Albuminomics

EASL Clinical Practice Guidelines: Drug-Induced Liver Injury

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EASL Clinical Practice Guidelines: Drug-Induced Liver Injury (2019)

Bibliographic info

  • Authors: European Association for the Study of the Liver (EASL) — Practice Guidelines Committee
  • Journal: Journal of Hepatology, 2019 (EASL CPG)
  • DOI: Listed in document header (DILI EASL.pdf)

Key question (guideline scope)

What are the evidence-based clinical practice guidelines for risk assessment, diagnosis, management, and monitoring of drug-induced liver injury (DILI) — particularly idiosyncratic DILI?

Content overview

DILI definition and epidemiology

  • Idiosyncratic DILI: unpredictable, dose-independent; most challenging type
  • Incidence: ~13.9 cases per 100,000 inhabitants (French population study — first rigorous prospective data)
  • HDS (herbal and dietary supplements): 16–20% of DILI cases (US DILIN; Spanish registry); increasing over time
  • Prognosis: Hy’s Law: jaundice + drug-induced hepatocellular injury → ~10% mortality/transplantation rate

Causality assessment

  • RUCAM scale (Roussel Uclaf Causality Assessment Method): primary diagnostic tool in clinical practice; evaluates time to onset, dechallenge/rechallenge response, risk factors, concomitant drugs, exclusion of other causes
  • Clinical Expert Opinion (CEO): consensus-based adjudication; complements RUCAM
  • Diagnosis: exclusion process — no specific DILI biomarker exists → requires ruling out alternative causes (viral hepatitis, autoimmune, metabolic, ischemic)

Phenotypic patterns of DILI

  • Hepatocellular: ALT elevation dominant; R ratio = ALT/ALP (normalized to ULN) ≥5
  • Cholestatic: ALP dominant; R ratio ≤2
  • Mixed: R ratio 2–5
  • Clinical presentations: acute hepatitis, cholestasis, steatosis, fibrosis, vascular lesions, autoimmune hepatitis-like

Key risk factors reviewed

  • Drug-specific: dose, lipophilicity, mitochondrial toxicity, reactive metabolite formation
  • Patient-specific: age, sex, alcohol, genetics (HLA associations), comorbidities

Current biomarker landscape

  • ⚠️ No specific, validated DILI biomarkers in clinical use
  • ALT/AST: most used but non-specific; delayed response (cell necrosis required to release)
  • Emerging: GLDH (glutamate dehydrogenase — mitochondrial marker, more specific for hepatocytes), osteopontin, cytokeratin-18, microRNAs (experimental)
  • Gap: biomarkers for early, pre-necrotic detection — exactly the gap HSA isoforms could fill

Management

  • Stop causative agent (de-challenge)
  • SBP and hepatorenal syndrome management (as per standard CLD guidelines)
  • N-acetylcysteine (NAC) for acetaminophen (paracetamol) DILI: established; possibly useful in non-APAP fulminant hepatic failure
  • Corticosteroids: no evidence for routine use in idiosyncratic DILI
  • Liver transplantation: for acute liver failure from DILI (without recovery prognosis)
  • Jaundice + coagulopathy → emergency referral

DILI surveillance and pharmacovigilance

  • Liver safety monitoring in clinical trials: defined stopping rules based on ALT/AST/bilirubin elevations
  • Hepatotoxicity registers: DILIN (USA), Spanish registry, EURODILI (Europe)

Clinical context

  • Disease: DILI — drug-induced liver injury
  • Relevance to our research: The absence of specific DILI biomarkers is the key clinical gap that HSA isoform profiling (early detection by el-balkhi-2024-seb) addresses. These guidelines define what a new biomarker must outperform (ALT/AST) and the performance thresholds needed.

Connections

  • DILI — primary disease page; this document is the reference standard
  • Liver fibrosis — progression context; severe DILI can cause fibrosis/cirrhosis
  • HSA — potential early DILI biomarker; Cys34 modifications preceding enzyme elevation
  • el-balkhi-2024-seb — our SEB test paper; demonstrates HSA detects liver injury at D3 vs ALT/AST at D7 — directly addresses the gap identified in these guidelines
  • PTM-CQFD project — plans to include DILI/drug safety monitoring as a future application

Take home notes

  • These guidelines confirm the key unmet need that motivates the SEB test and ALBOM: no specific DILI biomarker exists. ALT/AST are sensitive but non-specific and lag behind the actual injury.
  • Hy’s Law (jaundice + hepatocellular injury → ~10% mortality) underscores why early detection matters — by the time jaundice appears, severe injury has occurred.
  • The phenotypic diversity of DILI (hepatocellular/cholestatic/mixed) makes a single biomarker unlikely to cover all patterns. HSA PTMs (which reflect hepatocyte synthetic function and systemic oxidative stress) may work best for hepatocellular DILI.
  • Note: HDS-associated hepatotoxicity (herbal medicines, supplements) is increasing and hardest to diagnose. HSA isoforms would be non-specific to causative agent but could still detect early hepatic dysfunction.
  • RUCAM is the gold standard for causality — any new biomarker would likely complement RUCAM, not replace it.

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