Sex, Ethnicity and Clinical Outcomes in Autoimmune Hepatitis: Results from a Large, Multicenter, Longitudinal Cohort Study in Canada

Introduction: Autoimmune hepatitis (AIH) is a rare, chronic liver disease characterized by inflammation and immune-mediated damage of the liver tissue. AIH affects both sexes and all ages and ethnicities; although disease characteristics, progression and outcomes vary between these populations. The disease has an acute or chronic progressive course and may eventually lead to progressive liver fibrosis, cirrhosis and/or liver decompensation with some patients requiring a liver transplant (LT). Sex and ethnicity have been shown to affect the survival and clinical outcomes of other liver diseases; however, their influence on the progression of AIH is unclear. The aims of this thesis were to analyze the clinical significance of sex and ethnicity on treatment response and adverse clinical events in patients with AIH. Methods: We conducted a retrospective and prospective cohort study of patients with AIH from the Canadian Network for Autoimmune Liver disease (CaNAL). CaNAL is a collaboration between 15 academic and clinical liver care centers across Canada to create a large, national registry of people living with autoimmune liver diseases including AIH. We collected key demographic variables including sex and ethnicity and clinical and outcome variables, such as laboratory parameters (alanine transaminase (ALT)), development of cirrhosis and liver decompensation, LT, hepatocellular carcinoma (HCC) and death. We defined an adverse clinical event as a composite endpoint that included the development of decompensation, LT, HCC or death. A univariate and multivariate Cox regression was conducted to examine associations between sex and ethnicity and adverse clinical events. Results: Using a cohort of 1198 patients with AIH, we found that in comparison to females, males were younger at the time of AIH diagnosis (39.2 ± 19.5 vs. 45.0 ± 18.3 years, p<0.001); a higher proportion of males also developed HCC (4.0% vs. 1.8%, p=0.045) and underwent LT (19.3% vs. 9.1%, p<0.001). Male patients also demonstrated a lower treatment response compared to females (36.6% vs. 56.7%, p<0.001). In the multivariate analysis, male sex was associated with a higher risk for the development of an adverse clinical event such as liver decompensation, LT, HCC or death (HR 2.05, 95% CI 1.31-3.19, p=0.002). Compared to the White ethnicity, only Indigenous patients had a higher risk of developing an adverse clinical event in the multivariate analysis (HR 2.91, 95% CI 1.04-8.16, p=0.043). A greater proportion of Indigenous patients also had decompensation at diagnosis (23.5% vs. 8.5%, p=0.008), developed decompensation over the course of the disease (34.6% vs. 18.0%, p=0.040), underwent LT (26.5% vs. 11.3%, p=0.013) and died (26.5% vs. 13.0%, p=0.036) compared to non-Indigenous patients, but there was no significant difference in treatment response (60.0% vs. 51.4%, p=0.752). Conclusions: Male patients with AIH have a higher risk of developing adverse clinical events such as liver decompensation, HCC, LT or death and have a lower treatment response compared to females. From the ethnicity perspective, Indigenous patients with AIH have a higher risk of developing adverse clinical events compared to other ethnicities. Our results warrant consideration of tailoring treatment and follow-up strategies according to risk stratifications by sex and ethnicity in order to improve clinical outcomes and survival for at-risk groups, such as males and Indigenous patients.

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