Drug-induced liver injury or DILI is the leading reason for a drug that is approved by the Drug Administration to subsequently be withdrawn from the market.
DILI can result from both prescribed and over-the-counter (OTC) agents, including some herbal and dietary supplements. It is both difficult to predict and challenging to recognize.
Hy’s law: Jaundice (bilirubin >2 times upper limit of normal [ULN]) in combination with elevated serum aminotransferase levels (>3 times ULN) has the worst prognosis. These findings in a patient with a hepatocellular pattern of injury are associated with high mortality rates (10-50%) without transplantation. This pattern was first identified by Hyman Zimmerman and is now called Hy’s law.
Categorizing DILI on the basis of the three injury patterns—hepatocellular, cholestatic, and mixed hepatocellular-cholestatic may not characterize the injury completely. A clinical phenotype is also used; 12 DILI phenotypes have been described.
1. Acute hepatic necrosis
2. Acute hepatitis
3. Cholestatic hepatitis
4. Mixed hepatocellular-cholestatic hepatitis
5. Enzyme elevations without jaundice
6. Bland cholestasis
7. Hepatic steatosis and lactic acidosis
8. Nonalcoholic fatty liver
9. Chronic hepatitis
10. Sinusoidal obstruction syndrome (veno-occlusive disease)
11. Nodular regenerative hyperplasia
12. Hepatic adenoma and hepatocellular carcinoma
The 12 phenotypes can have distinctive immunological features:
The 12 phenotypes also have adverse outcomes:
· Acute liver failure
· Vanishing bile duct syndrome
Paracetamol is the leading cause of DILI. However, only about half of cases occur due to intentional overdose; the remaining half are due to chronic use or unintentional overdoses. Long-term use of supratherapeutic amounts is more toxic and recognized later than a single ingestion; therefore, these patients have higher rates of severe hepatotoxicity, liver-related complications and death, as compared to those who have attempted suicide with paracetamol.
Alcohol- and paracetamol-linked DILI: Ingesting alcohol and acetaminophen together does not increase the risk for hepatotoxicity due to the paracetamol. Alcohol, as a substrate of CYP2E1, may lower the risk for liver injury by competing with paracetamol for the enzymes thus decreasing the amount of the toxic metabolite produced. The role of chronic alcohol ingestion is controversial. A lower daily dose of paracetamol is recommended for these patients.
Patients with advanced liver disease should also limit their paracetamol intake. Cirrhosis, regardless of the etiology, reduces the metabolism of acetaminophen. Therefore, patients with either an alcohol use disorder or underlying liver disease should be advised to limit their daily amount of acetaminophen to less than 2 g/day.
Risk for DILI from statins: Mild to moderate transient asymptomatic elevations in serum aminotransferase levels are common with statins. This phenomenon occurs early after the initiation of therapy but eventually normalizes, despite ongoing therapy. So, this is a lab abnormality and not a true liver injury; liver biopsy shows no histopathologic change.
According to the Drug-Induced Liver Injury Network (DILIN), only 3.4% of reported drug-induced liver injuries were linked to statins. Growing evidence also shows that statins may actually reduce the risk for liver cancer and improve outcomes in those diagnosed with hepatocellular carcinoma.
Clinicians should not be afraid to use this class of agents to reduce the risk for cardiovascular disease.
Herbal does not mean risk-free. The DILIN found that 15%-20% of DILI cases could be attributed to herbal and dietary supplements. Most liver injury that is induced by herbal and dietary supplements is attributed to bodybuilding agents (anabolic steroids), green tea extract, and multi-ingredient nutritional supplements, many of which also list green tea as a component. Others implicated include those for weight loss, depression, sexual performance, gastrointestinal upset, immune support and joint support, as well as Chinese herbs.
(Source: Medscape; LiverTox, National Institute of Health)
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