Drugs and liver disease

Published on 09/04/2015 by admin

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Last modified 09/04/2015

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Chapter 41 DRUGS AND LIVER DISEASE

KEY POINTS

• Drugs have become the leading cause of acute liver failure in Western countries.
• The liver plays a central role in elimination of many drugs through a sophisticated series of metabolic enzymes.
• Clinical presentation varies from asymptomatic elevations of liver function tests to coma secondary to fulminant hepatic failure.
• Drug-related hepatotoxicity can mimic clinically and histologically almost any type of liver disease.
• Diagnosis is based on:

– Detailed drug history
– Thorough clinical examination
– Temporal relationship of exposure and symptoms and signs of liver disease
– Exclusion of other causes.

• Treatment: potential causative drugs must be stopped immediately.

INTRODUCTION

The liver plays a central role in the elimination of a large number of medications. It has an elaborate mechanism of transporters that can transfer drugs from the circulation into the hepatocyte and then their metabolic products into bile or back into the circulation for renal clearance.

The liver also has a sophisticated series of metabolic enzymes, which, in general, convert drugs from lipophilic substances to hydrophilic substances that can be more easily eliminated. The cytochrome P450 enzymes, which play the major role in drug metabolism, may produce reactive metabolites during this process and these are thought to be the mechanism by which many adverse hepatic reactions occur.

Epidemiology

Drug-induced hepatotoxicity is the leading cause of acute liver failure and liver transplantation in Western countries.

RISK FACTORS FOR DRUG HEPATOTOXICITY

Several environmental and genetic mechanisms may influence individual susceptibility to drug hepatotoxicity.

Age: older persons appear to be more susceptible to drug-induced hepatotoxicity.

Gender: women are more affected by the toxic adverse effects on the liver than men.

Alcohol: can modulate the hepatotoxic potential of drugs through CYP induction, inhibition or substrate competition.

Underlying preexisting liver disease: hepatotoxicity caused by isoniazid is more common in patients with viral hepatitis and/or HIV infection. Also HIV patients undergoing antiretroviral treatment have a higher risk of severe hepatotoxicity when co-infected with hepatitis B or C viruses, and an increased risk of hepatotoxicity from sulfamethoxazole/trimethoprim.

Genetic factors: genetic variations in human leucocyte antigen (HLA) molecules can predispose individuals to immunoallergic drug hepatotoxicity. Certain HLA class II alleles are important in explaining why a given drug may cause different patterns of liver damage in certain individuals. Susceptibility to isoniazid hepatotoxicity in predisposed individuals may be due to a relationship between N-acetyltransferase 2 deficiency and the propensity to develop hepatotoxicity.

PRESENTATION

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