Diagnosis of drug-induced liver damage

Drug-induced liver damage is most often caused by antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), cardiovascular, neuro- and psychotropic drugs, i.e., virtually all modern drugs. It should be assumed that any drug can cause liver damage, and if necessary, contact the manufacturers and organizations responsible for the safety of the drugs used.

When interviewing the patient or his relatives, it is necessary to find out the dose, method and duration of taking the drugs, and their use in the past.

Drug-induced liver injury usually occurs 5-90 days after the start of drug administration. A positive effect of drug withdrawal is indicated when transaminase activity decreases by 50% within 8 days after drug withdrawal. Repeated administration of the drug is unacceptable. However, repeated liver injury due to accidental administration serves as evidence of hepatotoxicity of the drug.

Liver diseases of other etiologies are excluded: hepatitis (A, B, C) and autoimmune liver disease, as well as biliary obstruction.

In difficult cases, liver biopsy can help with diagnosis. Drug-induced liver damage is characterized by fatty liver, granulomas, bile duct damage, zonal necrosis, and nonspecific changes in hepatocytes.

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Hepatocyte necrosis zone 3

Liver cell damage is rarely caused by the drug itself; it is usually caused by a toxic metabolite. Drug-metabolizing enzymes activate the chemically stable form of the drug, converting it into polar metabolites. These metabolites, which are powerful alkylating, arylating, or acetylating agents, covalently bind to liver molecules essential for hepatocyte function, resulting in necrosis. This is followed by depletion of intracellular detoxifying substances, particularly glutathione. In addition, oxidative reactions involving cytochrome P450 produce metabolites with an unpaired electron, the so-called free radicals. They can covalently bind to proteins and unsaturated fatty acids in cell membranes and, by causing lipid peroxidation (LPO), lead to their damage. As a result of excessive calcium concentration in the cytosol and suppression of mitochondrial function, the hepatocyte dies. Necrosis is most pronounced in zone 3, where the highest concentration of drug-metabolizing enzymes is observed, and the oxygen pressure in the sinusoid blood is minimal. Fatty liver of hepatocytes develops, but the inflammatory reaction is insignificant.

Tactics for drug-induced liver injury

	Notes
Suspicion of any drug	The manufacturer and the organizations responsible for the safety of the drugs used should be contacted.
Drug history	Find out all the medications being taken, their dosage, duration, and previous use
Stopping the reception	Rapid decrease in transaminase levels
Follow-up appointment	Usually accidental ingestion; intentional ingestion is rare
Exclusion of other liver diseases	Hepatitis A, B, C and autoimmune; biliary obstruction
Liver biopsy	If necessary; fatty liver, granulomas, zonal hepatitis, bile duct damage are characteristic

Hepatic necrosis is dose-dependent. This condition can be reproduced in animal experiments. Other organs are also affected, and kidney damage is often the most important. Mild transient jaundice is observed in mild cases. Biochemical examination reveals a significant increase in transaminase activity. PV increases rapidly. Light microscopy of the liver shows clearly demarcated necrosis of zone 3, diffuse fatty changes, and a mild inflammatory reaction. Sometimes pronounced periportal fibrosis is detected. A typical example of such a reaction is paracetamol intoxication.

The severity of zone 3 necrosis may be disproportionate to the dose of the drug taken. The mechanism of necrosis in such cases cannot be explained by a direct cytotoxic effect of the drug; idiosyncrasy to its metabolites is assumed. Halothane sometimes causes merging zonal or massive necroses, as well as an inflammatory reaction. The products of decreased metabolism, occurring with both oxidation and reduction of the drug, can have a high reactive capacity. Regardless of the method of formation, all metabolites can bind to cellular macromolecules and cause lipid peroxidation and inactivation of enzymes, both those involved in drug metabolism and those not involved in it.