Drug Induced Liver Injury (DILI)

The liver is the first stop on the path a drug takes after oral ingestion. From the liver’s “point of view”, drugs are like other exogenous agents and are handled by the liver for excretion. Absorption is largely into the portal system which brings intestinal blood to the liver where transformation and metabolism occur in preparation for elimination (e.g. in the urine, in bile etc.). Metabolism may occur in two phases: Phase I is preparation by oxidation, reduction, hydrolysis and other reactions of the compound for action in Phase II. The second phase occurs in the cytosol and involves reactions catalyzed by transferase enzymes. The cytochrome P-450 system plays a major role in this. The study of the P-450 system allows some degree of prediction of possible hepatotoxicity.
Liver toxicity is usually thought of as producing damage to the liver parenchymal cells (hepatocytes) but toxicity can also be produced affecting biliary cells, kupffer cells, fat storing cells etc.

Adverse events can be classified as Type A which represents pharmacologic effects and are often (but not always) predictable. There may be a dose response effect with worsening of the toxicity only after a particular blood level or threshold is reached of the drug or its metabolites. The classic example of this is acetaminophen (paracetamol) toxicity which is toxic only if more than about 6-8 grams a day are taken. Type B reactions are idiosyncratic and unpredictable. Many drugs can do this.
The toxicity produced by drugs can be of various types. Very common is inflammation (hepatitis) with cell necrosis and inflammation. Viruses can produce hepatitis also of course. Drug induced hepatitis may be acute (many drugs, alcohol) or chronic (e.g. methyldopa, alcohol). It may be catastrophic or mild. Drugs may cause bile flow impairment with or without inflammation and with or without bile duct damage. Oral contraceptives, allopurinol and chlorpromazine may produce cholestasis as can alcohol. Other drug toxicities include fatty liver (steatosis), granuloma production and injury to the blood vessels. Finally long exposure to some exogenous agents including drugs can produce malignancies of the liver.
Many drugs may produce mild elevations of transaminases (enzymes) such as aspartate transaminase (AST also known as SGOT), alanine aminotransferase (ALT also known as SGPT), GGTP, and alkaline phosphatase which are often called “liver enzymes” or “liver function tests”. This is something of a misnomer as other non-hepatic problems can raise these enzymes. Bilirubin can also be elevated with liver toxicity.
Mild reversible elevations of these lab tests are usually benign and reverse after the drug is stopped or sometimes decrease or return to normal even if the drug is continued. The real issue is to prevent severe, irreversible and sometimes fatal liver toxicity.
The clinical spectrum of liver toxicity can range from no signs or symptoms at all to mild, moderate, severe and fatal. There is no way to absolutely know that a drug induced liver toxicity. Even liver biopsy may not prove it.
There are some risk factors including the underlying medical condition, the very old or young, bad nutritional status, nutritional status, alcohol use (amount, chronic, acute) and concomitant medications. The frequency of severe liver toxicity may be less than one case per 10,000 which means that this will not be identified before marketing when only a few thousand patients at most are examined in clinical trials.
Unfortunately there is usually no way to predict which patients will get the severe or fatal types of liver injury. The incidence and amount of AST/ALT elevation, the time to onset or the type of injury do not always predict the risk and outcome of liver injury. Thus one cannot always take comfort from the fact that the liver enzymes were “only” twice normal.

by

Dr.Akshaya Srikanth

Pharm.D India