Drug induced liver injury : causes and management

Causes of drug induced liver injury and its management

1. Drug induced liver injury

2. Definition- Drug induced liver is defined as injury to liver that is associated with impaired liver function caused by exposure to a drug or other non infectious agent. Types of DILI: 1.direct hepatotoxicity 2. Idiosyncratic hepatotoxicity. 3.direct hepatotoxicity

3. I. Direct toxic effect • Hepatitis occurs with predictable regularity • Dose-dependent • Latent period short (several hours) • Clinical manifestations may be delayed (24-48 hours) • CCI4, phosphorus, Amanita mushroom,Tetracycline • Liver injury may go unrecognized until the onset of jaundice

4. II. Idiosyncraic drug reactions • Hepatitis is infrequent (1 in 1000-10000 px) • Unpredictable • Response is not dose-dependent • Liver injury may occur during or shortly after exposure to the drug • Isoniazid, phenytoin, statins, oral contraceptives • Extrahepatic manifestations: rash, fever, arthralgia, leukocytosis, eosinophilia

5. Alterations in Hepatic Morphology produced by some drugs/chemical agents • Cholestasis • Fatty liver • Hepatitis • Mixed hepatitis/cholestasis • Toxic (necrosis)

6. Acetaminophen toxicity • Direct toxin • Common in US and UK • Single dose of 10-15 grams → liver injury • >25 grams → fatal • Pain, nausea, vomiting, diarrhea in 4-12 hrs • Liver failure in 24-48 hrs • Aminotranferase levels app 10,000 units • In alcoholics, toxic dose may be 2 grams

7. Treatment • Supportive measures • Gastric lavage • Activated charcoal or cholestyramine (prevent absorption); should be given within 30 mins • N-acetylcysteine given

8. Risk factors for drug induced Liver Injury:

9. R ratio • First established by council for international organizations of medical science and later modified by US FDA drug hepatotoxicity steering committee • R ratio = (ALT of patient/ ALT ULN) / ALP of patient/ ALP ULN)

10. Hy's law • Refer to a signal in trial population • Has three component 1. Higher incidence of elevation of ALT >3* ULN compared to placebo 2. Individual showing ALT or AST >3* ULN with T. bilirubin >2* ULN without initial finding of cholestasis 3. Absence of any other cause of hepatitis

11. Investigations Diagnosis of DILI relies on exclusion of alternative causes of liver injury • Complete blood count • Liver function test, GGT • Prothrombin test, INR • Viral markers Liver imaging • Liver biopsy • Genetic testing for HLA genotyping

12. Treatment of DILI - Initial step in management of DILI is to discontinue the implicated agent • Spontanous recovery occurs over days to weeks. • Improvement may not occur immediately, or worsening injury occur despite drug withdrawl leads to hospitalization of patient • Patient with acute liver failure or encephalopathy should be managed conservatively •Liver transplantation .

13. Specific therapy