Drug Induced Liver Toxicity (DILT)

Illustration of the proposed mechanism of DILI, which involves drug metabolism, hepatocyte damage, activation of innate immune cells, and production of tissuedamaging and tissue-protective mediators. CYP indicates cytochrome P450; IFN, interferon; IL, interleukin; NK, natural killer cell; NKT, natural killer T cell; TNF, tumor necrosis factor.
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Liver injury occurs with many drugs through a variety of mechanisms . The annual incidence is generally felt to be between one in 10,000 to 100,000;

It is responsible for

It accounts for up to 10 percent of all adverse drug reactions. It is seen in up to 30 percent of patients who present with acute hepatitis and represents up to 10 percent of consultations by hepatologists, and about 1 percent of all general medical admissions. It is the cause of acute jaundice in up to 50 percent of patients.

It is the most common cause of acute liver failure in the United States, and is the most frequently cited reason for withdrawal of medications from the marketplace.
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Classifications of drug-induced liver injury

Type of classification Examples
Hepatocellular Cholestatic Mixed hepatocellular/cholestatic Direct hepatotoxicity Idiosyncratic

Clinical laboratory

Mechanism of hepatotoxicity

Immune-mediated Metabolic

Cellular necrosis or apoptosis

Cholestasis Steatosis

Histologic findings

Fibrosis Phospholipidosis Granulomatous Sinuoidal obstruction syndrome 5

SPECTRUM OF DRUGINDUCED LIVER INJURY

Classification is based upon: The clinical presentation and laboratory features, the mechanism of toxicity, and/or the histological findings. Acute presentations range from asymptomatic mild biochemical abnormalities to an acute illness with jaundice that resembles viral hepatitis to acute liver failure. Acute Presentation: jaundice (serum bilirubin >3 times the upper limit of normal) + aminotransferase elevations is associated with a worse prognosis than isolated aminotransferase abnormalities. some drugs are associated with chronic histologic inflammatory changes and a clinical syndrome resembling autoimmune hepatitis while others cause endothelial damage or thrombosis leading to vascular complications such as veno-occlusive disease or Budd-Chiari syndrome. Withdrawal of the offending drug usually leads to reversal of the injury. However, some types of toxicity can be associated with a progressive course, possibly leading to fibrosis or cirrhosis, despite discontinuation of the drug.

Subclinical

Many drugs can induce asymptomatic elevations in liver enzymes without producing overt clinical disease. Drug-induced liver injury (DILI) is generally considered subclinical or insignificant if the serum alanine aminotransferase (ALT) is <3 times the upper limit of normal. Subclinical liver disease has been described with :

Most subclinical ALT elevations are benign and resolve once the offending agent has been discontinued.

certain antibiotics, antidepressants, lipid-lowering drugs, sulfonamides, salicylates, sulfonylureas, and quinidine. A higher percentage of asymptomatic ALT elevations can be seen with other medications, including isoniazid (up to 20 percent) and tacrine (up to 50 percent).

1- Acute liver injury

The patterns of acute injury may present as: hepatocellular (cytotoxic) damage, cholestasis, a mixed pattern or, less commonly, steatosis Reversible and is getting worse when combined with jaundice The most common drugs in United States are:

acetaminophen followed by antibiotics. Worldwide, amoxicillin-clavulanate is one of the most commonly reported antibiotics that cause DILI. Its classic pattern of hepatotoxicity is cholestatic.

Hepatitis

Drug-induced acute hepatocellular injury is similar to that seen in viral hepatitis and includes hepatocellular necrosis or apoptosis, steatosis, and cellular degeneration. A characteristic finding on laboratory testing is an elevation in serum aminotransferases. A hepatocyte that has become sensitized to the immune system dies by apoptosis via death receptors at the cell surface. Moderate degrees of oxidative stress result in apoptosis at the intracellular level while severe oxidative stress leads to necrotic cell lysis (necrosis).
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P450

Drug toxicity

Liver is divided histologically into lobules. The center of the lobule is the central vein. At the periphery of the lobule are portal triads. Functionally, the liver can be divided into three zones, based upon oxygen supply. Zone 1 encircles the portal tracts where the oxygenated blood from hepatic arteries enters. Zone 3 is located around central veins, where oxygenation is poor. Zone 2 is located in between. Zone 3: has P450. Most susceptible area for drug toxicity is Zone 1

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Hepatocellular necrosis can be zonal or nonzonal, depending upon the offending agent. Zonal necrosis

Nonzonal necrosis appears in a viral hepatitis-like pattern. It is more often seen with compounds that produce unpredictable idiosyncratic injury (eg, phenytoin, methyldopa, isoniazid, and diclofenac). Certain medications, such as aspirin, produce a nonspecific pattern of injury, which is completely reversible but rarely may be associated with progressive hepatic failure.
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Zone 3: carbon tetrachloride , acetaminophen Zone 2: yellow phosphorus Zone 1: iron sulfate. There may be little or no inflammatory response; however, damaged cells may accumulate fat (triglycerides).

Liver needle biopsy showing severe recurrent hepatitis C, cholestatic type. This photomicrograph shows centrilobular cholestasis causing feathery degeneration of hepatocytes (long arrow). In addition, there are foci of parenchymal necrosis including acidophilic bodies (short arrows). H&E stain, original magnification 200x
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Cholestatic

Cholestatic Acute cholestatic injury often resembles extrahepatic obstructive jaundice. Cholestatic injury is typically recognized by predominant elevations in alkaline phosphatase and bilirubin. Compounds that have been associated with acute cholestatic injury include amoxicillin-clavulanate, chlorpromazine, nafcillin, trimethoprim-sulfamethoxazole, rifampin, erythromycin estolate, captopril, estradiol, and rarely, amiodarone. Patients rarely feel ill, with the most common symptoms being pruritus and jaundice. Serum aminotransferases are only mildly elevated (usually less than eightfold). The overall prognosis for purely cholestatic injury is better than for hepatocellular injury, although fatalities have been reported.

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Mixed Patterns

Mixed patterns of injury are common, and show elevations in both aminotransferases and alkaline phosphatase. An example of this pattern is seen in patients with hepatotoxicity due to Phenytoin. Such patients may be at increased risk to develop chronic liver disease compared with other forms of hepatotoxicity.
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Type of injury:

Hepatocellular

Cholestatic

Mixed

ALT
ALP ALT: ALP ratio

Twofold rise
Normal High, 5

Normal
Twofold rise Low, 2

Twofold rise
Twofold rise 2-5

Examples[16]

Acetaminophen Allopurinol Amiodarone HAART NSAID

Anabolic steroid Chlorpromazi ne Clopidogrel Erythromycin Hormonal contraception

Amitryptyline, Enalapril Carbamazepine Sulfonamide Phenytoin

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liver steatosis (Fat accumulation)

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Steatosis

Drugs that disrupt beta-oxidation of lipids and oxidative energy production lead to steatosis. Histologically, acute steatosis tends to be microvesicular and predominantly triglyceride. This is especially true of steatohepatitis related to:

Reye's syndrome, high-dose intravenous tetracycline, and amiodarone. Other drugs associated with microvesicular steatosis include camphor, cocaine, piroxicam, tolmetin, valproic acid, and the antiretroviral agents zidovudine (AZT), stavudine, and didanosine (ddI). Herbal remedies are being increasingly identified as causes of steatosis and other forms of injury.
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Extrahepatic manifestations

Some drugs causing liver injury may be associated with clinical features dominated by extrahepatic manifestations. As examples:

Drugs causing hypersensitivity reactions (eg, penicillin and procainamide) may be associated with fever, rash, and peripheral eosinophilia. Some drugs (eg, dapsone, phenytoin, sulfonamides) may be associated with a mononucleosis-like illness (pseudomononucleosis) including lymph node enlargement, lymphocytosis, and atypical lymphocytes. Toxicity to multiple organs (eg, bone marrow, kidney, lung, skin and vessels) may be seen with some drugs (eg, chlorpromazine, augmentin, erythromycin, and sulindac). Serologic markers of autoimmunity may be seen in patients with toxicity related to procainamide and hydrochlorothiazide, although their relationship to hepatic injury is unclear.

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Chronic hepatic injury

Drugs associated with chronic liver injury can resemble other causes of chronic liver disease such as autoimmune hepatitis or alcoholic liver disease. Chronic injury generally resolves upon discontinuation of the offending drug, but this pattern of liver injury may progress to cirrhosis and liver failure. 19

Chronic hepatitis

Chronic hepatitis Diclofenac

Methyldopa
Minocycline Nitrofurant oin Trazodone

1- Autoimmune-like This syndrome resembles type I (classic) autoimmune hepatitis. There is a female preponderance, serologic markers of autoimmunity (ANA, smooth muscle antibody), hyperglobulinemia, and histological features consistent with autoimmune hepatitis. The clinical manifestations range from asymptomatic biochemical abnormalities to development of cirrhosis. Drugs and herbs implicated include, fenofibrate, papaverine, phenytoin, propylthiouracil, germander, statins, and ecstasy . 2- Viral hepatitis-like This syndrome develops when drugs lead to either an acute or chronic hepatitis accompanied by autoimmune serologic markers differing from those seen with autoimmune-like disease. The antibodies resemble those seen in type 2 autoimmune hepatitis, a rare entity in the United States, and are directed against microsomal cellular components Examples include phenytoin, dihydralazine, and ticrynafen. 3-Rrare type of injury leads to a syndrome with the histologic characteristics of chronic hepatitis, but without autoimmune serologic markers. This is a more nondescript type of injury, which can be seen in association with lisinopril, sulfonamides, and trazodone. 4- Rarely, drugs may lead to chronic toxicity without active necroinflammatory disease. Examples include dantrolene, aspirin, and isoniazid. 20

Classification of and auto-antibodies in autoimmune hepatitis

Type Autoantibodies Antinuclear Anti-smooth muscle Anti-actin 1 (classic) Anti-soluble liver/ liver pancreas antigen (Anti-SLA/LP) Antimitochondrial

Anti-LKM-1 Anti-liver cytosol -1 (Anti-LC1)

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Steatosis
Drug-induced chronic steatosis is predominantly macrovesicular, in contrast to the microvesicular steatosis usually seen in acute drug Chronic injury. The clinical picture of macrovesicular steatosis tends to be less injury severe than that seen with acute microvesicular steatosis with the most common manifestation being hepatomegaly. Steato Serum aminotransferases are typically moderately elevated. hepatitis Drug-induced steatohepatitis may also resemble alcoholic liver disease. AmiodaroneHistologic changes include mallorys hyaline, neutrophilic inflammation, variable steatosis, and cirrhosis; phospholipidosis may also be present. Ethanol Drugs associated with these types of injury include diethylstilbestrol, Tamoxifen glucocorticoids, griseofulvin, methotrexate, nifedipine, tamoxifen, total parenteral nutrition, mercury, and ethanol. Valproic Steatosis may remain asymptomatic, or may evolve into steatohepatitis Acid with progression to cirrhosis within weeks to months followed by development of chronic liver failure and subsequent hepatic insufficiency (L-asparaginase, valproate, perhexilene maleate, and amiodarone)

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Fibrosis and cirrhosis

Progressive liver injury leads to scarring with subsequent cirrhosis. Clinical manifestations are typical of those seen with cirrhosis and portal hypertension from other causes. Drug-induced cirrhosis may result from steatosis (amiodarone) or chronic hepatitis. Gradual progression to cirrhosis can be seen without any manifestation of clinical illness (as with methotrexate or methyldopa) Cirrhosis may also result from lesions of chronic intrahepatic cholestasis, chronic cholestasis (floxuridine), chronic congestive hepatopathy with sinusoidal obstruction syndrome (azathioprine, mercaptopurine oral contraceptives) or hepatic vein thrombosis (oral contraceptives), and noncirrhotic portal hypertension (inorganic arsenic, copper sulfate, vinyl chloride, and vitamin A).
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Phospholipidosis

Phospholipidosis is rare. It may develop acutely, but is more commonly seen after prolonged administration of the offending agent. This condition has been described in animal models and in patients taking amiodarone, amitriptyline, chloroquine, perhexilene maleate, chlorpheniramine, chlorpromazine, or thioridazine. The lesions consist of lysosomes which are engorged with phospholipid, resulting in foamy hepatocytes. It is believed that an interaction between the phospholipid and the drug leads to the formation of a complex which prevents degradation of the phospholipid molecules.

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Chronic cholestasis

Chronic intrahepatic cholestasis Drugs causing chronic intrahepatic cholestasis may produce a syndrome resembling primary biliary cirrhosis. However, unlike primary biliary cirrhosis, serum antimitochondrial antibodies are usually not seen. Drugs which have been reported to cause chronic intrahepatic cholestasis include amitriptyline, ampicillin, amoxicillin-clavulanate, carbamazepine, chlorpromazine, cyproheptadine, erythromycin estolate, haloperidol, imipramine, organic arsenicals, prochlorperazine, phenytoin, trimethoprim-sulfamethoxazole, thiabendazole, tolbutamide, tetracycline, oral contraceptives, and anabolic steroids. Those drugs implicated in chronic intrahepatic cholestasis and also ductopenia include carbamazepine, chlorpromazine, chlorpropamide, co-trimoxazole, haloperidol, thiabendazole, and tricyclic antidepressants.

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Biliary sclerosis Toxicity predominantly involving the biliary tree is most commonly seen after therapy of metastatic carcinoma with floxuridine. The lesions resemble primary sclerosing cholangitis on cholangiography. Affected patients present with right upper abdominal pain, anorexia, weight loss, and jaundice.

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Vascular disease

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Vascular disease

Hepatic vein thrombosis Hepatic venous outflow obstruction (Budd-Chiari syndrome) may arise from drug-induced thrombosis of the hepatic veins or inferior vena cava. While often associated with myeloproliferative or coagulative disorders, the most prominent medications associated with this syndrome are the oral contraceptives. Without treatment, hepatic vein thrombosis will progress to portal hypertension, liver failure, and ultimately, death.

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Sinusoidal obstruction syndrome (venoocclusive disease)

hepatic venous outflow obstruction in sinusoidal obstruction syndrome (SOS) is due to occlusion of the terminal hepatic venules and hepatic sinusoids rather than the hepatic veins and inferior vena cava. Drugs that have been associated with SOS include pyrrolizidine alkaloids (found in herbal remedies) azathioprine, mercaptopurine, vitamin A, oral contraceptives, cyclophosphamide, tetracycline, and a number of chemotherapeutic agents.
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Neoplasia

Hepatic adenoma Hepatic adenoma is a benign tumor of the liver, which may rupture causing hemoperitoneum or may be associated with malignant transformation. The risk of hepatic adenoma is increased in women taking oral contraceptives (OCP) and in men taking anabolic steroids.

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Angiosarcoma This extremely rare tumor has been associated with use of thorotrast (a radiographic contrast agent used in the 1930s to 1950s), arsenic, potassium arsenite, radium, inorganic copper, and polyvinyl chloride, and anabolic steroids. The prognosis is poor with a mean life expectancy of six months following diagnosis. Hepatocellular carcinoma The main chemical associations with the development of hepatocellular carcinoma include aflatoxin, oral contraceptives, and alcohol.
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Industrial toxin

Herbal and alternative remedies

Example: Arsenic, Carbon tetraChloride, Vinyl Chloride

Ackee fruit, Bajiaolian, Camphor, Copaltra, Cycasin, Kava, pyrrolizidine alkaloids, Horse chestnut leaf, Valerian, Comfrey (often used in herbal tea) Jin Bu Huan, Ma-huang, Sho-wu-pian
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Chinese herbal remedies:

FDA strong withdrawal

Drugs withdrawn for hepatotoxicity

Troglitazone, bromfenac, trovafloxacin, ebrotidine, nimesulide, nefazodone, Ximelagatran, Pemoline,

Diabetes NSAID
antibiotics--fluoroquinolones

H2 receptor blocker NSAID Antidepressant Anticoagulant

psychotropic agent (ADHD)
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The following are the most common symptoms of drug-induced hepatitis. However, each individual may experience symptoms differently. Symptoms may include: fever rash or itchy red hives on skin joint pain sore muscles flu-like symptoms nausea vomiting decreased appetite sore muscles jaundice - yellowing of the skin and eyes.

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How is drug-induced hepatitis diagnosed? In addition to complete medical history and physical examination, diagnostic procedures for drug-induced hepatitis may include the following: specific laboratory blood tests, such as the following:

liver function studies cellular blood counts bleeding times electrolyte tests tests for other chemicals in the body drug screening tests

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Classification of liver test abnormalities

Hepatitis (hepatocellular) Cholestasis Mixed ALT ALT ALT 3 x ULN 2 x ULN 3 x ULN R R 5 2

ALP 2 x ULN R >2 to <5

ALT: alanine aminotransferase; ALP: alkaline phosphatase; ULN: upper limit normal; R: ALT/ULN divided by ALP/ULN.

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Acute injury Hepatocellular Acarbose

Cholestasis ACE inhibitors Amoxicillin/Clavulanate Anabolic Steroids Azathioprine

Mixed Amitryptilline Azathioprine

Methyl-dopa AcetaminophenNefazodone
Allopurinol Nevirapine Paroxetine Phenytoin Risperidone

Captopril
Carbamazepine Clindamycin Cyproheptadine

Aspirin
Buproprion Bromfenac Diclofenac

Chlorpromazine
Clopidogrel

Fluoxetine
Halothane Isoniazid Ketoconazole Lisinopril Losartan Ethanol

Cytarabine Sertraline Statins Erythromycins Tetracycline Estrogens Trazodone Thiazolidinediones Ethanol Trovafloxacin Irbesartan Valproate Phenothiazines Pyrazinamide Sulindac Riphampin Terbinafine Tricyclics

Enalapril
Flutamide Ibuprofen Nitrofurantoin

Phenobarbital
Phenothiazines Phenytoin Sulfonamides Trazodone Sulfonamides Verapamil
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Treatment for drug-induced hepatitis:

The goal of treatment for drug-induced hepatitis is to : 1- discontinue taking the causative agent 2- monitor the liver closely while it recovers. 3- Some drugs may cause a slight increase in liver enzymes without symptoms. It may not be necessary to discontinue using these medications. 4- N-acetylcysteine for acetaminophen toxicity 5- L-carnitine for cases of valproic acide overdose 6- Corticosteroids are of unproven benefit for most forms of
drug hepatotoxicity,

Additional Jaundice indicates worse prognosis

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7- Transplantation

References
1. 2.

3.

Principle of pharmacology Basic and clinical Pharmacology (Katzung) Internet resources for diagrams

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