Drug Induced Liver Toxicity (DILD)

7/30/2019 Drug Induced Liver Toxicity (DILD)

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Drug Induced Liver Toxicity

(DILT)


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Illustration of the proposed mechanism of DILI, which involves drug metabolism,

hepatocyte damage, activation of innate immune cells, and production of tissue-

damaging 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 drugsthrough a variety of mechanisms .

The annual incidence is generally felt tobe between one in 10,000 to 100,000;


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It is responsible for

It accounts for up to 10 percent of all adverse drugreactions.

It is seen in up to 30 percent of patients who presentwith acute hepatitis and represents up to 10 percent ofconsultations by hepatologists, and about 1 percent ofall general medical admissions.

It is the cause ofacute jaundice in up to 50 percent ofpatients.

It is the most common cause of acute liver failure in theUnited States, and is the most frequently cited reasonfor withdrawal of medications from the marketplace.


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Classifications of drug-induced liver injury

Type of classification Examples

Clinical laboratory

Hepatocellular

Cholestatic

Mixed hepatocellular/cholestatic

Mechanism of hepatotoxicity

Direct hepatotoxicity

Idiosyncratic

Immune-mediated

Metabolic

Histologic findings

Cellular necrosis or apoptosis

Cholestasis

Steatosis

Fibrosis

Phospholipidosis

Granulomatous

Sinuoidal obstruction syndrome


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SPECTRUM OF DRUG-INDUCED 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 abnormalitiesto an acute illness with jaundice that resembles viral hepatitis to acute liverfailure.

Acute Presentation: jaundice (serum bilirubin >3 times the upper limit of normal) +

aminotransferase elevations is associated with a worse prognosis than isolatedaminotransferase abnormalities.

some drugs are associated with chronic histologic inflammatory changes and aclinical syndrome resembling autoimmune hepatitis

while others cause endothelial damage or thrombosis leading to vascularcomplications 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.


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Subclinical

Many drugs can induce asymptomatic elevations in liverenzymes without producing overt clinical disease.

Drug-induced liver injury (DILI) is generally consideredsubclinical or insignificant if the serum alanineaminotransferase (ALT) is


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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 causeDILI. Its classic pattern of hepatotoxicity ischolestatic.
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Hepatitis

Drug-induced acute hepatocellular injury issimilar to that seen in viral hepatitis andincludes hepatocellular necrosis or apoptosis,steatosis, and cellular degeneration.

A characteristic finding on laboratory testing isan elevation in serum aminotransferases.

A hepatocyte that has become sensitized to theimmune system dies by apoptosis via deathreceptors at the cell surface.

Moderate degrees ofoxidative stress result inapoptosis at the intracellular level while severeoxidative stress leads to necrotic cell lysis(necrosis).


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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 canbe 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

P450

Drug toxicity


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

Zonal necrosis 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).

Nonzonal necrosis appears in a viral hepatitis-like pattern.It is more often seen with compounds that produceunpredictable idiosyncratic injury (eg,phenytoin,methyldopa, isoniazid, and diclofenac). Certainmedications, such as aspirin, produce a nonspecificpattern of injury,

which is completely reversible but rarely may beassociated with progressive hepatic failure.
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Liver needle biopsy showing severe recurrent hepatitis C,

cholestatic type. This photomicrograph shows centrilobularcholestasis causing feathery degeneration of hepatocytes (longarrow). In addition, there are foci of parenchymal necrosisincluding acidophilic bodies (short arrows). H&E stain, originalmagnification 200x
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Cholestatic

Cholestatic Acute cholestatic injury often resemblesextrahepatic obstructive jaundice. Cholestatic injury istypically recognized by predominant elevations in alkalinephosphatase and bilirubin.

Compounds that have been associated with acutecholestatic injury includeamoxicillin-clavulanate,chlorpromazine, nafcillin, trimethoprim-sulfamethoxazole,rifampin, erythromycin estolate, captopril, estradiol, andrarely, amiodarone.

Patients rarely feel ill, with the most common symptomsbeing pruritus and jaundice. Serum aminotransferases areonly mildly elevated (usually less than eightfold). Theoverall prognosis for purely cholestatic injury is betterthan for hepatocellular injury, although fatalities havebeen reported.
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Mixed Patterns

Mixed patterns of injury are common, andshow 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 developchronic liver disease compared with otherforms of hepatotoxicity.
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Type of injury: Hepatocellular Cholestatic Mixed

ALT Twofold rise Normal Twofold rise

ALP Normal Twofoldrise

Twofold rise

ALT: ALP ratio High, 5 Low, 2 2-5

Examples[16]

Acetaminophen

AllopurinolAmiodaroneHAARTNSAID

AnabolicsteroidChlorpromazi

neClopidogrelErythromycinHormonalcontraception

Amitryptyline,

EnalaprilCarbamazepineSulfonamidePhenytoin
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liver steatosis (Fat

accumulation)
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Steatosis

Drugs that disrupt beta-oxidation of lipids andoxidative energy production lead to steatosis.Histologically, acute steatosis tends to bemicrovesicular 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 steatosisinclude camphor, cocaine, piroxicam, tolmetin, valproicacid, and the antiretroviral agents zidovudine (AZT),stavudine, and didanosine (ddI).

Herbal remedies are being increasingly identified ascauses of steatosis and other forms of injury.
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Extrahepatic manifestations

Some drugs causing liver injury may be associated withclinical features dominated by extrahepatic manifestations.As examples: Drugs causing hypersensitivity reactions (eg, penicillin and

procainamide) may be associated with fever, rash, andperipheral 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 andhydrochlorothiazide, although their relationship to hepaticinjury is unclear.
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Chronic hepatic injury

Drugs associated with chronic liverinjury can resemble other causes of

chronic liver disease such asautoimmune hepatitis or alcoholic liverdisease.

Chronic injury generally resolves upondiscontinuation of the offending drug,but this pattern of liver injury may

progress to cirrhosis and liver failure.


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Chronic hepatitis

1- Autoimmune-like This syndrome resembles type I (classic) autoimmunehepatitis. There is a female preponderance, serologic markers of autoimmunity(ANA, smooth muscle antibody), hyperglobulinemia, and histological featuresconsistent with autoimmune hepatitis. The clinical manifestations range fromasymptomatic 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 eitheran acute or chronic hepatitis accompanied by autoimmune serologic markersdiffering from those seen with autoimmune-like disease. The antibodiesresemble those seen in type 2 autoimmune hepatitis, a rare entity in the UnitedStates, 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 ofchronic hepatitis, but without autoimmune serologic markers. This is a morenondescript 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.

Chronichepatitis

Diclofenac

Methyldopa

Minocycline

Nitrofurantoin

Trazodone
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Type Autoantibodies

1 (classic)

Antinuclear

Anti-smooth muscle

Anti-actin

Anti-soluble liver/ liver pancreas antigen(Anti-SLA/LP)

Antimitochondrial

2Anti-LKM-1

Anti-liver cytosol -1 (Anti-LC1)

Classification of and auto-antibodiesin autoimmune hepatitis


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Steatosis

Drug-induced chronic steatosis is predominantly macrovesicular, incontrast to the microvesicular steatosis usually seen in acute druginjury. The clinical picture of macrovesicular steatosis tends to be lesssevere than that seen with acute microvesicular steatosis with the mostcommon manifestation being hepatomegaly.

Serum aminotransferases are typically moderately elevated. Drug-induced steatohepatitis may also resemble alcoholic liver disease.

Histologic changes include mallorys hyaline, neutrophilic inflammation,variable steatosis, and cirrhosis; phospholipidosis may also be present.

Drugs associated with thesetypes of injury include diethylstilbestrol,glucocorticoids, griseofulvin, methotrexate, nifedipine, tamoxifen, total

parenteral nutrition, mercury, and ethanol. Steatosis may remain asymptomatic, or may evolve into steatohepatitis

with progression to cirrhosis within weeks to months followed bydevelopment of chronic liver failure and subsequent hepaticinsufficiency (L-asparaginase, valproate, perhexilene maleate, andamiodarone)

Chronicinjury

Steato-hepatitis

Amiodarone

Ethanol

Tamoxifen

ValproicAcid
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Fibrosis and cirrhosis

Progressive liver injury leads to scarring with subsequentcirrhosis.

Clinical manifestations are typical of those seen withcirrhosis and portal hypertension from other causes.

Drug-induced cirrhosis may result from steatosis(amiodarone) or chronic hepatitis. Gradual progression tocirrhosis can be seen without any manifestation of clinicalillness (as with methotrexate or methyldopa)

Cirrhosis may also result from lesions of chronicintrahepatic cholestasis, chronic cholestasis (floxuridine),chronic congestive hepatopathy with sinusoidalobstruction syndrome (azathioprine, mercaptopurine oralcontraceptives) or hepatic vein thrombosis (oralcontraceptives), and noncirrhotic portal hypertension(inorganic arsenic, copper sulfate, vinyl chloride, andvitamin A).
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Phospholipidosis

Phospholipidosis is rare. It may develop acutely, but ismore commonly seen after prolonged administration ofthe offending agent.

This condition has been described in animal models andin patients taking amiodarone, amitriptyline, chloroquine,perhexilene maleate, chlorpheniramine, chlorpromazine,or thioridazine.

The lesions consist oflysosomes which are engorgedwith phospholipid, resulting in foamy hepatocytes. It is

believed that an interaction between the phospholipid andthe drug leads to the formation of a complex whichprevents degradation of the phospholipid molecules.
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Chronic cholestasis

Chronic intrahepatic cholestasis Drugs causing chronicintrahepatic cholestasis may produce a syndrome resembling primarybiliary cirrhosis. However, unlike primary biliary cirrhosis, serumantimitochondrial antibodies are usually not seen.

Drugs which have been reported to cause chronic intrahepaticcholestasis include amitriptyline, ampicillin, amoxicillin-clavulanate,carbamazepine, chlorpromazine, cyproheptadine, erythromycinestolate, haloperidol, imipramine, organic arsenicals, prochlorperazine,phenytoin, trimethoprim-sulfamethoxazole, thiabendazole, tolbutamide,tetracycline, oral contraceptives, and anabolic steroids.

Those drugs implicated in chronic intrahepatic cholestasis and alsoductopenia include carbamazepine, chlorpromazine, chlorpropamide,co-trimoxazole, haloperidol, thiabendazole, and tricyclicantidepressants.
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Biliary sclerosis Toxicity predominantly involvingthe biliary tree is most commonly seen after therapyof metastatic carcinoma with floxuridine.

The lesions resemble primary sclerosing cholangitison 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 venousoutflow 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 prominentmedications associated with this syndrome are theoral contraceptives.

Without treatment, hepatic vein thrombosis willprogress to portal hypertension, liver failure, andultimately, death.


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Sinusoidal obstruction syndrome (veno-occlusive disease) hepatic venous outflow obstruction in sinusoidal

obstruction syndrome (SOS) is due to occlusion ofthe terminal hepatic venules and hepatic sinusoidsrather 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, oralcontraceptives, cyclophosphamide, tetracycline, anda number of chemotherapeutic agents.
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Neoplasia

Hepatic adenoma Hepatic adenoma is abenign tumor of the liver, which may rupturecausing hemoperitoneum or may be associated

with malignant transformation. The risk of hepatic adenoma is increased in

women taking oral contraceptives (OCP) andin men taking anabolic steroids.


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Angiosarcoma This extremely rare tumorhas been associated with use ofthorotrast (aradiographic contrast agent used in the 1930sto 1950s), arsenic, potassium arsenite,radium, inorganic copper, and polyvinylchloride, and anabolic steroids. Theprognosis is poor with a mean life expectancyof six months following diagnosis.

Hepatocellular carcinoma The mainchemical associations with the development ofhepatocellular carcinoma include aflatoxin,oral contraceptives, and alcohol.


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Industrial toxin Example: Arsenic, Carbon tetraChloride, Vinyl

Chloride

Herbal and alternative remedies Ackee fruit, Bajiaolian, Camphor, Copaltra,

Cycasin, Kava, pyrrolizidine alkaloids, Horsechestnut leaf, Valerian, Comfrey (often used in

herbal tea) Chinese herbal remedies:

Jin Bu Huan, Ma-huang, Sho-wu-pian
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FDA strong withdrawal

Drugs withdrawn for hepatotoxicity

Troglitazone, Diabetes

bromfenac, NSAID

trovafloxacin, antibiotics--fluoroquinolones

ebrotidine, H2 receptor blocker

nimesulide, NSAID nefazodone, Antidepressant

Ximelagatran, Anticoagulant

Pemoline, psychotropic agent (ADHD)
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The following are the most common symptoms ofdrug-induced hepatitis. However, each individual mayexperience symptoms differently. Symptoms mayinclude: 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-inducedhepatitis 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 testabnormalities

Hepatitis (hepatocellular) ALT 3 x ULN R 5

Cholestasis ALT 2 x ULN R 2

Mixed ALT 3 x ULNALP 2 x ULNR >2 to


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Acute injury

Hepatocellular

Acarbose

AcetaminophenAllopurinol

Aspirin

Buproprion

Bromfenac

Diclofenac

Fluoxetine

Halothane

Isoniazid

KetoconazoleLisinopril

Losartan

Ethanol

Methyl-dopa

NefazodoneNevirapine

Paroxetine

Phenytoin

Risperidone

Sertraline StatinsTetracyclineTrazodoneThiazolidinedionesTrovafloxacin

ValproatePyrazinamideRiphampin

Cholestasis

ACE inhibitors

Amoxicillin/Clavulanate

Anabolic Steroids

Azathioprine

Chlorpromazine

Clopidogrel

CytarabineErythromycins

Estrogens

Ethanol

Irbesartan

Phenothiazines

Sulindac

Terbinafine

Tricyclics

Mixed

Amitryptilline

Azathioprine

CaptoprilCarbamazepine

Clindamycin

Cyproheptadine

Enalapril

Flutamide

Ibuprofen

Nitrofurantoin

Phenobarbital

PhenothiazinesPhenytoin

Sulfonamides

Trazodone

Sulfonamides

Verapamil


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Treatment for drug-inducedhepatitis:

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 benecessary 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 ofdrug hepatotoxicity, 7- Transplantation

Additional Jaundice indicates worse prognosis
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References

1. Principle of pharmacology

2. Basic and clinical Pharmacology

(Katzung)

3. Internet resources for diagrams

39

Documents

Drug Induced Liver Toxicity (DILD)