DILI-Drug Induced

Liver Injury
*Drug induced liver injury is an uncommon but challenging clinical prob-
lem
*its incidence is estimated to be 14-19 cases per 100,000 persons.
3 to 5% of hospital admissions for jaundice.
*Its most frequent cause for acute liver failure in Western countries. More
Than half of cases.
*The diagnosis of drug-induced liver injury is particularly challenging,
since
it is based largely on exclusion of other causes.
*There are no specific diagnostic markers for drug-induced liver in-
jury, and special tests (liver biopsy, imaging, and testing for serologic
markers) are helpful mostly in ruling out other causes of liver injury
* more than 1200 agents (prescription and over-the-counter medications,
herbal products, nutritional supplements, metals, and toxins), along with
their potential to cause liver injury.12
Types of drug-induced liver injury

Drug-induced liver injury is typically classified as either direct or idiosyncratic, but

indirect injury is emerging as a third type.

Direct injury:
-Its caused by agents that are intrinsically toxic to the liver.
-The latency period is typically short,1-5 days after high
therapeutic dose.
 Idiosyncratic hepatotoxicity:
-its caused by agents that have little or no intrinsic toxicity that cause liver
injury in only rare cases typically 1in2000 to 1in100,000
-The latency period generally ranges from 5 to 90 days
-. Idiosyncratic liver injury is categorized as hepato- cellular, cholestatic,
or both (mixed) on the basis of the R ratio calculated by
dividing the alanine aminotransferase level by the alkaline phosphatase
level from the time of initial presentation.
-Hepatocelluar is defined as an R ratio of more than 5
-cholestatic injury value of less than 2
-mixed injury value of 2-5
 Indirect hepatotoxicity:
-its caused by the action of drug( what is does)
-its more frequent than idiosyncratic.
-Indirect injury can represent induction of a new liver
condition or an exacerbation of a preexisting condition, such
as induction of immune- mediated hepatitis or
worsening of hepatitis B or C or fatty liver disease.
Major Phenotypes
Direct Hepatoxicity:

-Serum enzyme elevations without jaundice constitute the most common pattern
of
direct drug- induced liver injury, with elevations of alanine aminotransferase or
alkaline phosphatase levels but without hyperbilirubinemia and with minimal
or no symptoms.
-The elevations resolve when the drug is stopped or the dose is lowered but can also
resolve spontaneously.
-Acute hepatic necrosis is the most common form of clinically apparent direct
hepatotoxicity. The injury occurs abruptly, soon after the medication has been
started, often after exposure to a single high dose or a dose increase.
-High doses of acetaminophen, aspirin, niacin, amiodarone, and many
antineoplastic agents can cause acute hepatic necrosis.
These drugs can be restarted in lower doses
-poisonous mushrooms can cause similar syndrome of acute hepatic necrosis
 Idiosyncratic Hepatotoxicity
-Acute hepatocellular hepatitis is the most common manifestation of idiosyn-
cratic liver injury
-The symptoms and course resemble those of acute viral hepatitis, with prominent
alanine aminotransferase elevations but alkaline phosphatase is moderate elevation.
-Drug-induced idiosyncratic acute hepatocellular injury is an important cause of
acute liver failure, accounting for 11 to 15% of cases in series from the United States
and Europe.
Common causes of drug-induced idiosyncratic acute hepatocellular injury are
isoniazid, nitrofurantoin, and diclofenac.
-All forms of idiosyncratic drug-induced hepatitis can be accompanied by
immunoallergic features, such as rash, fever, and eosinophilia signs of drug
hypersensitivity.
 Indirect Hepatotoxicity:
-Indirect drug-induced liver injury results from the medication’s actions rather
than from its inherent hepatotoxic effect.
-Fatty liver disease can be an indirect effect of drugs that cause
weight gain (risperidone and haloperidol)
-Acute hepatitis can be the indirect effect of anticancer chemotherapeutic agents
that cause a reactivation of hepatitis B, or antiretroviral agents that cause
immune reconstitution and exacerbation of hepatitis C.
Most Frequent Causes of Idiosyncratic
Prescription Drug–Induced Liver Injury
Herbal and dietary supplements.
-In studies from the United States, the proportions of cases of liver in-
jury
caused by herbal or dietary supplements increased from 7 to 9%in
2004–2007 to 19 to 20% in 2010–2014.

-typically multiple-ingredient dietary supplements marketed for weight loss,

bodybuilding, or improvements in sexual function, general well-being,

- the clinical phenotype of liver injury in most cases associated with herbal and
dietary supplements is acute hepatocellular hepatitis, which is often severe,
with a high rate of fulminant hepatic failure and need for liver transplantation.
Conclusions
-Drug-induced liver injury is an uncommon but clinically important form of
liver disease, its frequency driven by how often drugs are taken.

-Recognizing phenotypes of drug-induced liver injury is helpful in establishing the

diagnosis, identifying the responsible agent, and providing insights into
pathogenesis.

-A better understanding of the pathogenesis of drug-induced liver injury should

allow for better diagnostics and ultimately, improved approaches to prevention

and treatment.