William F. Balistreri, MD


November 30, 2017

In This Article

DILI in Children

The etiologies and outcomes of DILI in children are not well-established or predictable.

DiPaola and colleagues[4] reviewed the presenting features, etiologies, and outcomes of children with such suspected injuries who were enrolled in the DILIN studies. They analyzed all cases (n = 69) that involved children younger than 18 years with suspected DILI who were enrolled over a 12-year period. Of 57 cases adjudicated to be DILI via consensus expert opinion (RUCAM), 14 were considered definite DILI, 30 as highly likely to be DILI, and 13 as probable DILI. These cases constituted the study group.

The median duration of drug therapy was 140 days (range, 5-569 days). At onset, the median serum level of alanine aminotransferase was 411 U/L, alkaline phosphatase 203 U/L, and total bilirubin 3.3 mg/dL. The investigators recorded immunoallergic features, such as fever (37%), rash (25%), and peripheral eosinophilia (15%). Antimicrobials were the most frequently implicated agents (51%), followed by antiepileptics (21%); the top implicated agents were minocycline, valproate, azithromycin, and isoniazid.

Overall, 63% of children were hospitalized and three underwent liver transplant because of acute liver failure within 3 weeks after the onset of DILI. Among 49 children followed for at least 6 months, 16% had persistently abnormal liver tests. Thus, although the majority of cases of DILI in children were self-limited and benign, 5% of the cases of acute liver failure required transplantation and chronic hepatic injury occurred in another 16% of cases.

Can We Predict DILI?

Standard indices used to predict the outcome of patients with DILI are not ideal, because they are not liver-specific or mechanistically informative. Thus, they are not sufficiently predictive of outcome. This highlights the need for more precise options.

One presentation described novel biomarkers that could collectively provide prognostic and mechanistic insights in patients with suspected DILI. Several candidate biomarkers were quantified by Church and colleagues[5] in serum samples collected by the DILIN within 2 weeks of onset of illness from 145 patients adjudicated to have DILI. Their outcome was considered "adverse" if patients required a liver transplant or died within 6 months as a result of the DILI episode.

Logistic regression demonstrated that elevated levels of total keratin 18, caspase-cleaved keratin 18, alpha-fetoprotein, osteopontin, fatty acid binding protein 1, and macrophage colony-stimulating factor receptor were each significantly predictive of an adverse outcome. The serum "apoptotic index," the ratio of caspase-cleaved keratin 18 to total keratin 18, was also inversely correlated with an adverse outcome. The INR, as expected, was the best single predictor, followed by osteopontin.

Multiple forward regression analysis resulted in a predictive model that included the INR, total bilirubin, aspartate aminotransferase, osteopontin, and K18. This model exhibited higher specificity (0.98) than "Hy's law" or a Model for End-Stage Liver Disease score > 20 (whose specificities were 0.64 and 0.73, respectively).

Certain biomarkers were also correlated with hepatic histopathologic findings. The degree of inflammation was significantly correlated with macrophage colony-stimulating factor receptor, whereas the extent of coagulative/confluent necrosis was significantly correlated with alpha-fetoprotein and osteopontin. The semiquantitative score of necrosis was inversely correlated with the apoptotic index.

The investigators propose that incorporation of the new candidate biomarkers into traditional measurements of liver injury could potentially allow improved prediction of outcomes in patients with DILI. In addition, the new biomarkers may provide a "liquid biopsy" to assess the degree of inflammation and mode of hepatocyte death.

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