Hepatology
Drug-induced Liver Injury Stefan David, MD,1
and James P Hamilton, MD2 1. Research Fellow; 2. Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine
Abstract
Drug-induced liver injury (DILI) is common and nearly all classes of medications can cause liver disease. Most cases of DILI are benign, and improve after drug withdrawal. It is important to recognize and remove the offending agent as quickly as possible to prevent the progression to chronic liver disease and/or acute liver failure. There are no definite risk factors for DILI, but pre-existing liver disease and genetic susceptibility may predispose certain individuals. Although most patients have clinical symptoms that are identical to other liver diseases, some patients may present with symptoms of systemic hypersensitivity. Treatment of drug and herbal-induced liver injury consists of rapid drug discontinuation and supportive care targeted to alleviate unwanted symptoms.
Keywords Drug-induced liver injury (DILI), drug-induced hepatitis, drug-induced cholestasis, acetaminophen, vanishing bile duct syndrome, herbal toxicity
Disclosure: The authors have no conflicts of interest to declare. Acknowledgments: James P Hamilton, MD, is supported by a Clinician Scientist Award funded by the Johns Hopkins University School of Medicine. Received: March 18, 2010 Accepted: October 13, 2010 Citation: US Gastroenterology and Hepatology Review, 2010;6:73–80 Correspondence: James P Hamilton, MD, Johns Hopkins School of Medicine, 720 Rutland Avenuem Ross Building, Toom 918, Baltimore, MD 21205. E:
jpahamilton@jhmi.edu
Adverse drug reactions are an important cause of liver injury that may require discontinuation of the offending agent, hospitalization, or even liver transplantation.1
cause of acute liver failure in US.2
Indeed, drug-induced hepatotoxicity is the most frequent Because the liver is responsible for
concentrating and metabolizing a majority of medications, it is a prime target for medication-induced damage. Among hepatotoxic drugs, acetaminophen (paracetamol) is the most often studied. However, a broad range of different pharmacological agents can induce liver damage, including anesthetics, anticancer drugs, antibiotics, antituberculosis agents, antiretrovirals, and cardiac medications. In addition, a plethora of traditional medical therapies and herbal remedies may also be hepatotoxic.
Depending on the duration of injury and the histological location of damage, drug-induced liver injury (DILI) is categorized as acute or chronic, and either as hepatitis, cholestatic, or a mixed pattern of injury. The hepatitis pattern is characterized by hepatocyte necrosis and is associated with a poor prognosis. There are three types of acute cholestatic drug-induced injury: bland cholestasis is the result of abnormal biliary secretion, and is not accompanied by significant hepatocellular damage; cholestatic hepatitis (mixed type) refers to cholestasis with concomitant hepatic parenchymal damage; and the third form of acute cholestasis is defined by the presence of bile duct injury or cholangiolitis. Medications may cause chronic cholestasis through two additional mechanisms: through the obliteration of bile ducts, also known as the vanishing bile duct syndrome, or by extrahepatic biliary obstruction, known as secondary sclerosing cholangitis.3–6
© TOUCH BRIEFINGS 2010
Mechanisms of Drug-induced Liver Injury DILI may be the result of direct toxicity from the administered drug or their metabolites, or injury may result from immune-mediated mechanisms (see Figure 1). Although these mechanisms are distinct, they may also be interconnected; for example, initial hepatocyte destruction due to direct drug toxicity may be further enhanced by the subsequent inflammatory reaction. It is also important to recognize that oral medications with significant hepatic metabolism are more likely to result in DILI.7
Intermediate bioactive products generated in this step may interact with various cellular organelles (e.g. mitochondria) leading to hepatocyte dysfunction and cellular demise.9
The vast majority of drugs are liposoluble and metabolized in the liver and excreted in bile or urine. The first step of drug metabolism is known as a phase I reaction and is mediated by enzymes of the hepatic cytochrome p450 system.8
These potentially toxic
intermediate products are then inactivated through glucurono-, glutathione- or sulfa-conjugation in subsequent phase II reactions. In order to limit hepatotoxicity, the generation rate for phase I products should not exceed the liver’s capacity to inactivate them. Depletion or deficiency of the compounds responsible for the phase II conjugation reactions may result in accumulation of toxic metabolites. Such is the case in patients who abuse alcohol and ingest acetaminophen.10
In this example, even low-dose acetaminophen can result in severe liver damage.11
One of the earliest events in DILI is the inhibition of the mitochondrial respiratory chain, resulting in increased reactive oxygen species (ROS) and 73
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