1. Drug-induced liver injury part I
Domina Petric, MD

2. Significance and epidemiology

3. Occurrence vs. significance
BUT
The occurrence of adverse hepatic reactions to a drug are rare, ranging from 1 in 10,000 to 1 in 100,000.
Drug induced liver injury (DILI) contributes significantly to patient morbidity and mortality.
Hartleb et al
Lazarou et al
Lazerow et al
Lee and Senior 2005.
Pessayre et al
Zimmerman 1999.

4. Incidence
A population-based study in France concluded that the annual incidence of hepatic adverse drug reactions is approximately 14 in 100,000 (Sgro et al. 2002).
Sgro et al

5. Survival
Only 20% of patients presenting with acute liver failure due to DILI survive with supportive care (Ostapowicz and Lee 2000).
Ostapowicz and Lee 2000

6. DILI
DILI is the most frequent basis for drug-related regulatory actions (Watkins and Seeff 2006):
termination of clinical drug trials
failure to obtain US Food and Drug Administration (FDA) approval
restriction of use
postmarket withdrawal of drugs
Bellet Bakke et al Kaplowitz 2001.
Larrey Temple and Himmel 2002.

7. Prevention

8. Prevention
A major concern associated with DILI is the failure of the drug development system to more accurately identify potentially hepatotoxic drugs.

9. Challenges
Lack of specific diagnostic markers or tests to verify an episode of DILI.
Generally underpowered nature of clinical trials.
Idiosyncratic nature of these reactions.

10. Clinical spectrum

11. Clinical spectrum
Ranges from abnormalities in liver enzyme levels to fulminant hepatic failure resulting in liver transplantation or death.

12. Acute hepatocellular injury
The predominant form of DILI is acute hepatocellular injury, representing up to 90% of cases.
This type of hepatic damage is usually characterized by an initial early increase in ALT levels.
Acute hepatocellular injury manifests as cell death, characterized as either zonal or non-zonal, in the form of necrosis and/or apoptosis, steatosis, and other types of hepatocyte degeneration.
Larrey 2000.

13. Acute hepatocellular injury
Drugs known to cause hepatocellular necrosis include:
Sulfonamides
Acetaminophen
Diclofenac
Pemoline
Wikimedia Commons

14. Submassive hepatocellular injury
Submassive hepatocellular injury may be followed by hepatic fibrosis and cirrhosis.
Examples of culprit drugs include:
Methotrexate
Isoniazid
Valproic acid

15. Cholestatic injury
Cholestatic injury is usually associated with an early elevation in alkaline phosphatase (ALP) levels, with or without hyperbilirubinemia.
This injury represents the second most frequent type of DILI.
Amoxicillin/clavulanate is one of the most common causes of acute cholestatic injury that resembles biliary obstruction.

16. Cholestatic damage, cholestasis
Anabolic steroids (methyl testosterone and fluoxymesterone), contraceptive steroids and cyclosporine have been associated with pure cholestatic damage.
Chlorpromazine and carbamazepine have been linked with cholestasis with hepatocellular injury.

17. Mixed liver injury
Mixed pattern of liver injury is characterized by elevations of both ALT and ALP levels.
Clinicopathological manifestations include those present in both hepatocellular and cholestatic injury, as well as granulomatous reactions.
A mixed liver injury has been associated with carbamazepine, flutamide, phenobarbital, sulfonamides and verapamil.

18. Hy´s law
The combination of cellular injury and hepatic dysfunction as evidenced by jaundice was reported by Hyman Zimmerman to result in a mortality rate ranging from 10-50% (Zimmerman 1999).
These observations have subsequently been referred to as Hy’s Law.
Modified Hy’s Law: ALT levels ≥3 x ULN plus serum bilirubin levels ≥2 x ULN.
ULN-Upper Limit of Normal

19. Risk factors

20. preexisting liver disease
Risk factors
gender
age
nutritional status
preexisting liver disease
concomitant drug use
genetic background

21. Female sex The female sex is generally more susceptible to DILI.
Women are also more susceptible to hepatotoxicity from halothane, chlorpromazine and diclofenac.
AYD 1963.
Banks et al

22. Age
In general, the susceptibility to DILI is greater in adults than in children, which may be the result of decreased clearance, reduced hepatic blood flow and compounding drug-drug interactions.
Adults have an increased risk for hepatic injury from halothane, nitrofurantoin, floxacillin, and in particular isoniazid.
Black et al Fairley et al
Farell Stricker Zimmerman 1999.

23. Aspirin, erythromycin estolate
Adverse hepatic reactions for aspirin and erythromycin estolate are predominant in children.
Fairley et al Farell 1994.
Zimmerman 1999.

24. Valproic acid
Hepatotoxicity in regards to valproic acid is 1 in 37,000 (Bryant and Dreifuss 1996).
This risk is much more pronounced (1 per 500 exposed) in children younger than 3 years of age.

25. Nutritional status
Nutritional status may also represent a risk factor with respect to DILI.
Fasting and malnutrition have been shown to enhance the toxicity of acetaminophen, possibly by depletion of hepatic glutathione stores.
Farell 1994.
Pessayre et al
Stricker 1992.

26. Preexisting liver disease
Patients infected with the human immunodeficiency virus (HIV) receiving antiretroviral drug therapy have been reported to be at an increased risk for hepatotoxicity when they are coinfected with chronic hepatitis B virus and C virus.
den Brinker et al
Pol et al Sulkowski et al

27. Concomitant drug usage
Isoniazid has been observed to enhance acetaminophen toxicity (Murphy et al. 1990).
The induction of particular enzymes by one drug may facilitate the increased formation of toxic metabolites of a second drug.
Rifampicin-isoniazid combination: rifampicin facilitates the biotransformation of isoniazid into toxic metabolites (Farell 1994; Stricker 1992).

28. Concomitant drug usage
Inhibition of an enzyme pathway may influence important detoxification pathways.
Interaction of troleandomycin and estrogen: troleandomycin inhibits estrogen metabolism, thereby creating an overdose of estrogen resulting in cholestatic injury (Claudel et al. 1979).

29. Genetic factors
HLA polymorphisms

30. Literature
Holt M. Ju C. Drug-Induced Liver Injury. In: Uetrecht. J. Adverse Drug Reactions. Springer;2010.p.3-29.