Review Article
Adverse drug reactions and organ damage: The liver

https://doi.org/10.1016/j.ejim.2015.12.017Get rights and content

Highlights

  • Drug induced liver injury is the most challenging acute or chronic liver disease handles by physicians.

  • Drug induced liver injury depends on the interplay between drug, host and environmental risk factors.

  • Drug induced liver injury DILI encompass a wide spectrum of diseases with varying clinical/histological features.

  • Drug induced liver injury is an exclusion diagnosis in which clinical judgment remain essential.

  • Patients with hepatocellular liver injury induced by drugs are at risk of acute liver failure.

Abstract

Drug-induced liver injury (DILI) is among the most challenging acute or chronic liver conditions to be handled by physicians. Despite its low incidence in the general population, DILI is a frequent cause of acute liver failure. As such, the possibility of DILI should be considered in all patients who present with acute liver damage, independent of any known pre-existing liver disease. DILI can be classified as intrinsic/dose-dependent (e.g., acetaminophen toxicity) or idiosyncratic/dose-independent, with the latter form being relatively uncommon. Amoxicillin–clavulanate is the antimicrobial that is most frequently associated with idiosyncratic DILI. Large, ongoing, prospective studies in western countries have reported other drugs associated with DILI, including nonsteroidal anti-inflammatory drugs, statins, and herbal and dietary supplements. An important safety issue, DILI is one of the most frequently cited reasons for cessation of drug development during or after preclinical studies and for withdrawal of a drug from the market. This review summarizes the epidemiology, risk factors, commonly implicated drugs, clinical features, and diagnosis of DILI, with the aim of aiding physicians in the management of this debated problem. Old and new biomarkers for DILI and pharmacogenetic studies are also described.

Section snippets

1. Introduction

Drug-induced liver injury (DILI) encompasses adverse drug reactions (ADRs) involving the liver after the administration of a xenobiotic, such a drug or herbal and/or dietary supplement (HDS), at the usual dose interval [1]. Theoretically, most drugs are capable of inducing DILI, owing to the liver's pivotal role in drug metabolism.

The two main categories of DILI are intrinsic/dose-dependent and idiosyncratic/dose-independent, with the latter form being relatively uncommon. Liver injuries due to

2. Epidemiology and risk factors for idiosyncratic DILI

The clinical diagnosis of DILI is one of exclusion, owing to a lack of reliable and confirmatory tests. Accordingly, it is difficult to establish the exact burden of DILI on the healthcare system. Registries of idiosyncratic DILI cases have been established in different Western [8], [9], [17], [18] and Asian [19] countries. Registry data have greatly improved knowledge regarding the etiologies, pathogenic mechanisms, and clinical outcomes of DILI [20]. Patients enrolled in DILI registries are

3. Clinical features and diagnosis of DILI: causality assessment systems

Clinically, DILI represents a wide spectrum of diseases with diverse biochemical and histologic features. A clinical picture resembling acute hepatitis is the most common clinical presentation of acute liver disease of all etiologies and is pathognomonic of DILI. Other clinical features of hepatotoxicity may also be present, such as cholestatic hepatitis, nodular regeneration, cirrhosis, non-alcoholic fatty liver disease, veno-occlusive disease, and vanishing bile duct [20]. Liver biopsy may

4. Drugs frequently involved in DILI

Almost any class of drug can be involved in idiosyncratic DILI. Nonetheless, in the United States, antimicrobials and antidepressant/antipsychotics are the most commonly implicated drug classes, followed by NSAIDs, antiplatelet agents, statins, and HDS [6]. Since 2000, we have followed a prospective cohort of consecutive DILI patients at our tertiary referral center. This cohort primarily consists of women (54%), with a mean age of 54 years. We reported that almost 25% of patients in the DILI

5. APAP-induced liver injury

APAP-induced hepatotoxicity represents one of the best examples of predictive DILI, causing rapid liver injury in the centrilobular region [14]. Liver damage can be intentional (e.g., attempted suicide) or accidental (e.g., inadvertent drug intake in excess of the intended dose over several days). APAP is widely used as an analgesic and is available in many nonprescription and prescription products, including in combination with opioids [40]. For this reason, APAP overdose is the most common

6. Pathogenic mechanisms of DILI

After biotransformation by the cytochrome P450 system, a drug can become an active metabolite that is less toxic, more hydrophilic, and ready to be eliminated. Subsequently, UDP-glucuronosyltransferase, sulfotransferase, and glutathione-S-transferase hydrolyze the metabolite. Transport of the metabolite out of hepatocytes is mediated by the ATP binding cassette (ABC) transporter superfamily [50]. In general, drugs can either directly affect hepatocytes/cholangiocytes or elicit an innate or

7. Biomarkers of DILI

Currently, there are no clearly identified biomarkers of DILI that are useful for monitoring patients on drug therapy for early detection of hepatotoxicity or for making an appropriate diagnosis. Traditionally, ALT, ALP, and total bilirubin levels have been used clinically to identify the various types of DILI. However, patterns of liver injury may be categorized by the pathological conditions and underlying events, such apoptosis, necrosis, and necroptosis, inflammation, oxidative stress, and

8. Pharmacogenetic impact of DILI

Susceptibility to drugs depends on the presence of genetic variations among gene classes, such as those involved in drug disposition/transport, cellular stress, and inflammatory and immune response genes, including the human leukocytes antigen (HLA) system [61], [62]. Different drugs may share specific genetic susceptibility variants [63]. Furthermore, as some patients experience multiple DILI episodes caused by different drugs, there may exist a subgroup of individuals that is predisposed to

Learning points

  • An important safety issue, DILI is one of the most frequently cited reasons for cessation of drug development during or after preclinical studies and for withdrawal of a drug from the market. It is the most common cause of ALF in western countries.

  • Almost all drug classes can be involved in idiosyncratic DILI. Antimicrobials, antidepressant/antipsychotics and NSAIDs are the most common implicated drugs classes followed by, anti-platelets agents, statins and HDS; recently, body building products

Concluding remarks

This review was aimed at highlighting knowledge regarding the epidemiology, risk factors, clinical features, and diagnostic criteria of idiosyncratic and dose-related DILI. Diagnosis of DILI remains a debated issue, despite many efforts to identify proper diagnostic criteria and useful biochemical markers to assist physicians and predict outcomes. In this article, I have reported the most commonly implicated medications, the increasing use of HDS, the difficulties of diagnosis with currently

Conflict of interest

None.

Acknowledgment

I am really thankful to Antonio Craxì for his valuable advice and support in reviewing the manuscript.

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