Table 2

Selected biomarkers of DILI investigated by the IMI SAFE-T and the C-Path PSTC Consortia

MarkerOrigin of biomarkerSummary
MicroRNA (miR)-122Liver specificmiR-122 is an early and specific marker of hepatocellular injury and a sensitive marker of DILI.81–86
High mobility group box 1 (HMGB1)Detectable in numerous tissuesIn acetaminophen (APAP)-induced liver injury, hyperacetylated HMGB1 is significantly elevated in patients who die or require a liver transplant, whereas in spontaneous survivors it is not significantly different from healthy volunteers.87
Cytokeratin 18 full lengthEpithelial cellsThe full-length protein is released from necrotic cells. It is significantly elevated in APAP overdose patients who die/require a liver transplant compared with spontaneous survivors.83–85 87
Cytokeratin 18 caspase-cleaved fragment (caspase-cleaved keratin 18 (ccK18))Epithelial cellsThe caspase-cleaved fragment is released from apoptotic cells and helps define the type of cytotoxicity. ccK18 fragments in blood predict severity of disease in NASH and in hepatitis C.83–85 88
Cadherin 5Endothelial cellsCadherin 5 is a calcium-dependent cell adhesion protein (also called vascular endothelial cadherin) that is specific to endothelial cells. Initial results indicate a potential use as a susceptibility marker for DILI.89
Liver fatty acid-binding protein (L-FABP)Primarily liver; lower levels in the kidneys and small intestineL-FABP is a sensitive marker for hepatocellular injury following liver transplantation and in hepatitis C.90 91 In heparin-induced DILI, L-FABP levels correlate well with serum ALT levels.89
Glutamate dehydrogenase (GLDH)Mitochondrial matrix; primarily in the centrilobular region of the liver; lower levels in the kidney and brainA sensitive biomarker of liver toxicity with hepatocellular damage in preclinical species; shown to be elevated in humans with hepatic ischaemia or hepatitis; shown to correlate with ALT in patients with a broad range of clinically demonstrated liver injuries, including APAP-induced liver injury and to detect mild hepatocyte necrosis in patients treated with heparin. Marker for mitochondrial injury or cellular injury in multiple clinical DILI and acute liver failure studies.84 92 93
Glutathione S-transferase (GSTα)Centrilobular region of the liver; multiple tissuesHepatotoxicity biomarker shown in rats to have enhanced specificity and sensitivity compared with ALT; humans with APAP overdose show elevated GSTα levels earlier than ALT; GSTα may offer a better assessment of rapid changes in liver damage due to the shorter half-life of plasma GSTα compared with ALT or AST.94 95
Osteopontin (OPN)Multiple tissue and cell types, including liverElevated serum levels of OPN are detectable in patients with severe liver damage. Increased levels of serum OPN are associated with a poor prognosis. OPN is associated with inflammatory cell activation and with liver regeneration due to activation of hepatic stem cells.96 Hepatocytes are a major source of OPN and HMGB1 signalling to hepatic stellate cells, thereby promoting collagen-1 production. OPN is upstream of HMGB1 and both play a major role in the pathogenesis of liver fibrosis.97
Macrophage colony-stimulating factor receptor 1(MCSFR1)Cytokine receptor on macrophages/monocytesData from the ximelagatran biomarker discovery study suggest that MCSFR1 is shed from macrophages during DILI. MCSFR1 serum/plasma levels may have value as a prognostic marker for liver disease associated with inflammation.98
Sorbitol dehydrogenase (SDH)Multiple tissue and cell types, including liverSensitive enzymatic serum marker of liver toxicity in preclinical species. Shown to be elevated in humans with various liver diseases and to detect mild hepatocyte necrosis in patients treated with heparin. The biomarker serves two purposes:

  1. as an early marker of hepatocellular injury, possibly preceding ALT on a temporal scale

  2. as a specific marker of hepatocellular injury.92

Bile acidsSynthesised by the liver

  1. early markers of cholestasis, possibly preceding ALP and ALT on a temporal scale

  2. sensitive marker of inhibition of the bile salt export pump, known to be inhibited by several drugs75 76

  3. markers of liver synthetic function.

  • ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; C-Path PSTC, Critical Path Institute's Predictive Safety Testing Consortium; DILI, drug-induced liver injury; IMI, Innovative Medicines Initiative; SAFE-T, Safer and Faster Evidence-based Translation.