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Health See other Health Articles Title: Drug-Induced Liver Injury: What You Need to Know The liver is the principal site of the body's drug metabolism, so it isn't surprising that drug-induced liver injury (DILI) can occur. However, despite the common use of medications in today's society, DILI develops in only a small number of patients -- approximately 1 in 10,000 to 19 in 100,000 people are affected.[1] Antibiotics are a common cause of DILI in all age groups and are the drugs most frequently associated with childhood liver injury. Acetaminophen is a common cause of acute liver injury in adults. The American College of Gastroenterology (ACG) has recently published guidelines for the diagnosis and management of DILI.[2] The guidelines point out the importance of a careful patient history with respect to the use of medications or herbal supplements in those with recent-onset liver disease, and the need to consider drug-induced causes in patients with what appears to be acute viral hepatitis or chronic liver disease of other types. Herbal supplements are commonly used in the United States. These are difficult to ascertain as the cause of liver injury, owing to a lack of uniformity and the presence of impurities or other components in herbal preparations. If the history identifies the use of herbal supplements in a patient with liver disease, these supplements should be discontinued. Many excellent reviews of herbal preparations and liver injury are available.[3-5] Premarketing studies of new medications do not consistently identify the potential for hepatotoxicity because in clinical trials, patients are often carefully chosen or excluded from participation on the basis of alcohol use, or a preexisting hepatic or other chronic disorder. Postmarketing surveillance of new medications is important. The broad range of personal factors present in the general population of individuals taking a new medication can lead to the identification of hepatotoxicity, or even prompt withdrawal of the drug from the market. Pathophysiology of Drug-Induced Liver Injury The pathogenesis of DILI is not fully understood.[7] Potential relationships include intrinsic or direct hepatotoxicity, liver injury from activation of immunologic mechanisms, or drug-induced impairment of mitochondrial function. Personal, genetic, and environmental factors can also contribute to the development of liver injury from medications.[8] Furthermore, patients are often taking more than one medication, and it may be the combined effect that allows liver injury to develop. Some drugs are direct hepatotoxins; others produce an idiosyncratic reaction that causes liver injury. Most DILI is idiosyncratic and seemingly independent of dose, duration of medication use, or route of drug administration.[7] Acetaminophen is an intrinsic hepatotoxin when taken in sufficient dosage. It is the only common pharmaceutical in use that produces direct hepatotoxicity, and it is the most frequent cause of acute liver failure in the United States and the United Kingdom.[9] In general, the risk for DILI is related to the class of drug, the quantity of drug consumed; the patient's age and sex; and such concurrent factors as diabetes mellitus, excessive ethanol intake, or the use of other medications.[2,10] Drugs administered in higher doses are more likely to cause liver injury,[11] especially drugs that require extensive hepatic metabolism.[12] Increased patient age also carries a greater risk for DILI,[13] although children are at greater risk for injury from such medications as antibiotics.[14] Women appear to be at higher risk from medications that produce chronic hepatitis-like manifestations,[1,2] and pregnancy carries a risk for hepatotoxicity from tetracycline.[15] Genetic factors also influence drug metabolism and can result in more severe hepatotoxicity[16]: for example, isoniazid in black persons and Hispanic persons.[17] Human leukocyte antigen (HLA) subtypes are associated with hepatotoxicity,[18] as evidenced by the liver injury that develops in patients with HLA-B*5701 with the use of flucloxacillin.[19] Alcohol intake and malnutrition can also influence drug-induced hepatotoxicity.[20] The role played by environmental factors in DILI is unclear. Underlying cirrhosis does not typically increase the likelihood of idiosyncratic drug hepatotoxicity.[21] Medications can produce many manifestations of liver disease, including hepatocellular injury (acute hepatitis, massive liver cell necrosis, and autoimmune hepatitis-like disease), cholestasis (pure cholestasis, cholestasis and hepatitis, cholestasis with bile duct injury, and vanishing bile duct syndrome), fatty liver, peliosis, and hepatic tumors (hepatocellular carcinoma, cholangiocarcinoma, and angiosarcoma). Clinical Manifestations of Drug-Induced Liver Injury The diagnosis of DILI can be difficult to establish, and other causes of acute and chronic liver disease must be excluded. Of greatest importance, in patients who have abnormal liver tests and are taking medications or herbal preparations, DILI should always be considered. A careful history and physical examination can link the timing of drug use to the onset of liver disease. Liver injury from medications usually occurs within 6 months of drug initiation and typically within the first 1-4 weeks. Other risk factors for DILI (older age, concomitant medication use, alcohol consumption, and reexposure to a previously used medication) should be identified and the symptoms and signs of other forms of chronic liver injury sought. In general, the symptoms of DILI are nonspecific and include nausea, vomiting, pruritus, malaise, right upper-quadrant discomfort, and loss of appetite. Such signs as excoriations, fever, eosinophilia, rash, or serum sickness can all be indicators of liver disease, along with jaundice, dark urine, or light-colored stools. The simultaneous occurrence of medication use, rash, eosinophilia, fever, and liver injury should raise the question of autoimmune liver injury. Autoantibodies, including antinuclear and smooth-muscle antibodies, may also be present.[18] If, after careful evaluation, the diagnosis of DILI is still not clearly established, the ACG guidelines suggest referral for expert consultation.[2] Laboratory Testing Liver tests should be obtained in all patients with suspected DILI. Calculating the ratio of the alanine aminotransferase (ALT) value/ALT upper limit of normal (ULN) divided by the alkaline phosphatase (AP) value/AP ULN can help to differentiate hepatocellular from cholestatic liver injury (Figure).[2] The ratio is typically ≥ 5 in hepatocellular injury, < 2 in cholestatic liver injury, and between 2 and 5 in mixed hepatocellular/cholestatic liver injury. Figure. Calculation of the ratio of ALT and AP to assess type of drug-induced liver injury. ALT = alanine aminotransferase; AP = alkaline phosphatase; R = ratio; ULN = upper limit of normal. In acute hepatocellular injury, aminotransferases are modest, although often elevated more than twofold. The ratio of aspartate aminotransferase (AST) to ALT is close to 1, with the ALT often higher than the AST. If the AST/ALT ratio is ≥ 2, acute alcoholic hepatitis or nonalcoholic fatty liver disease should be considered in the differential diagnosis. Minimal or no elevation of AP is typical in acute DILI. Very high aminotransferase levels develop with severe hepatocellular injury, such as that occurring with excessive acetaminophen ingestion. The differential diagnosis of acute hepatocellular injury from drugs includes acute viral hepatitis, autoimmune hepatitis, acute Budd-Chiari syndrome, Wilson disease, and ischemic liver injury.[2] Medication-induced cholestatic liver injury is associated with marked elevation of AP and minimal to modest elevation of aminotransferases. Jaundice can be present. The differential diagnosis of cholestatic DILI includes primary biliary cirrhosis; hepatic replacement disease from granulomata or tumors; and intrahepatic cholestasis or extrahepatic bile duct injury from such cholangiopathies as sclerosing cholangitis, tumors, stones, or bile duct strictures. The ACG guidelines recommend obtaining ultrasonography of the liver and biliary tree in all patients with suspected drug-induced cholestasis, plus an antimitochondrial antibody titer if ultrasonography does not show bile duct abnormality or pursuing cholangiography if choledocholithiasis, sclerosing cholangitis, or hepatobiliary tumors are suspected.[2] Reactivation of hepatitis B virus (HBV) infection can result in acute viral hepatitis after administration of corticosteroids or other immunosuppressive agents. Testing for HBV should be considered in all patients with known risk factors for hepatitis B carriage before receiving immunosuppressive medications. Although acute hepatitis E might be considered in patients with hepatocellular or mixed hepatocellular/cholestatic liver injury, in the United States, only 3% of those with suspected DILI are positive for hepatitis E virus (HEV),[22] and routine testing in patients with suspected DILI is not recommended.[2] Non–organ-specific autoantibodies (antinuclear and smooth-muscle antibodies) may develop in patients with DILI but are typically present in low titers, compared with the high titers observed in patients with idiopathic autoimmune hepatitis. With severe acute hepatocellular or cholestatic DILI, coagulopathy with elevation of the international normalized ratio may be caused by either hepatocellular injury or malabsorption of vitamin K. Histology of Drug-Induced Liver Injury Liver biopsy can be helpful in the diagnosis of DILI by providing evidence of disease severity. Biopsy should also be considered when liver tests worsen despite discontinuing the offending medications or when autoimmune hepatitis is suspected.[2] Depending on the drug, DILI can present with the following histologic findings: Acute hepatocellular necrosis (acetaminophen and isoniazid); Cholestasis (anabolic steroids and sulfonamides); Bile duct injury with cholestasis (chlorpromazine); Vanishing bile duct syndrome (amoxicillin/clavulanate); Fatty liver (tetracycline, amiodarone, and chemotherapy agents); Reye syndrome (aspirin); Peliosis (azathioprine); Granulomata (sulfonamides); Fibrosis (methotrexate and hypervitaminosis A); Autoimmune hepatitis-like disease (oxyphenisatin); Vascular injury (veno-occlusive disease from busulfan or melphalan); and Malignant tumors (anabolic steroids). Treatment of Drug-Induced Liver Injury In general, the treatment of patients with suspected DILI entails withdrawal of the offending medication and provision of supportive care.[23,24] For patients with acetaminophen overdose, administration of the unapproved medication N-acetylcysteine (NAC) should be considered.[25] ACG guidelines do not recommend NAC administration to children.[2] Abnormal laboratory tests, including aminotransferases, AP, and bilirubin, should be repeated after drug withdrawal until they become normal. Chronic DILI can occur and may respond to corticosteroids after other causes of the liver injury have been excluded. One question that frequently comes up is whether there is a risk for statin-induced acute liver injury in patients with cirrhosis from such diseases as nonalcoholic steatohepatitis. No significant risk for hepatotoxicity from statin use in patients with advanced liver disease has been observed.[2] Prognosis Patients with medication-induced acute hepatocellular injury tend to have a worse prognosis than those with drug-induced cholestasis or mixed hepatocellular/cholestatic liver injury. Medication-related acute hepatic failure remains the most frequent cause of liver transplantation for acute liver failure in the United States. Hyman Zimmerman suggested that patients with acute hepatocellular injury who also developed jaundice had a 10% likelihood of hepatic failure and death,[26,27] an observation that has been referred to as "Hy's Law."[2] Other studies have found that a serum ALT value > 3 times normal occurring with a bilirubin level at least twice normal is associated with 10% mortality.[28] Among patients with drug-induced acute hepatic failure, 40% will require liver transplantation or die as a result of their liver injury. Patients with drug-induced cholestasis may require months or up to 1 year or more for their liver tests to return to normal.[1] Chronic DILI resembling autoimmune hepatitis can develop. Treatment with corticosteroids should be considered if clinical findings support the diagnosis and liver tests do not improve with cessation of the offending drug. As a rule of thumb, rechallenging a patient with a drug suspected of causing DILI should be avoided.[2] Take-Away Points The diagnosis of DILI is largely a process of exclusion of other causes of liver disease, coupled with a thoughtful history and physical examination that identify causative medications. The ACG guidelines[2] propose an algorithm defined by identification of suspected DILI as hepatocellular, cholestatic, or mixed hepatocellular/cholestatic liver injury, with a differential diagnosis and clinical judgment that establish the final diagnosis. Individuals with suspected hepatocellular or mixed hepatocellular/cholestatic liver injury should be evaluated for acute viral hepatitis caused by HBV and other nonhepatotropic viruses (cytomegalovirus, Epstein-Barr virus, herpes simplex), and for autoimmune hepatitis and other forms of acute liver injury, such as Budd-Chiari syndrome and Wilson disease. Remember that Wilson disease typically presents as acute liver injury before the age of 25 years, although it can present later in life. Routine testing for HEV in patients with suspected DILI is not currently recommended. Patients with cholestatic liver injury should be evaluated with ultrasonography to exclude primary biliary cirrhosis, and with cholangiography as needed for suspected stones, strictures, or tumors. The guidelines also recommend consideration of liver biopsy for patients with possible autoimmune hepatitis or when abnormal liver tests fail to resolve promptly. Patients with suspected DILI should stop taking offending medications, and NAC can be administered to adults with acute liver failure. Reexposure to a drug suspected of causing DILI is discouraged. Editors' Recommendations Drug-Induced Liver Injury Guidelines Released by ACG Risk of Liver Injury With New Oral Anticoagulants Poster Comment: Medication-related acute hepatic failure remains the most frequent cause of liver transplantation for acute liver failure in the United States. Something that needs to be gotten across in high school health: Avoid behavior that requires medication or damages the liver. Post Comment Private Reply Ignore Thread
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