What causes falsely elevated procalcitonin levels in patients with Acute-on-Chronic Liver Failure (ACLF)?

Causes of Falsely Elevated Procalcitonin in ACLF

Procalcitonin is unreliable for diagnosing bacterial infection in ACLF because severe hepatocyte necrosis and massive systemic inflammation inherent to the syndrome itself cause marked PCT elevation regardless of infection status.

Primary Mechanism: Hepatocyte Injury and Systemic Inflammation

The fundamental problem with PCT in ACLF stems from the pathophysiology of the syndrome itself:

• Massive hepatocyte necrosis directly elevates PCT levels independent of bacterial infection, rendering the biomarker unreliable in this setting 1
• Systemic inflammation in ACLF is a defining feature of the syndrome, with severity correlating to organ failures and mortality, and this inflammatory state alone drives PCT elevation 2
• Studies demonstrate that ALF patients show median PCT values near or above 2.0 ng/mL (the threshold typically indicating severe sepsis) even in the absence of documented infections 1

Specific Clinical Scenarios Causing False Elevation

Acetaminophen (Paracetamol) Toxicity

• Acetaminophen-induced liver injury causes particularly marked PCT elevation that is disproportionate to the degree of liver cell injury 1, 3
• Patients with APAP toxicity demonstrate median PCT >2.0 ng/mL regardless of SIRS features or infection status 1
• The mechanism is not fully explained by liver cell death alone and remains incompletely understood, but PCT levels in paracetamol intoxication are significantly higher than in acute liver failure from other causes 3

Alcohol-Related Hepatitis

• Active alcoholism and alcohol binge are major precipitants of ACLF, particularly in Western countries, and lead to severe inflammatory responses 4
• These patients develop more severe syndrome manifestations than other triggers, suggesting heightened inflammatory activation that would elevate PCT 4

Renal Dysfunction in ACLF

• Renal failure is a defining organ failure in ACLF, present in many patients 4
• While chronic renal failure alone typically does not elevate PCT significantly, CAPD patients show elevated PCT (median 1.18 μg/L) even without infection 5
• The combination of acute kidney injury with hepatic failure in ACLF may contribute to PCT accumulation 5

Poor Discrimination Between Infected and Non-Infected States

Critical evidence demonstrates PCT's failure in ACLF:

• No significant differences in PCT levels exist between ALF patients with documented infections (severe sepsis/septic shock groups) versus those without infections (non-SIRS/SIRS groups without documented infections) (p = 0.169) 1
• Some culture-positive patients had PCT <2.0 ng/mL** while many **culture-negative patients with hepatocyte necrosis had PCT >2.0 ng/mL 1
• The massive inflammation observed in ACLF overwhelms PCT's discriminatory capacity for bacterial infection 1

Alternative Biomarkers with Better Performance

When infection diagnosis is critical in ACLF:

• Presepsin ≥2300 pg/mL shows superior performance (sensitivity 81.7%, specificity 92.7%, AUROC 0.959) for diagnosing bacterial infections in cirrhotic patients with ACLF 6
• PCT ≥0.9 ng/mL may still have utility when combined with presepsin (sensitivity 80.3%, specificity 86.6%, AUROC 0.909), but this threshold is much lower than traditional sepsis cut-offs 6
• CRP has poor specificity in ACLF patients, as it is elevated in many renal disease states and overlaps significantly between infected and non-infected patients 5

Clinical Implications

Do not rely on PCT elevation alone to diagnose bacterial infection in ACLF patients. Instead:

• Maintain high clinical suspicion and perform systematic workup for common precipitants including proven bacterial infection, as recommended by EASL guidelines 4
• Recognize that bacterial infections account for 30-57% of ACLF cases and are critical precipitants requiring early treatment 4
• Use culture-based diagnosis and clinical criteria rather than PCT thresholds 1
• Consider presepsin as an alternative biomarker if available, with better discrimination in this population 6
• Remember that 40-50% of ACLF cases have no identifiable precipitant, so absence of infection markers does not exclude ACLF 4, 2