Circulating Kidney Injury Molecule 1 Predicts Prognosis and Poor Outcome in Patients With Acetaminophen-Induced Liver Injury.

UNLABELLED: Acute kidney injury in the context of acetaminophen (APAP; paracetamol)-induced liver injury is an important predictor of the requirement for urgent liver transplantation (LT) to avoid death. However, the prognostic biomarker used to report kidney dysfunction (serum creatinine concentration) has suboptimal sensitivity and specificity. Kidney injury molecule 1 (KIM-1) can be quantified in plasma as a sensitive and specific biomarker of kidney injury in both clinical and preclinical studies. Therefore, plasma KIM-1 has potential as a sensitive prognostic biomarker of patient outcome post-APAP overdose. In a cohort of APAP overdose patients (N = 74) with and without established liver injury, we quantified plasma KIM-1 by immunoassay on the first day of admission to a LT unit and assessed its diagnostic performance to predict outcome compared with serum creatinine concentration. Day 1 plasma KIM-1 was significantly elevated in patients that died or required LT, compared to spontaneous survivors (1,182 ± 251 vs. 214 ± 45 pg/mL; P < 0.005). Receiver operator characteristic analysis demonstrated the superiority of KIM-1 (area under the curve [AUC]: 0.87; 95% confidence interval [CI]: 0.78-0.95; 0.56 sensitivity at 0.95 specificity), compared with serum creatinine (AUC, 0.76; 95% CI: 0.64-0.87; 0.08 sensitivity at 0.95 specificity) and other current prognostic indicators, when measured on the first day of enrollment into the study. Furthermore, KIM-1 was found to be a statistically significant independent predictor of outcome at the 5% level (P < 0.0386) in a multivariable logistic regression model that considered all measured factors (pseudo-R^2 = 0.895). CONCLUSION: Early measurement of plasma KIM-1 represents a more sensitive predictor of patient outcome than serum creatinine concentration post-APAP overdose. With further development, plasma KIM-1 could significantly improve prognostic stratification.

Circulating microRNAs as potential markers of human drug-induced liver injury.

UNLABELLED: New biomarkers of liver injury are required in the clinic and in preclinical pharmaceutical evaluation. Previous studies demonstrate that two liver-enriched microRNAs (miR-122 and miR-192) are promising biomarkers of acetaminophen-induced acute liver injury (APAP-ALI) in mice. We have examined these molecules, for the first time, in humans with APAP poisoning. Serum miR-122 and miR-192 were substantially higher in APAP-ALI patients, compared to healthy controls (median ΔΔCt [25th, 75th percentile]) (miR-122: 1,265 [491, 4,270] versus 12.1 [7.0, 26.9], P < 0.0001; miR-192: 6.9 [2.0, 29.2] versus 0.44 [0.30, 0.69], P < 0.0001). A heart-enriched miR-1 showed no difference between APAP-ALI patients and controls, whereas miR-218 (brain-enriched) was slightly higher in the APAP-ALI cohort (0.17 [0.07, 0.50] versus 0.07 [0.04, 0.12]; P = 0.01). In chronic kidney disease (CKD) patients, miR-122 and -192 were modestly higher, compared to controls (miR-122: 32.0 [21.1, 40.9] versus 12.1 [7.0, 26.9], P = 0.006; miR-192: 1.2 [0.74, 1.9] versus 0.44 [0.30, 0.69], P = 0.005), but miR-122 and -192 were substantially higher in APAP-ALI patients than CKD patients (miR-122: P < 0.0001; miR-192: P < 0.0004). miR-122 correlated with peak ALT levels in the APAP-ALI cohort (Pearson R = 0.46, P = 0.0005), but not with prothrombin time. miR-122 was also raised alongside peak ALT levels in a group of patients with non-APAP ALI. Day 1 serum miR-122 levels were almost 2-fold higher in APAP-ALI patients who satisfied King's College Criteria (KCC), compared to those who did not satisfy KCC, although this did not reach statistical significance (P = 0.15). CONCLUSION: This work provides the first evidence for the potential use of miRNAs as biomarkers of human drug-induced liver injury.

Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity.

AIMS: Paracetamol (acetaminophen) poisoning remains the major cause of severe acute hepatotoxicity in the UK. In this large single centre cohort study we examined the clinical impact of staggered overdoses and delayed presentation following paracetamol overdose. RESULTS: Between 1992 and 2008, 663 patients were admitted with paracetamol-induced severe liver injury, of whom 161 (24.3%) had taken a staggered overdose. Staggered overdose patients were significantly older and more likely to abuse alcohol than single time point overdose patients. Relief of pain (58.2%) was the commonest rationale for repeated supratherapeutic ingestion. Despite lower total ingested paracetamol doses and lower admission serum alanine aminotransferase concentrations, staggered overdose patients were more likely to be encephalopathic on admission, require renal replacement therapy or mechanical ventilation and had higher mortality rates compared with single time point overdoses (37.3% vs. 27.8%, P= 0.025), although this overdose pattern did not independently predict death. The King's College poor prognostic criteria had reduced sensitivity (77.6, 95% CI 70.8, 81.5) for this pattern of overdose. Of the 396/450 (88.0%) single time point overdoses in whom accurate timings could be obtained, 178 (44.9%) presented to medical services >24 h following overdose. Delayed presentation beyond 24 h post overdose was independently associated with death/liver transplantation (OR 2.25, 95% CI 1.23, 4.12, P= 0.009). CONCLUSIONS: Both delayed presentation and staggered overdose pattern are associated with adverse outcomes following paracetamol overdose. These patients are at increased risk of developing multi-organ failure and should be considered for early transfer to specialist liver centres.

Circulating apoptotic and necrotic cell death markers in patients with acute liver injury.

BACKGROUND: The host response to cell death underpins the immune activation that follows acute liver injury, and measurement of circulating cell death markers could therefore aid prognostication following paracetamol overdose. Nucleosomes, formed during apoptosis, can complex with high-mobility group box 1 (HMGB1) protein and may play a pathogenic role in liver injury. AIMS: To explore the levels and prognostic significance of nucleosomes, HMGB1, and other cell death markers following acute liver injury. METHODS: Levels of plasma nucleosomes, HMGB1, caspase-cleaved cytokeratin-18 (M30) and total cytokeratin-18 (M65) were measured by immunoassay, in a cohort of 33 patients with paracetamol- and non-paracetamol-induced acute liver injury. RESULTS: Admission nucleosome levels in paracetamol overdose patients were significantly higher than in chronic liver disease and healthy control subjects, but were similar in paracetamol and non-paracetamol patients (P=0.11). Nucleosome levels were not associated with death or requirement for liver transplantation, fulfillment of poor prognostic criteria or organ failure in paracetamol patients. Nucleosome levels correlated with levels of HMGB1 (r=0.500, P=0.009), alanine aminotransferase (r=0.410, P=0.038) and M65 (r=0.709, P<0.001), but not with M30 (r=0.309, P=0.124). None of the cell death markers analysed improved prognostication in paracetamol patients beyond the King's College criteria. CONCLUSIONS: Plasma nucleosomes are significantly elevated following acute liver injury. Neither apoptotic nor necrotic cell death markers accurately predict survival following paracetamol-induced hepatotoxicity, suggesting that the extent and type of cell death play a limited role in determining outcome.

Overdose pattern and outcome in paracetamol-induced acute severe hepatotoxicity.

AIMS: Paracetamol (acetaminophen) hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. Conflicting data regarding the outcomes of paracetamol-induced ALF resulting from different overdose patterns are reported. METHODS: Using prospectively defined criteria, we have analysed the impact of overdose pattern upon outcome in a cohort of 938 acute severe liver injury patients admitted to the Scottish Liver Transplantation Unit. RESULTS: Between 1992 and 2008, 663 patients were admitted with paracetamol-induced acute severe liver injury. Of these patients, 500 (75.4%) had taken an intentional paracetamol overdose, whilst 110 (16.6%) had taken an unintentional overdose. No clear overdose pattern could be determined in 53 (8.0%). Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics compared with intentional overdose patients. Unintentional overdoses had significantly lower admission paracetamol and alanine aminotransferase concentrations compared with intentional overdoses. However, unintentional overdoses had greater organ dysfunction at admission, and subsequently higher mortality (unintentional 42/110 (38.2%), intentional 128/500 (25.6%), P < 0.001). The King's College poor prognostic criteria had reduced sensitivity in unintentional overdoses (77.8%, 95% confidence intervals (CI) 62.9, 88.8) compared with intentional overdoses (89.9%, 95% CI 83.4, 94.5). Unintentional overdose was independently predictive of death or liver transplantation on multivariate analysis (odds ratio 1.91 (95% CI 1.07, 3.43), P = 0.032). CONCLUSIONS: Unintentional paracetamol overdose is associated with increased mortality compared with intentional paracetamol overdose, despite lower admission paracetamol concentrations. Alternative prognostic criteria may be required for unintentional paracetamol overdoses.