BIOLOGY

Biology

Biology

Introduction

Drug hepatotoxicity manifests with clinical signs and symptoms caused by an underlying pathological injury. The clinical presentation may or may not suggest the underlying liver injury, and therefore, the types of injuries are sometimes described separately. Some drugs usually cause one clinical and pathologic injury and other drugs can cause a variety of injuries, often making the diagnosis more challenging (Pessayre & Mansouri, 1999: 367).

Table 1: Potentially Hepatotoxic Drugs

Finding

Drug

Hepatocellular:Elevated ALT

Acarbose

Acetaminophen

Allopurinol

Amiodarone

Baclofen

Bupropion

Fluoxetine

Germander

HAART drugs

Isoniazid

Kava kava

Ketoconazole

Lisinopril

Losartan

Methotrexate

NSAIDs

Omeprazole

Paroxetine

Pyrazinamide

Rifampin

Risperidone

Sertraline

Statins

Tetracyclines

Trazodone

Trovafloxacin

Valproate

Cholestatic:Elevated alkaline phosphatase and total bilirubin

Amoxicillin/clavulanate

Anabolic steroids

Chlorpromazine

Clopidogrel

Oral contraceptives

Erythromycins

Estrogens

Irbesartan

Mirtazapine

Phenothiazines

Terbinafine

Tricyclic antidepressants

Mixed:Elevated alkaline phosphatase and ALT

Amitriptyline

Azathioprine

Captopril

Carbamazepine

Clindamycin

Cyproheptadine

Enalapril

Nitrofurantoin

Phenobarbital

Sulfonamides

Trazodone

Verapamil

Clinical manifestations

The manifestations of drug-induced hepatotoxicity are highly variable, ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure. The injury may suggest a hepatocellular injury, with elevation of aminotransferase levels as the predominant symptom, or a cholestatic injury, with elevated alkaline phosphatase levels (with or without hyperbilirubinemia) being the main feature. In addition, drugs that cause mild aminotransferase elevations with subsequent adaptation are differentiated from those that result in true toxicity that require discontinuation (Fromenty & Pessayre, 1995: 101).

Asymptomatic elevations in aminotransferase: Some drugs cause asymptomatic elevations of liver enzymes that do not progress despite continued use of the drug.

As many as 50% of patients receiving tacrine for Alzheimer disease have elevated enzyme levels. Alkaline phosphatase and bilirubin levels are rarely elevated, and severe injury is rare. Rechallenging a patient with this medication may even be appropriate, and in more than 80% of cases, the alanine aminotransferase (ALT) abnormalities resolve or do not reoccur.

This tolerance is also observed in 25-50% of the patients taking drugs such as methyldopa or phenytoin, and it is especially well described with INH.

5-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are also associated with a mild elevation in enzyme levels in less than 5% of cases.

Other drugs include sulfonamides, salicylates, sulfonylureas, and quinidine.

If the clinician is not familiar with the drug or if any question remains about the safety of continuing a drug, consultation with a hepatologist should be considered.

Mechanisms of Injury

It is widely recognised that drug-induced liver injury (DILI) is mediated by two chief mechanisms: intrinsic and idiosyncratic hepatoxicity. Intrinsic hepatotoxins cause hepatocellular damage in a predictable dose-dependent manner directly by the drug or indirectly by its metabolite. Some drugs, such as acetaminophen, cause intrinsic hepatotoxicity, but the majority of agents in this category are industrial, household or environmental toxins such as carbon tetrachloride and alkaloids in mushrooms (Pessayre & Fromenty, 2007: 49). The majority of drugs lead to idiosyncratic liver injury and can be classified into metabolic and immunological categories. In the former, the drug is metabolised into a toxic metabolite in predisposed individuals, while the latter is akin to “drug allergy” or hypersensitivity following sensitisation to the drug. In general, intrinsic hepatotoxicity manifests with hepatocellular necrosis with little inflammation, while idiosyncratic drug reactions often show inflammation-dominant hepatic injury.

How Paracetomol, Flutamide and Perhexilene can Lead to Hepatotoxcity

Paracetomol can Lead to Hepatotoxcity

It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to ...