**8.5 Drug-Induced Liver Injury (DILI)**

Hepatotoxicity and drug-induced liver injury (DILI) are terms used interchangeably. DILI can be defined as a liver injury induced by a drug or herbal medicines leading to liver test abnormalities or liver dysfunction with reasonable exclusion of other competing etiologies. Most cases of DILI are due to idiosyncratic or unexpected reactions. In contrast to paracetamol-induced hepatotoxicity, which occurs with dose-dependent overdose of the drug. Idiosyncratic drug reactions have been traditionally considered dose independent. However, drugs with well-documented idiosyncratic DILI have been shown to have a dosedependent component. Idiosyncratic DILI, excluding injury caused by acetaminophen overdose, accounts for 7–15% of the cases of acute liver failure in Europe and the United States and is the most frequent reason for the withdrawal of an approved drug from the market. Estimates of the rate of incidence of DILI leading to hospital referral vary from 2.4 per 100,000 person-years (in a retrospective population-based study of 1.64 million UK subjects) to 13.9 per 100,000 inhabitants (in a prospective analysis in France). Complementary or alternative medicines are used by at least 20% of individuals in Western, Eastern, and African cultures, and reports of DILI have increased. Given its rarity, DILI may not be identified during clinical trials and may come to light only after the culprit drug has obtained market approval and large numbers of patients have been exposed. In addition, in preregistration clinical trials, mild asymptomatic liver injuries, often characterized by asymptomatic elevations in liver enzymes, are commonly seen. However, drugs capable of inducing severe DILI as well as drugs that have a low potential for causing severe injury (e.g., aspirin and heparin) can generate similar patterns of liver injury. It is therefore necessary to develop an approach that can distinguish drugs that are likely to cause severe DILI from drugs that are unlikely to do so.

Adverse Reactions and Gastrointestinal Tract 519

Acute liver injury Isoniazid, disulfiram, paracetamol

Cholestatic hepatitis Flucloxacillin, amoxicillin clavulanate

inflammatory bowel disease cause also adverse drug reactions but the extended use of IBP makes them responsible of most of the adverse reactions with gastrointestinal drugs: hypergastrinemia, hypomagnesemia, tumors and, recently, enteric infections, pneumonia and osteoporosis (Maffei, 2007). There is a controversy about the probability of some of theses adverse drug reactions with IBPs. In the recent review by Thomson (2010) they failed to found risk of carcinoid tumors, cancer or nosocomial pneumoniae. There still controversy

The main strategies for reducing adverse drug reactions are: drug interaction calculators, renal insufficiency calculators, prescribing programs and collaboration between

The world Health Organization defines pharmacovigilance as the science and activities related to the detection, assessment, understanding, and prevention of adverse affects or any other possible drug-related problem. The field has grown significantly in recent years as postapproval safety studies for new medication become increasingly required, encompassing retrospective analysis of heath-care claims databases, meta-analysis, patients

Recognition, reporting and careful characterization of these troubling, often unexpected ADRs are vital to future prevention of these event because detection of patterns and common features of ADRs can enhance our understanding of new mechanism and risk factors. The expansion of electronic database capabilities in hospital and primare-care setting offers the promise of better safety-based detection and monitoring systems that can detect ADRs earlier and prevent ADRs in the future. Hospital informatics systems linking to electronic medical records and including patient genotype with medication ordering and dispensing will reduce medication errors and inappropriate prescribing while improving

Ductopenia Amoxicillin, Trimethoprim-sulpha

Nodular regenerative hyperplasia Azathioprine, 6-thioguanine

Chronic hepatitis Phenytoin, isoniazid

Bland cholestasis Estrogens, nimesulide

Fibrosis Methotrexate

about the risk of osteoporosis with the long term use of IBPs.

**10. Strategies to diminish adverse drugs reactions** 

pharmacists, pharmacologists and clinical physicians.

registries, and prospective case-control studies.

Table 2. Types of DILI (adapted from Björnsson )

Autoimmune hepatitis Minocycline, nitrofurantoin Granulomatous hepatitis Carbamazepine, quinidine Steatohepatitis Amiodarone, valproate

**Type Drugs** 

RUCAM algorithm (Roussel Uclaf Causality Assessment Method) was the first algorithm developed specifically for DILI. After the meeting sponsored by the CIOMS (Paris, 1989), with the support of Russel Uclaf pharmaceutical company, the terminology and diagnosis criteria for causality assessment was proposed. The algorithm was validated using external cases with positive rechallenge (49 cases) and 28 controls (patients with acute liver damage not related to drugs) with available information before occurrence of re-exposure, with results of high sensitivity (86%), specificity (89%), positive predictive value (93%) and negative predictive value (78%) [Algorithm RUCAM are showed in Table 1 and 2 of Appendix 2].

International DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that could be define and characterize the spectrum of clinician syndromes that constitute DILI. In Appendix 2 of supplementary information you will find threshold criteria for definition of a case as being DILI (Box 1), the pattern of liver injury (Box 2), severity (Box 3), causality assessment (Box 4), and chronicity (Box 5). Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases (Box 6), including autoimmune hepatitis (Box 7).

A very large number of different drugs have been associated with liver injury. There is a clear difference in the documentation or the evidence for hepatotoxicity associated with these drugs. Isoniazid, phenytoin, disulfiram, amoxicillin/clavulanate, halothane and chlopromazine are drugs with well characterized hepatotoxicity. More recently antibiotics (amoxicillin/clavunalate, erytromicin, flucloxacillin, trimethoprim-sulpha, nitrofurantoin, isoniazid and rifampicin), analgesics and NSAIDs (diclofenac, dextropropoxyphene, paracetamol, ibuprofen) probably the most common type of drugs associated with DILI. In hospitalized patients, antineoplasic agents seem to commonly lead to DILI and are probably underreported. In a Spanish pharmacovigilance prospective program based on laboratory signals at hospital all patients with liver test abnormalities ( x 3 upper limits of normal) were evaluated being antibiotics (19.5%), hormonal contraceptives (14.6%) and anticancer agents (10%) were the most frequent drug-groups associated to liver injury. In out-patients, the single most common drug implicated in ine series was diclofenac. Among patients with acute liver failure resulting from drugs in the US who underwent liver transplantation, paracetamol (acetaminophen) was the most common causative drug, followed by isoniazid, propylthiouracil, phenytoin and valproate.. Herbal and dietary supplements are implicated in approximately 11% of patients who developed acute serious liver disease of unknown cause in Spain.

The expectrum of DILI is varied, acute liver injury with or without jaundice, chronic hepatitis, although rare, liver cirrhosis has been reported to occur with long-standing drug treatment suspected to have caused DILI, and approximately 25-30% of DILI present with symptom of immunoallergic drug reactions. Table 2 showed the most common types of liver injury that have been identified with drugs.
