Juan F. Gallegos-Orozco, MD and Hugo E. Vargas, MD
What is the prevalence of drug-induced liver injury (DILI) or hepatotoxicity as a cause of acute liver failure?
DILI accounts for more than 50% of cases of acute liver failure. Acetaminophen is the most common cause in the United States.
What is the clinical importance of jaundice in patients with DILI and elevated aminotransferases?
It is a marker of poor prognosis, with an estimated mortality of 10%.
What is the clinical importance of eosinophilia in patients with DILI?
It is a marker of improved short-term prognosis.
What are the common steps of hepatic metabolism of orally administered drugs?
• Phase I: Allows drugs to become hydrophilic and is accomplished by oxidation, reduction or hydrolysis; catalyzed primarily by cytochrome P450 enzyme superfamily.
• Phase II: A polar group is added to allow excretion of the metabolites from phase I. This is accomplished through conjugation with glutathione, glucuronic acid, or sulfate to produce a more water-soluble product and facilitate urinary or biliary excretion.
• Phase III: Transport of drugs and drug-products into the bile. This is mediated by adenosine triphosphate (ATP)-dependent transporters located in the bile canaliculi.
What two types of drug reactions have been described in DILI?
1. Direct reactions: Dose-dependent, reproducible, and predictable course.
2. Idiosyncratic reactions: Generally manifest after a latency period of 5–90 days and are characteristically unpredictable and not dose-related and can be divided in two main categories:
b. Immunologic (hypersensitivity reaction to a specific drug).
What are the biochemical patterns of liver chemistries in DILI?
• Hepatocellular: alanine transaminase (ALT) > 5 times upper limit of normal (ULN), alkaline phosphatase (AP) <2 ULN; R > 5 (R, ratio of serum ALT/ULN for ALT to serum AP/ULN for AP).
• Cholestatic: ALT <5 x ULN, AP >2 x ULN; R <2.
• Mixed: ALT >3 x ULN, AP >2 x ULN; R 2-5.
What are some of the important enzyme systems that detoxify reactive drug metabolites produced by cytochrome P450?
The most important protective system is glutathione and glutathione-S-transferase, which is very abundant in hepatocytes. Another important enzyme is epoxide hydrolase, which breaks down reactive epoxides produced from drugs such as phenytoin.
What drugs are commonly mentioned in association with fulminant liver failure?
Acetaminophen, amoxicillin/clavulanic acid, phenytoin, isoniazid (INH), niacin, and valproic acid are a few examples.
Provide examples of medications in which concomitant chronic alcohol consumption may increase the risk of DILI.
Chronic alcohol intake increases the risk of liver fibrosis during therapy with methotrexate and enhances acetaminophen hepatotoxicity and susceptibility to liver damage from INH, halothane, and cocaine.
What other risk factors have been implicated in the development of liver fibrosis during methotrexate treatment?
Obesity, type 2 diabetes mellitus, insulin resistance, and psoriasis.
True/False: All patients with DILI require a liver biopsy.
False. Liver biopsy is not necessary in the management of patients with DILI, although it can be useful under certain circumstances:
• Patient has chronic liver disease and clinical presentation is difficult to ascribe to DILI versus underlying liver disease.
• To characterize the histological pattern of injury of drugs not previously known to be hepatotoxic.
• To identify more severe or residual lesions, such as advanced fibrosis, which could have prognostic significance.
How common is hepatotoxicity due to highly active antiretroviral therapy (HAART) in patients with HIV/AIDS?
Up to 30% of patients on HAART experience significant aminotransferase elevations.
What are the common risk factors for HAART hepatotoxicity in patients with HIV/AIDS?
Coinfection with hepatitis C or hepatitis B virus, advanced liver disease of any cause, and elevated aminotransferase levels before initiating HAART.
What are the most common HAART drugs implicated in hepatotoxicity?
• Didanosine and stavudine (nucleoside reverse transcriptase inhibitors) have been reported to cause a rare, but potentially fatal, hepatic steatosis and lactic acidosis.
• Nevirapine (nonnucleoside reverse transcriptase inhibitor) has a black-box warning as a cause of fatal and non-fatal hepatotoxicity. It has been associated with a hypersensitivity syndrome (rash, fever, and eosinophilia).
• Ritonavir and tipranavir (protease inhibitors) can both cause hepatotoxicity and acute liver failure.
What is antiretroviral-associated portal hypertension?
It is a novel clinical condition in which patients on antiretroviral therapy present with variceal hemorrhage, ascites, and other signs of portal hypertension. Didanosine has been implicated in its pathogenesis and removal of the drug results in clinical improvement.
What is the importance of antibiotics in DILI?
As a group, antibiotics have been implicated in up to 45% of cases of DILI in the United States. The most common antibiotic associated with DILI is amoxicillin with clavulanic acid, and is second only to acetaminophen as a cause of DILI in the United States.
What are the main characteristics of DILI from amoxicillin/clavulanic acid?
Cholestasis, which may be severe, is the most common pattern of injury. Other clinical features include skin rash, eosinophilia, and fever. Hepatotoxicity associated with amoxicillin/clavulanic acid is usually mild and subsides within 12 weeks of discontinuation of the drug. Rarely can it cause chronic liver disease with cholestasis and ductopenia with prolonged use.
What are the common features of INH hepatotoxicity?
It is the most frequent antimicrobial agent implicated in cases of DILI worldwide and commonly causes hepatocellular necrosis that can lead to liver failure and death.
What are risk factors for overt liver injury from INH?
Increasing age, female gender, and heavy alcohol use. Concomitant use of rifampin results in a fourfold increase in the risk of clinical hepatitis.
What are the common features of rifampin hepatotoxicity?
Hepatotoxicity from rifampin is less common than with INH. As a competitive inhibitor of bile salt uptake and export, it causes a mild cholestatic pattern of injury.
Describe the mechanism of acetaminophen hepatotoxicity.
Acetaminophen is a direct hepatotoxin when given in excessive doses or in therapeutic doses when the protective detoxifying pathway (P450 2E1) of the liver is overwhelmed. Accumulation of the toxic metabolite N-acetyl-p- benzoquinone-imine (NAPQI) is the cause of hepatocyte necrosis.
Describe the histology of the liver after an acute overdose of acetaminophen. What explains this pattern of liver injury?
The liver shows a nearly pure necrosis, most marked in zone 3 (around the central vein). This probably results from the metabolism of acetaminophen by cytochrome P450, which is more abundant in zone 3.
What is a toxic dose of acetaminophen?
In nonalcoholic individuals, acetaminophen is toxic in doses >7.5 g/24 hours. Chronic alcoholics or malnourished individuals are more susceptible to acetaminophen toxicity even when taken in therapeutic doses. It is generally recommended that patients with chronic liver disease limit the daily dose of acetaminophen to no more than 2 g/day.
List risk factors for acetaminophen hepatotoxicity.
Regular heavy use of alcohol. Phenobarbital, INH, and other drugs that induce cytochrome P450. Obesity may also increase the risk of toxicity because it is associated with increased cytochrome P450 2E1. Fasting reduces glutathione levels.
Why does alcohol increase the risk of acetaminophen hepatotoxicity?
Alcohol induces cytochrome P450 2E1, which metabolizes acetaminophen to a toxic, reactive quinoneimine compound. Alcohol also causes depletion of glutathione, which functions to detoxify such reactive substances in the liver.
What drugs or chemicals are inducers or substrates of P450 2E1?
INH has the greatest effect on cytochrome P450 2E1 induction. Ethanol, acetaminophen, carbon tetrachloride, chloroform, halothane, cocaine, benzene, and nitrosamines are other substrates or inducers of P450 2E1. This explains some of the interactions among alcohol and a number of other toxins and carcinogens. Alcohol metabolism by P450 2E1 produces reactive oxygen species, which are thought to contribute to the toxicity of alcohol.
How is prognosis estimated in patients with acute liver failure caused by acetaminophen?
The O’Grady or King’s College criteria are commonly used to predict a fatal outcome and the need for liver transplantation in patients with fulminant liver failure. For acute acetaminophen toxicity, these criteria include: pH <7.3 (irrespective of encephalopathy grade) or international normalization ratio (INR) >6.5 (prothrombin time >100 seconds), serum creatinine >3.4 mg/dL, and grade III or IV hepatic encephalopathy.
What is the difference between macrovesicular and microvesicular fatty liver, in terms of lipid composition and pathophysiology?
Macrovesicular fat is mostly triglyceride accumulated due to increased influx and decreased efflux of lipid. Microvesicular fat is mostly unesterified fatty acid, which accumulates in conditions in which mitochondrial oxidation of fatty acids is impaired.
What drugs or toxins often cause macrovesicular steatosis of the liver?
Ethanol, glucococorticoids, methotrexate, and chlorinated hydrocarbons (such as carbon tetrachloride) are good examples.
What drugs or toxins result in severe microvesicular steatosis of the liver?
Aspirin in an overdose or in Reye’s syndrome, tetracycline, and valproic acid. Some nucleoside analogs used in treating HIV disease, such as zidovudine and lamivudine, can cause mitochondrial dysfunction with microvesicular steatosis. The nucleoside analog fialuridine, used in clinical trials for treatment of hepatitis B, caused severe mitochondrial dysfunction with microvesicular steatosis, lactic acidosis, and liver failure.
What drugs or toxins mimic the histological features of alcoholic hepatitis?
The best example is amiodarone. Nifedipine, diethylstilbesterol (DES), and tamoxifen can also cause Mallory’s hyaline and steatosis.
A liver biopsy shows extensive homogenous intracellular material in hepatocytes. Electron microscopy shows whorls of concentric intracellular membranes. What is this and what drugs or toxins can cause it?
This is phospholipidosis, caused by amiodarone, perhexiline maleate, chlorpheniramine, and a few other drugs. A number of the drugs that cause this are lipophilic cations.
What is peliosis hepatis?
Peliosis hepatis is a condition characterized by vascular pools in the liver, from a few millimeters to a centimeter in size, perhaps related to obstruction of the sinusoidal-central vein junction. Peliosis has been associated with hepatomegaly. Such livers are prone to bleeding after biopsy. Peliosis hepatis is associated with the use of anabolic steroids, estrogens, and thiopurines.
What is nodular regenerative hyperplasia (NRH) and what medications can cause this condition?
NRH is characterized by a diffusely nodular liver without fibrosis. NRH is thought to result from diffuse obstruction of microscopic arterioles with regeneration of better perfused areas. It is associated with the use of oral contraceptives, anabolic steroids, azathioprine, busulfan, and 6-thioguanine.
List some medications that may cause indirect hyperbilirubinemia.
Rifampin interferes with the uptake of unconjugated bilirubin by hepatocytes. Nicotinic acid can increase unconjugated bilirubin in patients with Gilbert’s syndrome. Elevation of unconjugated bilirubin can also be a sign of hemolysis, which could be drug induced, such as seen with ribavirin during treatment for chronic hepatitis C.
What drugs may cause inflammation involving microscopic bile ducts?
Sulfa drugs often result in some combination of cholestasis and hepatocellular injury. Sulfonylurea use may lead to a syndrome histologically resembling primary biliary cirrhosis (PBC) but with negative antimitochondrial antibody (AMA). Diclofenac has caused a number of cases resembling PBC, sometimes with positive AMA. A large number of drugs cause chronic cholestasis. Carbamazepine may result in hepatic inflammation centered on bile ductules.
Explain what is meant by “vanishing bile ducts” and list some drugs that may cause this.
This refers to the disappearance of microscopic bile ductules, which normally number one to two per portal triad on a liver biopsy. The syndrome of vanishing bile ducts occurs in advanced PBC or in chronic liver allograft rejection. Some drugs associated with this syndrome include carbamazepine, phenothiazines, and thiabendazole.
What drugs cause damage or inflammation to large bile ducts?
The best example is FUDR (5-fluoro-deoxyuridine) given by intra-arterial infusion. This results in a syndrome resembling sclerosing cholangitis and is probably due to vascular injury.
What drugs can lead to a chronic hepatitis mimicking autoimmune hepatitis?
Sulfonamides, propylthiouracil, alpha-methyldopa, nitrofurantoin, minocycline, and ecstasy (a drug of abuse, methylene-3,4-dioxy-methamphetamine [MDMA]) are examples. Some of these drugs induce antinuclear antibodies and other autoantibodies. Halothane toxicity may be accompanied by features of autoimmune hepatitis, including antimitochondrial antibodies.
List drugs that may cause cirrhosis with chronic use.
• Perhexeline maleate
What dose of vitamin A is needed to cause hepatotoxicity?
Large doses, in the range of a million IU/day, cause acute toxicity. Chronic use of more than 40,000 IU/day for months may cause chronic hepatotoxicity. Lower doses may be toxic in heavy alcohol users and persons with hyperlipidemia and elevated chylomicrons.
What is the appearance of vitamin A toxicity on liver biopsy?
The liver biopsy shows vitamin A droplets in sinusoidal fat-storing cells (Ito cells or hepatic stellate cells), Kupffer cell activation, inflammation, and fibrosis. This fibrosis can lead to portal hypertension without accompanying cirrhosis.
What liver neoplasms may be drug-induced and name the drugs implicated?
• Hepatocellular carcinoma: anabolic steroids, oral contraceptives, Thorotrast (thorium dioxide), vinyl chloride, aflatoxin.
• Angiosarcoma: Thorotrast (thorium dioxide), vinyl chloride, arsenic, anabolic steroids.
• Adenoma: oral contraceptives, anabolic steroids.
What hepatic vascular abnormalities are associated with drug toxicity?
• Veno-occlusive disease (VOD): Bush tea from Senecio, Crotalaria, Heliotropiu and some comfrey tea containing pyrrolizidine alkaloids, alkylating agents (common in hematopoietic stem cell transplantation).
• Peliosis hepatis: anabolic steroids, estrogens, azathioprine, 6-thioguanine, and Thorotrast (thorium dioxide).
• Hepatic vein thrombosis (Budd-Chiari syndrome): oral contraceptives.
How common is the use of herbal and dietary supplements in the general population?
Approximately 20% of American adults self-reported using herbal or dietary supplements in 2004. Importantly, only a third of consumers reported the use of these products to a healthcare provider.
How frequently are herbal and dietary supplements implicated in DILI?
Herbal and dietary supplements are implicated in approximately 10% of all cases of DILI in the United States.
What herbal medicines have been associated with hepatotoxicity?
Creosote bush (chaparral tea), germander, kava, black cohosh, mistletoe, usnic acid, green tea extract, pyrrolizidine alkaloids (found in comfrey tea), and constituents of Chinese herbal medicines are some examples.
Describe features of hepatotoxicity from nicotinic acid?
High-dose nicotinic acid used to treat hypercholesterolemia may cause jaundice and severe hepatocyte necrosis, occasionally resulting in fulminant liver failure. Hepatotoxicity seems to be more common with sustained-release formulations.
Which nonsteroidal anti-inflammatory drugs (NSAIDs) are most prone to cause hepatotoxicity?
Sulindac and diclofenac.
What are the main features of sulindac hepatotoxicity?
Mild hepatitis with cholestasis.
What are the main features of diclofenac hepatotoxicity?
This NSAID has caused rare cases of acute hepatitis with liver cell necrosis, often with associated antinuclear antibodies. Fulminant liver failure has occurred. Some patients have developed antimitochondrial antibodies with a histologic picture similar to PBC.
What determines the relative hepatotoxicity of inhalational anesthetics?
For the halogenated alkanes, this generally is proportional to their rate of metabolism by cytochrome P450 (halothane > enflurane > isoflurane).
What types of hepatotoxicity do 6-mercaptopurine and azathioprine cause?
An acute allergic-type reaction can occur with hepatocyte necrosis and very elevated aminotransferase levels and cholestasis. Chronic use may cause NRH and peliosis hepatis, and possibly contribute to veno-occlusive disease.
What are the main features of tetracycline hepatotoxicity?
Hepatotoxicity has occurred with high-dose intravenous use of tetracycline but can also occur with oral use. On liver biopsy, there is accumulation of microvesicular fat in hepatocytes. It appears to be due to a toxic effect on mitochondria.
In what setting does cocaine hepatotoxicity occur?
Hepatocyte necrosis usually occurs in the setting of an overdose, especially in a heavy alcohol drinker. Induction of cytochrome P450 2E1 by alcohol probably causes increased metabolism of cocaine to toxic products.
What toxins are found in toxic mushrooms?
These are mainly the amatoxins and phallotoxins. The amatoxins include a variety of cyclic peptides, which inhibit RNA polymerase type II and, thus, inhibit the synthesis of messenger RNA. The phallotoxins promote the polymerization of cellular actin.
What solvent used in manufacturing rubber products may cause hepatotoxicity?
Methyl formamide, used in manufacturing rubberized cloth, has caused a type of acute hepatitis when used without proper ventilation.
What type of food poisoning is associated with acute liver failure?
Bacillus cereus is a sporulating bacterium that can cause diarrhea and vomiting when it grows in rice and other grain products that have been improperly cooked or reheated. B. cereus produces an emetic toxin that has led to cases of acute liver failure by interfering with mitochondrial function.
What type of hepatotoxicity is associated with cyanobacteria?
Some strains of cyanobacteria (“blue-green algae”) produce microcystins. These interfere with the hepatocyte cytoskeleton and cause liver hemorrhage and necrosis. Such liver toxicity is best known to occur in cattle but multiple cases have also occurred in humans in a hemodialysis center due to contaminated water.
How common are liver granulomas?
Granulomas of the liver are found in 5%–10% of patients in liver biopsy series.
What drugs may cause granulomatous hepatitis?
Sulfa drugs, quinidine, allopurinol, nitrofurantoin, phenotiazines, carbamazepine, and phenytoin among many others.
What are the main types of granulomas?
• Lipogranulomas, which form around fat droplets associated with ingestion of mineral oil, waxes, or other lipid material.
• Epithelioid granulomas, which are usually formed in response to a hypersensitivity reaction. A special form of epithelioid granuloma is the fibrin-ring granuloma commonly described in Q-fever and allopurinol toxicity.
What are the two most common causes of hepatic epithelioid granulomas in the United States?
Sarcoidosis and tuberculosis.
What is the most common symptom in patients with hepatic granulomas?
Fever of unknown origin is the most common symptom; however, symptoms correlate with the underlying illness. Fever is present in most cases of sarcoidosis and tuberculosis.
What are the most common physical findings in patients with conditions that cause hepatic granulomas?
Splenomegaly, hepatomegaly, and moderate lymphadenopathy.
What is the most common pattern seen in biochemical tests that would suggest a granulomatous liver disease?
A moderate to marked increase in serum alkaline phosphatase (3 to 10 times normal) and a slight increase in serum aminotransferases (2 to 6 times normal).
True/False: Granulomatous diseases of the liver usually result in a clinically significant alteration of hepatic function.
False. Most diseases that cause granulomas of the liver do not cause significant alteration of hepatic function. Sarcoidosis and PBC are exceptions.
Sarcoidosis is a disease characterized by epithelioid cell granulomas. What organs are affected by these granulomas?
Granulomas occur in many organs in sarcoidosis, but mainly affect the lungs, lymph nodes, and liver.
What percentage of individuals with sarcoidosis have granulomas in the liver?
Approximately two-thirds. The majority of granulomas are located in the portal area, although they may appear anywhere within the hepatic nodule.
What is the most consistently abnormal lab value in sarcoidosis?
Elevated serum alkaline phosphatase. Other commonly abnormal lab values include elevated serum angiotensin-converting enzyme (50%–80% of cases), elevated serum calcium, and a moderate normocytic anemia.
What are the names of the two inclusion bodies found in approximately half of granulomas associated with sarcoidosis?
Schaumann bodies and asteroid bodies. Schaumann bodies are basophilic structures with concentric proteinaceous calcified laminations. Asteroid bodies are star-like radiating structures found within a clear space.
What percent of patients with Hodgkin’s disease have hepatic granulomas?
Up to 12%. Up to 2% of patients with non-Hodgkin’s lymphoma have hepatic involvement.
What histologic characteristics are typical of Hodgkin’s disease granulomas?
These granulomas, which are seen in both portal tracts and parenchyma, are typically epithelioid without caseation and occasionally contain Langerhan’s giant cells.
What percentage of cases of PBC is associated with liver granulomas and/or granulomatous necrosis?
Approximately 25%. The presence of granulomas in PBC is associated with a better prognosis.
Name six drugs that have been associated with hepatic granuloma formation.
Name findings that might suggest that liver granulomas are from a drug reaction.
Portal location of granulomas, peripheral eosinophilia, and tissue eosinophilia. There is no pathognomonic characteristic of drug-related hepatic granulomas.
What is the typical sequela after the removal of the offending drug in cases of liver granulomas?
None. The granulomas quickly resolve without fibrosis or calcification.
What systemic vasculitis that usually manifests itself in the respiratory tract is also associated with granulomatous hepatitis, elevated alkaline phosphatase, and/or aminotransferases and ascites in 15%–30% of cases?
What percentage of patients with polymyalgia rheumatica, giant cell arteritis, and temporal arteritis has liver test abnormalities?
True/False: Hypogammaglobinemia is associated with liver test abnormalities.
True/False: Celiac disease is associated with liver test abnormalities.
True. The abnormalities generally normalize following initiation of a gluten-free diet.
• • • SUGGESTED READINGS • • •
Chang CY, Schiano TD. Review article: drug hepatotoxicity. Aliment Pharmacol Ther. 2007;25:1135-1151.
Lewis JH. Granulomas of the liver. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff’s Diseases of the Liver. 10th ed. Philadelphia: Lipincott Williams & Wilkins; 2007:1425-1448.
Pugh AJ, Barve AJ, Kalkner K, Patel M, McClain CJ. Drug-induced hepatotoxicity or drug-induced liver injury. Clin Liver Dis. 2009;13:277-294.