Drug-induced liver injury (DILI) is the single most common reason for regulatory actions concerning drugs, including failure to gain approval for marketing, removal from the market place, and restriction of prescribing indications. DILI is also a significant cause of morbidity and mortality in many patient populations. To stimulate and facilitate research into DILI, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has recently established the Drug-Induced Liver Injury Network (DILIN). One of the initial projects to be conducted by the network is to retrospectively establish a nationwide registry of patients who have suffered severe idiosyncratic liver injury associated with drugs (ILIAD), and to collect, and store serum, DNA from these patients (hereafter referred to as the “ILIAD protocol”). This ILIAD protocol will serve as a resource for subsequent mechanistic investigations of the basis for susceptibility to severe idiosyncratic DILI.

Data from the DILIN Retrospective study through the grant 3 cycle (2018) are available from the Repository.

The primary goal of the ILIAD protocol is to create: (a) a clinical database consisting of individuals who have experienced severe DILI caused by seven specific drugs (isoniazid, phenytoin, clavulanic acid / amoxicillin and valproic acid, nitrofurantoin, trimethoprim-sulfamethoxazole, minocycline) and one drug class (quinolone antibiotics); and, (b) to create a bank of biological specimens obtained from these individuals. These biological specimens will be DNA, plasma. A secondary goal of the ILIAD protocol is to maintain a registry of cases in the ILIAD database so that they may be re-contacted in the future. It is expected that this will facilitate additional studies exploring the mechanisms of DILI.
An important goal of this study is to generate hypotheses for consideration in future studies. Type-II error, i.e., failing to find an interesting association when there is one, is an important consideration. Thus, as a compromise between type-I and type-II error, α = 0.01 will be applied to declare any effect statistically significant. Because the suspected DILI mechanism is thought to be different for each drug, statistical analysis will be performed separately for each medication. The conditional logistic regression model will be the primary analytic model. Stratification variables, and any other covariates (other than the matching variables) known or suspected to distinguish cases from controls will be included as covariates. The adjusted odds ratio, together with its confidence interval, will be estimated from the associated regression parameters. Supplementary analyses as described in Liang and Zeger will be applied using a generalized linear mixed model approach.

To be included in the ILIAD registry, the following criteria must be satisfied:

• The treating gastroenterologist / hepatologist or health care professional must believe that the subject suffered drug-induced liver injury;
• The subject must be alive and the date of onset of the qualifying DILI episode must have occurred on or after January 1, 1994;
• The implicated medication is one of the following: isoniazid, phenytoin, combination clavulanic acid / amoxicillin,valproic acid, nitrofurantoin, trimethoprim-sulfamethoxazole, minocycline, and quinolone antibiotics.
• The subject is taking only one of these medications in the period leading up to the onset of the qualifying DILI episode.

• INR > 1.5;
• serum AST or ALT > 3 × ULN or > 3 times the baseline level, if the baseline level is elevated;
• bilirubin > 1 × ULN or > 1 times the baseline level, if the baseline level is elevated; unexplained elevated arterial or venous NH3 levels; or,
• liver biopsy showing steatosis.