Circulating Cell‐Free Mitochondrial DNA as a Prognostic Biomarker in Patients With HBV‐Related Acute‐on‐Chronic Liver Failure

Acute-on-chronic liver failure (ACLF), particularly hepatitis B virus-related ACLF (HBV-ACLF), is a severe condition with high short-term mortality. This study aimed to evaluate the prognostic value of circulating cell-free mitochondrial DNA (cf-mtDNA) in predicting short-term mortality in HBV-ACLF patients. A total of 320 HBV-ACLF patients were included in the study population, with 192 patients in the derivation cohort and 128 in the validation cohort. Plasma cf-mtDNA levels were quantified using qPCR. Plasma cf-mtDNA levels were significantly elevated in HBV-ACLF patients (3.95 log₁₀ copies/μL) compared to healthy controls (2.99 log₁₀ copies/μL) and patients with chronic liver disease (3.03 log₁₀ copies/μL) (p < 0.001). Plasma cf-mtDNA levels progressively increased with disease severity and were associated with multi-organ failure. Sequential measurements of cf-mtDNA showed a significant decrease in survivors (4.00 vs. 3.78 log₁₀ copies/μL, p = 0.019), while non-survivors maintained persistently elevated levels with minimal change (4.19 vs. 4.15 log₁₀ copies/μL, p = 0.359). The cut-off value of 3.9 log₁₀ copies/μL for cf-mtDNA effectively stratified patients into high- and low-risk groups, with significantly lower survival rates in the high-risk group (28-day: 46.2% vs. 86.0%, p < 0.001; 90-day: 37.7% vs. 72.1%, p < 0.001). Using cf-mtDNA in combination with key clinical parameters, we developed a novel prognostic score that exhibited superior predictive accuracy for 28- and 90-day mortality (AUROCs: 0.907 and 0.906, respectively), outperforming established prognostic scores (all p < 0.05). These findings were validated in an independent cohort. Cf-mtDNA is a superior biomarker for predicting short-term mortality in HBV-ACLF. Its association with multi-organ failure and disease severity highlights the potential utility in early risk assessment and treatment optimization.