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KEY CONCEPTS

KEY CONCEPTS

  • image Through its normally functioning enzymes and processes the liver often causes a drug to become toxic through a process known as bioactivation.

  • image Drug-induced liver disease (DILD) can have many different clinical presentations: idiosyncratic reactions, allergic hepatitis, toxic hepatitis, chronic active toxic hepatitis, toxic cirrhosis, and liver vascular disorders.

  • image The mechanisms of DILD are diverse, representing many phases of biotransformation, and are susceptible to genetic polymorphism.

  • image The assessment of a possible liver injury caused by drugs should include what is known in the literature, the timing involved, the clinical course, and, always, an exploration for preexisting conditions that may have encouraged the lesion’s development.

  • image Liver enzyme assays in serum can help to determine if a particular type of liver damage is present.

  • image Monitoring for DILD must be tailored to the drug and the patient’s potential risk factors.

The number of drugs associated with adverse reactions involving the liver is extensive, but in clinical practice is dominated by alcohol, antibiotics, antiseizure medications and acetaminophen.1 Complementary (herbal) medicines contribute disproportionately as well to this disease burden Drug-induced liver disease (DILD) is potentially fatal, often debilitating outcome of drug treatment. DILD is thought to be responsible for 11% to 13% of all cases of acute liver failure in the United States.1,2

Drug-induced liver disease accounts for as much as 20% of acute liver failure in pediatric populations and a similar percentage of adults with acute liver failure.3 In approximately 75% of these cases, liver transplantation is ultimately required for patient survival.4 Of patients who required liver transplantation according to the United Network for Organ Sharing, acetaminophen, isoniazid, antiepileptics, and antibiotics collectively account for just over 60% of cases.5

The liver’s function affects every other organ system in the body; it in turn is exposed to every substance absorbed from the gut and every injected substance that enters the bloodstream. This chapter will first explore the underlying mechanisms in DILD. Then proceed to develop the key therapeutic skill required in recognizing and categorizing what is and what is not DILD.

MECHANSIMS OF DRUG-INDUCED DISEASES

Stimulation of Autoimmunity

Autoimmune injuries involve antibody-mediated cytotoxicity or direct cellular toxicity.6,7 This type of injury occurs when enzyme–drug adducts migrate to the cell surface and form neoantigens. The liver plays host to all of the cells that make up the innate immune response system in the body along with Kupffer cells, which are a type of macrophage. These cells sit in anticipation around the hepatocytes, in the space of Disse and elsewhere waiting for antigens (or neoantigens) to present themselves. The neoantigens serve as targets for cytolytic attack by killer T-cells, and others.8 Halothane, sulfamethoxazole, carbamazepine, nevirapine, fluoroquinolones, and antitumor necrosis factor (TNF) alpha inhibitors are associated with autoimmune injuries.2,9 Stimulation of ...

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