Biomarkers for risk assessment in paracetamol hepatotoxicity
Authors: William Bernal
Journal: The Lancet. Gastroenterology & hepatology (2017)

Managing patients at risk of paracetamol (acetaminophen)-induced hepatotoxicity after overdose continues to be a clinical challenge. Each year about 100 000 people present to emergency departments in the UK with paracetamol poisoning after overdose—and in much of the developed world it is the most common cause of acute liver failure.1PHEParacetamol overdose and poisoning.in: The 2nd Atlas of variation in risk factors and healthcare for liver disease in England. Public Health England, London2017: 128-129Google Scholar, 2Bernal W Wendon J Acute liver failure.N Engl J Med. 2014; 370: 1170-1171Crossref PubMed Scopus (7) Google Scholar However, in most cases presenting to hospital after overdose, the amount of drug consumed is insufficient to result in liver injury, or to warrant treatment with the highly effective antidote acetylcysteine. Most patients could be safely discharged from medical care without admission for follow-up psychiatric evaluation as required. In some patients, however, early treatment with acetylcysteine after hospital admission is required to prevent major hepatic injury, but identifying patients who will benefit is not straightforward. Current treatment decisions for its administration are based on thresholds of a nomogram that plots blood paracetamol concentration against time of drug ingestion. This approach relies on accurate recall of the timing and circumstances of overdose, and a consistent individual risk for the development of liver injury. Real-world experience suggests that this recall is not always reliable, with recall of overdose clouded by other intoxicants or acute psychiatric illness, and inter-individual variation in susceptibility to hepatotoxicity. Furthermore, the nature of the overdose—for instance, staggered rather than single timepoint ingestion—might make decision making even more complex because the nomogram cannot be applied in this setting. The consequences of getting the decision to treat or not to treat with acetylcysteine wrong can be substantial, resulting in either unnecessary hospital admission and possible risk of treatment-associated adverse effects, or a missed opportunity to prevent liver injury when acetylcysteine treatment is inappropriately deferred—potentially resulting in avoidable acute liver failure and even the need for liver transplantation to avoid death. In The Lancet Gastroenterology & Hepatology, James Dear and colleagues3Dear J Clarke J Francis B et al.Risk stratification after paracetamol overdose using mechanistic biomarkers: results from two prospective cohort studies.Lancet Gastroenterol Hepatol. 2017; (published online Nov13.)http://dx.doi.org/10.1016/S2468-1253(17)30266-2Summary Full Text Full Text PDF PubMed Scopus (74) Google Scholar report an attempt to improve decision making and guide administration of acetylcysteine in patients after paracetamol overdose, testing whether the use of a panel of mechanistic biomarkers of early cellular injury and death can better stratify patients by risk. In plasma or serum samples from more than 1000 patients presenting to hospital after a real-world mixture of single timepoint, staggered, or unknown timing overdoses with paracetamol, they tested for microRNA-122 (miR-122), high mobility group box-1 (HMGB1), keratin-18 (K18), and glutamate dehydrogenase (GLDH)—all good candidates as sensitive predictors of later hepatotoxicity and reflecting key early steps in liver injury through mitochondrial dysfunction, necrosis, apoptosis, and immunological activation. All markers correlated with alanine aminotransferase (ALT; a conventional enzymatic marker of hepatocellular injury) concentration and, in patients who were admitted to hospital with normal ALT, predicted later increase in ALT concentration with high sensitivity and specificity, and with markedly better discrimination than paracetamol concentration alone. HMGB1 and miR-122—which principally reflect hepatic necrosis and immunological activation—showed particular promise, including in staggered or unknown patterns of overdose. However, with standard care and use of acetylcysteine, only 11% of the 1187 tested participants had a peak ALT of more than 100 IU/L—a small increase—3·3% had ALT greater than 1000 IU/L and only 2·6% showed minor prolongation of the international normalised ratio (INR), a measure of liver-derived coagulation factor synthesis more closely related to eventual prognosis than is ALT. No patient in the study by Dear and colleagues died or required liver transplant. Will these biomarkers replace the current approaches to risk stratification? I suspect not in the near future. Even if transformed into clinically available assays their measurement is likely to be time consuming, and it is not clear that they would be cost effective. Acetylcysteine is cheap, effective, and well tolerated—so if there is even a remote possibility of liver injury on the basis of paracetamol concentration or other clinical or circumstantial risk factors, the patient should be treated anyway. The adage should continue to be: if in doubt, give acetylcysteine. The advantage from the use of these markers in the setting of paracetamol overdose might rather come from truncation of acetylcysteine treatment duration and hospital stay in those showing no further evolution of liver injury, but this practical and economic case is yet to be made. An exciting and perhaps more likely prospect is the application of these biomarkers in detection and analysis of early hepatotoxicity in drug development. I report personal fees from Vital Therapies, outside the submitted work. Risk stratification after paracetamol overdose using mechanistic biomarkers: results from two prospective cohort studiesPersonalised treatment pathways could be developed by use of miR-122, HMGB1, and full-length K18 at hospital presentation for patient stratification. This prospective study supports their use for hepatic safety assessment of new medicines. Full-Text PDF Open Access