What determines survival in autoimmune liver disease overlap syndromes: A critical commentary

Abstract

Recently, Jayabalan et al published an important study. The authors defined the liver outcome score as a novel biomarker for predicting liver-related mortality in patients with autoimmune hepatitis-primary biliary cholangitis overlap syndrome. After thoroughly reviewing their work, we offer insights that primarily relate to their study design to enhance the medical community’s understanding of this complex disease.

Key Words: Autoimmune liver disease overlap syndromes; Autoimmune hepatitis; Primary biliary cholangitis; Primary sclerosing cholangitis; Criterion; Interventions; Comment

Core Tip: We thoroughly reviewed the study by Jayabalan et al and highlighted several aspects that require clarification, including the exclusion criteria, diagnostic criteria for patient inclusion, and the potential impact of medical interventions on mortality outcomes during follow-up. Addressing these methodological considerations strengthens the validity and generalizability of the findings. In addition, we propose suggestions for guiding future research in this field.

TO THE EDITOR

We have thoroughly read the article by Jayabalan et al[1] with great interest and wish to extend our gratitude to the authors for their commendable endeavor. We prospectively investigated predictors of survival in patients with autoimmune liver disease (AILD) overlap syndrome[1]. This study's conclusion suggests that the liver outcome score (LOS) has potential as a predictive tool for liver-related mortality in individuals with autoimmune hepatitis (AIH) and primary biliary cholangitis overlap (AIH-PBC) syndromes[1]. However, several aspects of this study require further investigation to strengthen the overall findings.

IMPACT OF STRINGENT EXCLUSION CRITERIA ON THE CREDIBILITY OF STUDY RESULTS

The exclusion criterion was a history of liver transplantation prior to enrollment[1]. We hypothesized that some enrolled patients might have concurrent liver pathologies of other causes, such as alcoholic liver disease or viral hepatitis. Previous studies have reported that viral infections can trigger the development of AIH, with hepatitis C virus (HCV) infection being particularly associated with the activation of latent AIH[2]. In addition, patients with AIH and hepatitis B virus infection tend to have a better prognosis than those with HCV infection[2]. Notably, Batskikh et al[3] reported that 26.1% of patients with AILD were antibody against hepatitis B core antigen (anti-HBc)-positive, with notably higher seropositivity in the PBC subgroup than in the overall AILD cohort (P < 0.05). Among patients with AILD, 46.6% exhibited advanced fibrosis (METAVIR F3-F4), and patients with PBC and F3-F4 fibrosis presented significantly elevated anti-HBc positivity rates compared to those with early stage fibrosis (P < 0.05). A noteworthy multicenter study from China revealed that patients with AILD-induced cirrhosis exhibited a significantly lower prevalence of acute-on-chronic liver failure (ACLF) than the pooled cohort of patients with cirrhosis, across all etiology groups (14% vs 22.8%, P < 0.001)[4]. ACLF demonstrated a strong independent association with an elevated short-term mortality risk. Therefore, we posit that non-autoimmune etiologies may perturb hepatic synthetic and fibrotic biomarkers - specifically serum albumin reduction, γ-glutamyltransferase, and hyaluronic acid elevation. Since these biochemical alterations could mediate increased LOS and adversely affect clinical prognosis, thus potentially introducing bias in outcome assessments, we suggest that patients with potential liver injuries of other etiologies should be excluded, to ensure the accuracy and reliability of the study results.

COMPARATIVE VALIDATION OF DIAGNOSTIC CRITERIA ENHANCES THE GENERALIZABILITY OF RESEARCH OUTCOMES

In their study, the diagnoses of AIH, PBC, and primary sclerosing cholangitis (PSC) were established in accordance with the criteria stipulated by the International AIH Group, the European Association for the Study of the Liver Clinical Practice Guidelines, and the American College of Gastroenterology Clinical Guidelines, respectively[1,5-7]. Given the global nature of AILDs and their varying prevalence and management strategies across regions, the diagnostic criteria should prioritize region-specific guidelines endorsed by local hepatic associations. In the absence of validated regional criteria, it is advisable to adopt diagnostic standards from epidemiologically comparable geographic or ethnic populations, to enhance clinical applicability. We recommend that future studies implement comparative analyses of diverse diagnostic criteria to optimize patient selection and outcome interpretation, thereby strengthening the cross-population applicability of research findings. This would also allow for a more nuanced understanding of the impact of diagnostic variability.

IMPACT OF MEDICAL INTERVENTIONS ON STUDY OUTCOMES

The author’s analyses focused solely on liver-related mortality, without considering the potential impact of medical interventions on mortality outcomes during follow-up[1]. However, it is crucial to examine how these interventions influence study outcomes, and a thorough assessment of the medical treatments in the patients is necessary to ensure the accuracy and robustness of the findings. Beyond liver transplantation, the mainstay therapies for AILD consist of immunosuppressive regimens (e.g., prednisolone/azathioprine) for AIH and ursodeoxycholic acid (UDCA) as first-line therapy for PBC[8]. Heterogeneity in treatment status and therapeutic response within this cohort directly influences clinical endpoints, thus potentially compromising the predictive validity of the LOS for prognostic assessment. Therefore, we recommend stratifying future analyses by treatment parameters that include: (1) Immunosuppressant classes/duration; (2) UDCA utilization patterns; and (3) Concomitant therapies.

LARGE-SCALE, MULTI-CENTER PROSPECTIVE COHORT STUDIES ARE NEEDED TO VALIDATE AND EXTEND RESEARCH FINDINGS

The authors noted that the main limitation of their study was its relatively small sample size[1]. To address this issue, future research should include larger and more diverse study cohorts and adopt a multicenter design, to validate the findings and improve our understanding of the relevance of LOS in the prognosis of patients with AIH-PSC. The study cohort comprised 22 participants, who were likely constrained by the low epidemiological prevalence of the disease. Based on power calculations that accounted for projected attrition rates and population prevalence metrics, we recommend sample sizes of 50 or more individuals, when possible, to achieve statistical robustness (α = 0.05, β = 0.2). To enhance generalizability, we recommend augmenting the cohort diversity through multicenter designs that encompass ethnographically distinct populations. Concurrently, the integration of real-world evidence from heterogeneous healthcare settings should be prioritized to address the selection bias inherent in single-center studies, and we suggest that authors investigate the relationship between LOS and complications in these patients. We look forward to the results of future large-scale multicenter studies.

CONCLUSION

LOS has presented significant potential as a novel biomarker for predicting liver-related mortality in patients with AIH-PBC. Further rigorous research is required to confirm the validity of this conclusion.