What are the novel markers for diagnosing acute on chronic liver failure (ACLF)?

Novel Markers of Acute-on-Chronic Liver Failure

While several novel biomarkers show promise for ACLF diagnosis and prognostication, no single marker or combination has been validated as sufficiently accurate for clinical use—current diagnosis still relies on clinical criteria combining elevated bilirubin, elevated INR, and at least one extrahepatic organ failure. 1

Inflammatory Markers Under Investigation

The most extensively studied novel markers are systemic inflammatory biomarkers, which reflect the pathophysiological hallmark of ACLF—a cytokine storm and exaggerated inflammatory response. 1, 2

C-Reactive Protein and White Blood Cell Count

• Elevated C-reactive protein (CRP) and white blood cell (WBC) counts identify patients at higher risk of developing ACLF in the "pre-ACLF" state, though they lack sufficient accuracy as standalone predictive biomarkers. 1
• These markers progressively increase during follow-up in patients who subsequently develop ACLF compared to those with decompensated cirrhosis who do not progress. 1
• Both CRP and WBC are incorporated into prognostic scoring systems (CLIF-C ACLF score includes WBC count). 1, 3

Serum Lactate

• Serum lactate has emerged as a particularly valuable marker that correlates with the number of organ failures and mortality in critically ill cirrhotic patients. 1
• The MELD-Lactate (MELD-LA) model measured at hospitalization demonstrates excellent predictive accuracy for in-hospital mortality, outperforming MELD, MELD-Na, or lactate alone. 1
• Lactate levels at admission increase in parallel with the number of organ failures. 1
• When added to the CLIF-C ACLF score, lactate improves prognostic performance. 1

Renal Biomarkers

The AASLD 2024 guidance specifically identifies renal biomarkers as a priority research direction for differentiating causes of acute kidney injury and assessing treatment response. 1

Promising Renal Markers Include:

• Neutrophil gelatinase-associated lipocalin (NGAL) for prediction of short-term mortality and AKI differentiation 1
• Cystatin C for mortality prediction 1
• Kidney injury molecule-1 (KIM-1) 1
• Interleukin-18 (IL-18) 1
• Liver fatty-acid binding protein (L-FABP) 1

Critical caveat: These renal biomarkers remain investigational and require validation in larger studies before clinical implementation. 1

Other Novel Biomarkers Under Study

Metabolic and Dysbiosis Markers

• Serum metabolites and markers of dysbiosis are being investigated for their role in predicting short-term mortality, though specific validated markers have not yet been established. 1

Brain Failure Biomarkers

• Research is ongoing to identify biomarkers for prediction and specific diagnosis of hepatic encephalopathy-related brain failure, but none are currently validated for clinical use. 1

Current Limitations and Clinical Reality

The PREDICT study definitively demonstrated that no individual or combination of clinical or analytical variables were identified as accurate biomarkers to predict ACLF development, despite identifying high-risk "pre-ACLF" patients with elevated inflammatory markers and severity scores. 1

Why Novel Markers Remain Investigational:

• Heterogeneous ACLF definitions across geographical regions complicate biomarker validation 1
• Lack of standardized cutoff values and timing of measurement 1
• Insufficient large-scale validation studies 1
• Most promising markers require incorporation into composite scoring systems rather than standalone use 1

Practical Clinical Approach

Until novel biomarkers are validated, diagnosis must rely on the AASLD-defined minimum critical components: acute onset with rapid deterioration, liver failure (elevated bilirubin AND elevated INR), and at least one extrahepatic organ failure. 1, 4

For Risk Stratification, Use:

• CLIF-C ACLF score (includes WBC count, age, and organ failures) 1, 3
• MELD-Lactate when available for superior prognostic accuracy 1
• NACSELD ACLF score (includes WBC count, albumin, age, MELD) 1
• AARC score (includes lactate, bilirubin, creatinine, INR, hepatic encephalopathy) 1

Common pitfall: Do not use MELD or MELD-Na alone for ACLF prognostication, as they underestimate mortality by failing to account for extrahepatic organ failures. 1, 4