Comparing the accuracy of three diagnostic criteria and a refined pathological scoring system in drug-induced liver injury: From suspected to definite

Background Drug-induced liver injury(DILI) is difficult in diagnose, criteria used now are mostly based on history review. We tried to evaluate the value of these criteria and histopathology features in DILI to perform a method diagnosing DILI more definitely. Methods We enrolled 458 consecutive hospitalized DILI patients from 1st January 2012 to 31st December 2018, using Roussel-Uclaf Causality Assessment Method(RUCAM), Maria&Victorino scale (M&V) and Digestive Disease Week-Japan criterion(DDW-J) to perform the evaluation. A refined pathological scale was calculated and combined with those criteria using logistic regression analysis. Area under receiver operating characteristics(AUROC) were used to estimate diagnostic accuracy. Results The AUROC of the three clinical diagnostic criteria were 0.730 (95%CI:0.667-0.793), 0.793(95%CI:0.740-0.847) and 0.764(95%CI:0.702-0.826) respectively. The AUROC of the refined pathological scale combined with the three criteria were 0.843(95%CI:0.747-0.914), 0.907(95%CI:0.822-0.960) and 0.881(95%CI:0.790-0.942) respectively. In hepatocellular type, the AUROCs were 0.894(95%CI:0.787-0.959), 0.960(95%CI:0.857-0.994) and 0.940(95%CI:0.847-0.985); In cholestatic type, the AUROCs were 0.750(95%CI:0.466-0.931), 0.500(95%CI:0.239-0.761) and 0.500(95%CI:0.239-0.761); In mixed type, the AUROCs were 0.786(95%CI: 0.524-0.943), 0.869(95%CI:0.619-0.981) and

Comparing the accuracy of three diagnostic criteria and a refined pathological scoring system in drug-induced liver injury: From suspected to definite CURRENT

KEYWORDS
drug-induced liver injury, DILI, RUCAM, diagnostic accuracy, liver pathology Introduction Drug-induced liver injury (DILI) is a serious, worldwide health problem. In the United States and Europe, it is the most common reason for acute liver failure, even though it accounts for <1% of acute liver injury cases (1)(2)(3). Studies showed that DILI occurs with an annual incidence of approximately 13.9 per 100,000 inhabitants in France compared to 19.1 per 100,000 in Iceland (4,5). In China, a retrospective study of 22,030 DILI patients showed that only 50.65% of them were cured, but 1.60% died (6). Additionally, DILI is a potentially severe adverse drug reactions that is a major concern for healthcare systems and the pharmaceutical industry, with a cost of £1 billion in the United Kingdom and $4 billion in the United States (7).
Despite its potentially severe outcomes and drug post-marketing restrictions, diagnosing DILI is still a major challenge, and remains a diagnosis of exclusion. Based on patient data and the typical 'signatures' associated with certain drugs, expert opinion recommends using causality scores to help diagnose, but due to the lack of a reliable method, no objective scales that assesses the causality of a given drug in DILI patients, beyond expert opinion, has been developed (8). On the other hand, histopathology plays an irreplaceable role in providing direct and objective information about the characteristics of liver injury, for example, defining injury patterns (9

Diagnostic criterion scales
Three diagnostic criterion scales: the RUCAM, M&V and DDW-J, were used in this study.
Liver biopsy and refined DILI-PSS     Table 4.  Table 5 shows the results of the characteristics of histological findings according to injury type. The mean ± SD of the refined DILI-PSS score  (16). However, studies have shown that diagnosis scales may not be the best way to diagnose DILI. For example, in the case of patients diagnosed with DILI when a low score is obtained or opposite and different results are obtained using different scales (23,24). Although it may be agreed that M&V and DDW-J were based on original RUCAM, they were invented to better diagnosis DILI. The M&V scoring system is different from RUCAM in terms of time limit and score setting, and extrahepatic clinical manifestations are added as diagnostic criteria, however, the diagnostic accuracy for patients with chronic liver injury after a long-term incubation period and drug withdrawal is poor (25). DDW-J concerned the genes encoding drug-metabolizing enzymes in different ethnics groups, and was probably proposed for Asian populations, but further clinical research is still needed (26). Our study showed that the M&V was better in confirming DILI in suspected patients. Occasionally, the reviewer's opinions begrudgingly abided by the final assessment, and thus, the reviewer decision was different from that produced by the grading process, as in cases of score of 3 or 4 in the RUCAM categories,

Patients' demographic and clinical characteristics
where the likelihood of DILI was balanced around a 50% likelihood (27). Although the DDW-J score was proposed by Japanese scholars for Asian populations, virtually no drug lymphocyte stimulation test (DLST) is performed during our actual clinical diagnosis and treatment process. Also, questions remained that: on which grade of these scales, can we say a it is DILI.
Some emerging biomarkers, such as microRNAs (28,29), high mobility group box 1 (HMGB1) and caspase-cleaved keratin18 (ccK18) (30,31), have been identified in the assessment of DILI. Coupled with traditional liver enzyme tests, these new biomarkers are still questionable. ALT and AST are also present in skeletal muscle and elevated in patients in polymyositis or during extreme exercise (32), and ALP is also present in bone tissue and increased by osteoblast activity; TBIL is elevated after the processing of erythrocytes and subsequent degradation of haemoglobin or alteration of bilirubin transporters (33). Thus, the physiological processes underlying changes in these markers may be unrelated to damage to the liver (34). Therefore, no biomarkers are currently suitable for diagnosing DILI.
As histopathological examination can detect damage directly, diagnosis can be assisted by eliminating (or confirming) conflicting causes of liver injury and by conducting a biopsy associated with DILI patterns (35). In our study, the following limitations should be considered. First, the standards of diagnosed DILI and suspected DILI were based on China's clinical guidelines and confirmed by multidisciplinary consultation, thus, the diagnosis of patients may not be applicable to a wider population. Second, we used liver biopsies as a reference standard but not all patients underwent a liver biopsy. Only 302 patients were enrolled after exclusion (65.94% of the total 458 patients), and the uneven specific deposition in specimens may present a bias. Third, the number of cases such as non-resident DILI patients is lacking.
Moreover, the refined DILI-PSS were not performed in biopsy slices from patients with other diseases or healthy volunteers, which was not available for a more scientific and rigorous evaluation.
In conclusion, our study compared the accuracy of the three diagnostic criteria in diagnosing DILI from suspected patients and validated diagnostic ability of the   Figure 1 The distribution of characteristics in DILI patients.