.

Renand Amédée A Habes Sarah S Mosnier Jean-François JF Aublé Hélène H Judor Jean-Paul JP Vince Nicolas N Hulin Philippe P Nedellec Steven S Métairie Sylvie S Archambeaud Isabelle I Brouard Sophie S Gournay Jérôme J Conchon Sophie S

Hepatology communications 20180806 8

Autoimmune hepatitis (AIH) is a rare disease characterized by an immune attack of the liver. This study consists of a comprehensive analysis of immune alterations related to AIH at diagnosis, and during remission phase under treatment. A total of 37 major lymphocyte populations were analyzed from the peripheral blood of new-onset AIH patients (AIHn; n = 14), AIH patients with controlled disease (n = 11), and healthy subjects (n = 14). Liver biopsy analyses were performed to complete the blood ph ...[more]

PMID: 30094407

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Project description:Background and aimsDecompensated cirrhosis in autoimmune hepatitis has poor prognosis. Besides liver transplant, treatment for this entity is undefined. We explored the outcomes of autoimmune hepatitis (AIH)-related decompensated cirrhosis with active disease on treatment with steroids.MethodsIn this retrospective analysis, clinical data, laboratory parameters, and prognostic scores, such as baseline model for end-stage liver disease (MELD) scores, were compared among patients of AIH with decompensated cirrhosis with mild/no ascites (n = 38), gross ascites (n = 24), and compensated cirrhosis (n = 32) when administered steroids. The primary outcome was transplant-free survival at 12 months. Biochemical remission rates and other adverse events were also assessed and compared between these groups.ResultsSteroids were initiated at lower doses (25 mg/day-mild/no ascites, 20 mg/day-gross ascites) in patients with decompensated cirrhosis and at 40 mg/day in those with compensated cirrhosis. Transplant-free survival was 25.4%, 74.6%, and 96.9% (P = 0.001), and biochemical remission occurred in 5.1%, 49.0%, and 64.1% (P = 0.001) at 12 months in patients with gross ascites, mild/no ascites, and compensated cirrhosis, respectively. Infections were seen more frequently in decompensated cirrhosis, while other adverse events were comparable. Among decompensated cirrhosis, those with mild/no ascites had better prognostic scores, fewer posttreatment infections, and more frequent biochemical remission than those with gross ascites, achieving rates comparable to compensated cirrhosis. On multivariate analysis, the MELD score (subdistributional hazards ratio [sHR]; 95% confidence interval: 1.153 [1.07-1.24]; P = 0.001) and ascites (sHR: 2.556 [1.565-5.65]; P = 0.020) predicted survival.ConclusionType and severity of decompensation affect outcomes in patients with AIH-related cirrhosis. Those with mild/no ascites have comparable outcomes to those with compensated cirrhosis upon treatment with low-dose steroids.

Project description:Autoimmune hepatitis (AIH) is a chronic hepatitis with an increasing incidence. The majority of patients require life-long immunosuppression and incomplete treatment response is associated with a disease progression. An abnormal iron homeostasis or hyperferritinemia is associated with worse outcome in other chronic liver diseases and after liver transplantation. We assessed the capacity of baseline parameters including the iron status to predict the treatment response upon standard therapy in 109 patients with untreated AIH type 1 (AIH-1) in a retrospective single center study. Thereby, a hyperferritinemia (> 2.09 times upper limit of normal; Odds ratio (OR) = 8.82; 95% confidence interval (CI): 2.25-34.52) and lower immunoglobulins (<1.89 times upper limit of normal; OR = 6.78; CI: 1.87-24.59) at baseline were independently associated with the achievement of complete biochemical remission upon standard therapy. The predictive value increased when both variables were combined to a single treatment response score, when the cohort was randomly split into a training (area under the curve (AUC) = 0.749; CI 0.635-0.863) and internal validation cohort (AUC = 0.741; CI 0.558-0.924). Patients with a low treatment response score (<1) had significantly higher cumulative remission rates in the training (p<0.001) and the validation cohort (p = 0.024). The baseline hyperferritinemia was accompanied by a high serum iron, elevated transferrin saturations and mild hepatic iron depositions in the majority of patients. However, the abnormal iron status was quickly reversible under therapy. Mechanistically, the iron parameters were not stringently related to a hepatocellular damage. Ferritin rather seems deregulated from the master regulator hepcidin, which was down regulated, potentially mediated by the elevated hepatocyte growth factor. In conclusion, baseline levels of serum ferritin and immunoglobulins, which are part of the diagnostic work-up of AIH, can be used to predict the treatment response upon standard therapy in AIH-1, although confirmation from larger multicenter studies is pending.

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Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment.

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Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment.

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