Drugs and liver disease

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


In general, adverse hepatic drug reactions are ‘idiosyncratic’—that is, they are unpredictable. The clinical spectrum of drug-induced liver disease varies greatly.


Drug-related hepatotoxicity can mimic clinically and histologically almost any type of liver disease (Table 41.1). Presenting symptoms are similarly diverse, from asymptomatic elevations of liver function tests to coma secondary to fulminant hepatic failure. Anorexia and tiredness can be the presentations of hepatitic reactions while itch, dark urine and jaundice occur in more severe cholestatic syndromes.


TABLE 41.1 Drug-induced liver disease






























Condition Drug
Acute hepatocellular necrosis Isoniazid, cloxacillin, halothane, methyldopa, paracetamol
Fatty liver Tetracycline, valproic acid, corticosteroids, non-steroidal antiinflammatory drugs, perhexiline, amiodarone
Granulomatous reactions Hydralazine, allopurinol, carbamazepine
Acute cholestasis Oral contraceptive steroids, anabolic androgens, chlorpromazine, flucloxacillin
Chronic cholestasis Chlorpromazine, flucloxacillin, amitriptyline
Chronic hepatitis/necrosis Methyldopa, nitrofurantoin, dantrolene
Fibrosis and cirrhosis Methotrexate
Vascular disorders Oral contraceptive steroids, anabolic androgens, azathioprine


History


A thorough drug history has to be taken in all patients presenting with symptoms or investigations suggesting liver disease. This needs to include all medications taken over the previous 3 months, including over-the-counter preparations and complementary medicines. If the suspicion of hepatic drug reaction is high, the patient may need to be questioned again and the local medical officer and the local pharmacist called to ascertain all medications taken.


In general, patients with preexisting liver disease are not more susceptible to adverse hepatic drug reactions, but once one occurs it may lead to more severe liver dysfunction.

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Mar 29, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Drugs and liver disease

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