Drug induced liver injury

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rachita Navara, M.D. [2]

Drug induced liver injury has been historically underreported.

Over the last fifty years, the United States Food and Drug Administration has withdrawn several drugs from the market for causing severe liver injury. Notably in 1997 to 1998, bromfenac and troglitazone were withdrawn from the market for causing severe hepatocellular injury. Drug induced liver injury remains the most frequent single cause of drug withdrawals from the market today.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rachita Navara, M.D. [2]

Drug induced liver injury may be classified into multiple subtypes based on clinical presentation, mechanism, or histologic findings.^[1]

Drug induced liver injury may be classified into multiple subtypes based on clinical presentation, mechanism, or histologic findings.

• Elevation of serum transaminases ≥ 2-5 times the upper limit of normal
• May have hyperbilirubinemia
• May have abnormal synthetic function tests (e.g. International Normalized Ratio, albumin)

• Elevation of alkaline phosphatase ≥ 3 times the upper limit of normal
• May have hyperbilirubinemia
• May have abnormal synthetic function tests (e.g. International Normalized Ratio, albumin)

• Both alkaline phosphatase and transaminases are elevated in roughly equal proportion, and/or an alanine aminotransferase to alkaline phosphatase ratio between 2-5

• e.g. Acetaminophen-induced centrilobular necrosis

• e.g. Stimulation of immune reponse by biologic agents, independent of dose, akin to drug hypersensitivity
• e.g. Altered host genes involved in drug metabolism

Histologic findings may be further subclassified into:

• Hepatitis (hepatocellular injury)
• Cholestasis
• Granulomatous
• Steatosis
• Fibrosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rachita Navara, M.D. [2]

The exact pathogenesis of drug induced liver injury is not fully understood. Possible mechanisms include both hepatocellular and extracellular processes.

The following are possible mechanisms for drug induced liver injury:

• Apoptosis of hepatocytes: Activation of the apoptotic pathways by the tumor necrosis factor-alpha receptor of Fas may trigger the cascade of intercellular caspases, which results in programmed cell death.

• Bile duct injury: Toxic metabolites excreted in bile may cause injury to the bile duct epithelium.

• Cytolytic T-cell activation: Covalent binding of a drug to the P₄₅₀ enzyme acts as an immunogen, activating T cells and cytokines and stimulating a multifaceted immune response.

• Disruption of the hepatocyte: Covalent binding of the drug to intracellular proteins can cause a decrease in ATP levels, leading to actin disruption. Disassembly of actin fibrils at the surface of the hepatocyte causes blebs and rupture of the membrane.

• Disruption of the transport proteins: Drugs that affect transport proteins at the canalicular membrane can interrupt bile flow. Loss of villous processes and interruption of transport pumps such as multidrug resistance–associated protein 3 prevent the excretion of bilirubin, causing cholestasis.

• Mitochondrial disruption: Certain drugs inhibit mitochondrial function by a dual effect on both beta-oxidation energy production by inhibiting the synthesis of nicotinamide adenine dinucleotide and flavin adenine dinucleotide, resulting in decreased ATP production.

The classic division of drug reactions is into at least 2 major groups:

1. Drugs that directly affect the liver
2. Drugs that mediate an immune response.

Drug Toxicity Mechanisms

• Hypersensitivity: Phenytoin is a classic, if not common, cause of hypersensitivity reactions. The response is characterized by fever, rash, and eosinophilia; this is an immune-related response with a typical short latency period of 1-4 weeks.

• Idiosyncratic Drug Reactions: Idiosyncratic drug reactions can be subdivided into those that are classified as hypersensitivity or immunoallergic and those that are metabolic-idiosyncratic.

• Intrinsic or predictable drug reactions: Drugs that fall into this category cause reproducible injuries in animals, and the injury is dose related. The injury can be due to the drug itself or to a metabolite. Acetaminophen is a classic example of a known intrinsic or predictable hepatotoxin at supertherapeutic doses. Another classic example is carbon tetrachloride.

• Metabolic-idiosyncratic: This type of reaction occurs through an indirect metabolite of the offending drug. Unlike intrinsic hepatotoxins, the response rate is variable and can occur within a week or up to one year later. It occurs in a minority of patients taking the drug, and no clinical manifestations of hypersensitivity are noted. INH toxicity is considered to fall into this class. Not all drugs fall neatly into one of these categories, and overlapping mechanisms may occur with some drugs (e.g., halothane).

The human body identifies almost all drugs as foreign substances (i.e. xenobiotics) and subjects them to various chemical processes (i.e. metabolism) to make them suitable for elimination. This involves chemical transformations to (a) reduce fat solubility and (b) to change biological activity. Although almost all tissue in the body have some ability to metabolize chemicals, smooth endoplasmic reticulum in liver is the principal “metabolic clearing house” for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids, and proteins), and exogenous substances (e.g. drugs).^[1] The central role played by liver in the clearance and transformation of chemicals also makes it susceptible to drug induced injury.

Drug metabolism is usually divided into two phases: phase 1 and phase 2. Phase 1 reaction is thought to prepare a drug for phase 2. However many compounds can be metabolized by phase 2 directly. Phase 1 reaction involves oxidation, reduction, hydrolysis, hydration and many other rare chemical reactions. These processes tend to increase water solubility of the drug and can generate metabolites which are more chemically active and potentially toxic. Most of phase 2 reactions take place in cytosol and involve conjugation with endogenous compounds via transferase enzymes. Chemically active phase 1 products are rendered relatively inert and suitable for elimination by this step.

A group of enzymes located in the endoplasmic reticulum, known as cytochrome P-450, is the most important family of metabolizing enzymes in the liver. Cytochrome P-450 is the terminal oxidase component of an electron transport chain. It is not a single enzyme, rather consists of a family of closely related 50 isoforms, six of them metabolize 90% of drugs.^[2][3] There is a tremendous diversity of individual P-450 gene products and this heterogeneity allows the liver to perform oxidation on a vast array of chemicals (including almost all drugs) in phase 1. Three important characteristics of the P450 system have roles in drug induced toxicity:

1. Genetic diversity: Each of the P-450 proteins is unique and accounts to some extent for the variation in drug metabolism between individuals. Genetic variations (polymorphism) in CYP450 metabolism should be considered when patients exhibit unusual sensitivity or resistance to drug effects at normal doses. Such polymorphism is also responsible for variable drug response among patients of differing ethnic backgrounds.

Cytochrome P-450 enzyme induction and inhibition^[3][4][5]

Potent inducers	Potent inhibitors	Substrates
Rifampicin, Carbamazepine, Phenobarbital, Phenytoin, (St John’s wort),	Amiodarone, cimetidine, ciprofloxacin, fluconazole, fluoxetine, erythromycin, isoniazid, diltiazem	Caffeine, clozapine, omeprazole, losartan, theophylline

2. Change in enzyme activity: Many substances can influence P-450 enzyme mechanism. Drugs interact with the enzyme family in several ways.^[6] Drugs that modify Cytochrome P-450 enzyme are referred to as either inhibitors or inducers. Enzyme inhibitors block the metabolic activity of one or several P-450 enzymes. This effect usually occurs immediately. On the other hand inducers increase P-450 activity by increasing its synthesis. Depending on inducing drug’s half life, there is usually a delay before enzyme activity increases.^[3]

3. Competitive inhibition: Some drugs may share the same P-450 specificity and thus competitively block their bio transformation. This may lead to accumulation of drugs metabolised by the enzyme. This type of drug interaction may also reduce the rate of generation of toxic substrate.

Patterns of drug-induced liver disease

Type of injury:	Hepatocellular	Cholestatic	Mixed
ALT	≥ Twofold rise	Normal	≥ Twofold rise
ALP	Normal	≥ Twofold rise	≥ Twofold rise
ALT: ALP ratio	High, ≥5	Low, ≤2	2-5
Examples[7]	Acetaminophen Allopurinol Amiodarone HAART NSAID	Anabolic steroid Chlorpromazine Clopidogrel Erythromycin Hormonal contraception	Amitryptyline, Enalapril Carbamazepine Sulphonamide Phenytoin

Chemicals produce a wide variety of clinical and pathological hepatic injury. Biochemical markers (i.e. alanine transferase, alkaline phosphatase and bilirubin) are often used to indicate liver damage. Liver injury is defined as rise in either (a) ALT level more than three times of upper limit of normal (ULN), (b) ALP level more than twice ULN, or (c) total bilirubin level more than twice ULN when associated with increased ALT or ALP.^[8][7] Liver damage is further characterized into hepatocellular (predominantly initial Alanine transferase elevation) and cholestatic (initial alkaline phosphatase rise) types. However they are not mutually exclusive and mixed type of injuries are often encountered.

Specific histo-pathological patterns of liver injury from drug induced damage are discussed below.

• Zonal Necrosis: This is the most common type of drug induced liver cell necrosis where the injury is largely confined to a particular zone of the liver lobule. It may manifest as very high level of ALT and severe disturbance of liver function leading to acute liver failure.

Causes:

Acetaminophen (Tylenol), carbon tetrachloride

• Hepatitis: In this pattern hepatocellular necrosis is associated with infiltration of inflammatory cells. There can be three types of drug induced hepatitis. (A) viral hepatitis type picture is the commonest, where histological features are similar to acute viral hepatitis. (B) in the focal or non specific hepatitis scattered foci of cell necrosis may accompany lymphocytic infiltrate. (C) chronic hepatitis type is very similar to autoimmune hepatitis clinically, serologically as well as histologically.

Causes:

(a) Viral hepatitis like: Halothane, Isoniazid, Phenytoin

(b) Focal hepatitis: Aspirin

(c) Chronic hepatitis: Methyldopa, Diclofenac

• Cholestasis: Liver injury leads to impairment of bile flow and clinical picture is predominated by itching and jaundice. Histology may show inflammation (cholestatic hepatitis) or it can be bland without any parenchymal inflammation. In rare occasions it can produce features similar to primary biliary cirrhosis due to progressive destruction of small bile ducts (Vanishing duct syndrome).

Causes:

(a) Bland: Oral contraceptive pills, anabolic steroid, Androgens

(b) Inflammatory: Allopurinol, Co-amoxiclav, Carbamazepine

(c) Ductal: Chlorpromazine, flucloxacillin

• Steatosis: Hepatotoxicity may manifest as triglyceride accumulation which leads to either small droplet (microvesicular) or large droplet (macrovesicular) fatty liver. There is a separate type of steatosis where phospholipid accumulation leads to a pattern similar to the diseases with inherited phospholipid metabolism defects (e.g. Tay-Sachs disease)

Causes:

(a) Microvesicular: Aspirin (Reye’s syndrome), Ketoprofen, Tetracycline

(b) Macrovesicular: Acetamenophen, methotrexate

(c) Phospholipidosis: Amiodarone, Total parenteral nutrition

• Granuloma: Drug induced hepatic granulomas are usually associated with granulomas in other tissues and patients typically have features of systemic vasculitis and hypersensitivity. More than 50 drugs have been implicated.

Causes:

Allopurinol, Phenytoin, Isoniazid, Quinine, Penicillin, Quinidine

• Vascular lesions: They result from injury to the vascular endothelium.

Causes:

Venoocclusive disease: Chemotherapeutic agents, bush tea

Peliosis hepatis: anabolic steroid

Hepatic vein thrombosis: Oral contraceptives

• Neoplasm: Neoplasms have been described with prolonged exposure to some medications or toxins. Hepatocellular carcinoma, angiosarcoma and liver adenomas are the ones usually reported.

Causes:

Vinyl chloride, Combined oral contraceptive pill,Anabolic steroid, Arsenic, Thorotrast

No specific genes have been implicated in the pathogenesis of drug induced liver injury.

On gross pathology, steatosis, fibrosis, and even cirrhosis can be caused by drug induced liver injury.

On microscopic histopathological analysis, there are three main patterns of drug induced liver injury:^[9]

• Most common pattern in idiosyncratic drug induced liver injury. Involves most of the liver parenchyma.
• Example inciting drugs: antiepileptics including phenytoin and valproic acid, monoamine oxidase inhibitors, and isoniazid as well as other antimicrobials including sulfonamides and azoles

• Example inciting drugs: recreational drugs including cocaine and 3,4-methylenedioxymethylamphetamine (ecstasy), industrial organic compounds such as carbon tetrachloride, and some herbal preparations

• Most rare; can be accompanied by necrosis
• Example inciting drugs: tetracycline, nucleoside analogues (e.g. zidovudine). See steatosis, fatty liver

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rachita Navara, M.D. [2]

Hundreds of prescription and nonprescription medications as well as supplements have been implicated in drug induced liver injury. A free searchable database of causative agents is available through the National Institute of Health.

• Acetaminophen
• Azithromycin
• Ethanol
• Statins
• Tetracycline
• Rosiglitazone
• Amiodarone
• Valproic Acid
• Methotrexate
• Isoniazid
• Rifampin

Cardiovascular	No underlying causes
Chemical / poisoning	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	5-Azacytidine, Abacavir, Abiraterone, Acetaminophen, Agomelatine, Albendazole, Allopurinol, Altretamine, Amineptine, Amiodarone, Amitriptyline, Amoxicillin, Amphotericin B, Amprenavir, Anabolic steroids, Antituberculosis drugs, Apixaban, Arsenic trioxide, Asafetida, Asparaginase, Atorvastatin, Atovaquone, Azathioprine, Benoxaprofen, Bexarotene, Black cohosh extract, Bosentan, Bosutinib, Bromfenac, Bumetanide, Carfilzomib, Cascara, Caspofungin, Chaparral, Chenodeoxycholic acid, Chlormezanone, Chlorzoxazone, Ciprofloxacin, Clofarabine, Combined oral contraceptive pill, Comfrey, Crizotinib, Cyclobenzaprine, Dantrolene, Daptomycin, Dasatinib, Deferasirox, Desipramine, Diclofenac, Disulfiram, Docetaxel, Donepezil, Dothiepin, Dronedarone, Eltrombopag, Emtricitabine, Entecavir, Ephedra, Erlotinib, Erythromycin estolate, Ethanol, Ethinylestradiol, Ethionamide, Etretinate, Febuxostat, Felbamate, Fenofibrate, Fingolimod, Fluconazole, Flucytosine, Fluoxymesterone, Flutamide, Fluvastatin, Fosamprenavir, Frusemide, Fusidic acid, Ganciclovir, Gemcitabine, Gemtuzumab ozogamicin, Gold salts, Golimumab, Halothane, Imatinib mesylate, Imipenem, Interferon alpha, Interferon beta, Interleukin 2, Ipilimumab, Isoniazid, Isotretinoin, Kava root extract, Ketoconazole, Lapatinib ditosylate, Leflunomide, Lovastatin, Maraviroc, Meropenem, Mesalazine, Methotrexate, Methyldopa, Methyldopate, Micafungin, Minocycline, Mirtazapine, Mithramycin, Naltrexone, Nandrolone, Natalizumab, Nelfinavir, Nevirapine, Niacin, Nicotinic acid, Nimesulide, Nitisinone, Nitrofurantoin, Norfloxacin, Nortriptyline, Ondansetron, Oxyphenisatine, Paclitaxel, Para-amino salicylic acid, Pazopanib, Pegvisomant, Pemoline, Pentostatin, Phenelzine, Phenylbutazone, Phenytoin, Pralatrexate, Pravastatin, Procainamide, Propylthiouracil, Prothionamide, Pyrazinamide, Pyritinol, Pyrrolizidine alkaloids, Regorafenib, Rifabutin, Rifampicin, Riluzole, Ritonavir, Rivaroxaban, Rosuvastatin, Saquinavir, Simvastatin, Sitaxentan, Sorafenib, Stanozolol, Statins, Succimer, Suloctidil, Sulphasalazine, Sulphinpyrazone, Tegafur, Telithromycin, Teriflunomide, Thiabendazole, Thioguanine, Ticlopidine, Tipranavir, Tizanidine, Tolbutamide, Tolcapone, Tolrestat, Trabectedin, Troglitazone, Trovafloxacin, Ursodeoxycholic acid, Valganciclovir, Valproic acid, Velnacrine, Verapamil, Voriconazole, Ximelagatran, Zotepine, Alcohol, Carbimazole, Phenothiazines, Clofibrate, Tetracyclines
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	No underlying causes
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	No underlying causes
Musculoskeletal / Ortho	No underlying causes
Neurologic	No underlying causes
Nutritional / Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Opthalmologic	No underlying causes
Overdose / Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal / Electrolyte	No underlying causes
Rheum / Immune / Allergy	No underlying causes
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	No underlying causes

5-Azacytidine Abacavir Abiraterone Acetaminophen Agomelatine Albendazole Alcohol Allopurinol Altretamine Amineptine Amiodarone Amitriptyline Amoxicillin Amphotericin B Amprenavir Anabolic steroids Antituberculosis drugs Apixaban Arsenic trioxide Asafetida Asparaginase Atorvastatin Atovaquone Azathioprine Benoxaprofen Bexarotene Black cohosh extract Bosentan Bosutinib Bromfenac Bumetanide Carbimazole Carfilzomib Cascara Caspofungin Chaparral Chenodeoxycholic acid Chlormezanone Chlorzoxazone Ciprofloxacin Clofarabine Clofibrate Combined oral contraceptive pill Comfrey Crizotinib Cyclobenzaprine Dantrolene Daptomycin Dasatinib Deferasirox Desipramine Diclofenac Disulfiram Docetaxel Donepezil Dothiepin Dronedarone Eltrombopag Emtricitabine Entecavir Ephedra Erlotinib Erythromycin estolate Ethanol Ethinylestradiol Ethionamide Etretinate Febuxostat Felbamate Fenofibrate Fingolimod Fluconazole Flucytosine Fluoxymesterone Flutamide Fluvastatin Fosamprenavir Frusemide Fusidic acid Ganciclovir Gemcitabine Gemtuzumab ozogamicin Gold salts Golimumab Halothane Imatinib mesylate Imipenem Interferon alpha Interferon beta Interleukin 2 Ipilimumab Isoniazid

Isotretinoin Kava root extract Ketoconazole Lapatinib ditosylate Leflunomide Lovastatin Maraviroc Meropenem Mesalazine Methotrexate Methyldopa Methyldopate Micafungin Minocycline Mirtazapine Mithramycin Naltrexone Nandrolone Natalizumab Nelfinavir Nevirapine Niacin Nicotinic acid Nimesulide Nitisinone Nitrofurantoin Norfloxacin Nortriptyline Ondansetron Oxyphenisatine Paclitaxel Para-amino salicylic acid Pazopanib Pegvisomant Pemoline Pentostatin Phenelzine Phenothiazines Phenylbutazone Phenytoin Pralatrexate Pravastatin Procainamide Propylthiouracil Prothionamide Pyrazinamide Pyritinol Pyrrolizidine alkaloids Regorafenib Rifabutin Rifampicin Riluzole Ritonavir Rivaroxaban Rosuvastatin Saquinavir Simvastatin Sitaxentan Sorafenib Stanozolol Statins Succimer Suloctidil Sulphasalazine Sulphinpyrazone Tegafur Telithromycin Teriflunomide Tetracyclines Thiabendazole Thioguanine Ticlopidine Tipranavir Tizanidine Tolbutamide Tolcapone Tolrestat Trabectedin Troglitazone Trovafloxacin Ursodeoxycholic acid Valganciclovir Valproic acid Velnacrine Verapamil Voriconazole Ximelagatran Zotepine

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rachita Navara, M.D. [2]

Drug induced liver injury must be differentiated from other diseases that cause serum transaminase elevations and symptoms of acute liver injury^[1]:

The following diseases are in the differential of drug induced liver injury:

• Acute viral hepatitis
• Alcoholic liver disease
• Autoimmune hepatitis
• Budd-Chiari syndrome
• Cholangitis
• Cholecystitis
• Cholestatic liver disease
• Coagulation disorders
• Hemochromatosis
• Malignancy
• Pregnancy-related conditions of liver
• Shock liver
• Wilson disease

Some medications (e.g. minocycline, nitrofurantoin) cause autoimmune-like drug induced liver injury, which must be distinguished from autoimmune hepatitis using serum studies such as antinuclear antibody, immunoglobulin G, and anti-smooth muscle antibody.

In patients below the age of forty, it is important to rule out Wilson’s Disease, though rare, with serum ceruloplasmin. However, ceruloplasmin may also be falsely normal or even elevated as an acute-phase reactant during episodes of acute hepatitis. Further testing if indicated would include slit lamp examination and 24-hour urine copper collection.

If tender hepatomegaly and ascites are present, ultrasound with doppler should be obtained to assess for Budd-Chiari syndrome.

Other etiologies that may have overlapping presentations with cholestatic liver injury include:

• Extrahepatic etiologies:
  • Choledocholithiasis
  • Malignancy (e.g. lymphoma)
• Intrahepatic etiologies
  • Primary biliary cirrhosis
  • Primary sclerosing cholangitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rachita Navara, M.D. [2]

Epidemiologic data on drug induced liver injury is likely an underrepresentation given the lack of active reporting and surveillance systems for drug induced liver injury worldwide.^[1]

The prevalence of drug induced liver injury is estimated to be 44,000 cases annually. It is the most common cause of acute liver failure in the United States, representing 13% of total cases. However, drug induced liver injury accounts for only a small proportion of all idiosyncratic adverse drug reactions.^[1]

The incidence of drug induced liver injury is approximately 10 to 20 per 100,000 individuals worldwide.^[2]

The case fatality rate of drug induced liver injury is approximately 10 to 50%, depending on the inciting drug. In the United States, the mortality rate is between 9-12%.

It was previously thought that the incidence of drug induced liver injury increases with age. However, more recent studies have demonstrated that patients of all age groups may develop drug induced liver injury.^[1]

Due to the higher proportion of females in many retrospective and prospective cohorts of drug induced liver injury, it was thought that females are more commonly affected than males.^[3] However, more recent reviews have demonstrated that drug induced liver injury affects men and women equally.^[4]

There is no racial predilection to drug induced liver injury.

In the Western world, the most common cause of drug induced liver injury is acetaminophen. The next leading cause is antimicrobials, particularly penicillin derivatives in Europe.^[5]

The most common class of drugs implicated in drug induced liver injury worldwide is antimicrobials, particularly antituberculosis medications in India.^[5]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rachita Navara, M.D. [2]

Common risk factors in the development of drug induced liver injury include age, alcohol intake, drug usage, and female gender. However, most reactions are idiosyncratic and do not follow predictable responses, making it difficult to predict the risk of liver injury from a given drug in an individual patient.

Common risk factors in the development of drug induced liver injury include:

• Age: Apart from accidental exposure, hepatic drug reactions are rare in children. Elderly persons are at increased risk of hepatic injury because of decreased clearance, drug-to-drug interactions, reduced hepatic blood flow, variation in drug binding, and lower hepatic volume. In addition, poor diet, infections, and multiple hospitalizations are important reasons for drug-induced hepatotoxicity.
• Alcohol ingestion: Alcoholic persons are susceptible to drug toxicity because alcohol induces liver injury and cirrhotic changes that alter drug metabolism. Alcohol causes depletion of glutathione (hepatoprotective) stores that make the person more susceptible to toxicity by drugs.
• Drug formulation: Long-acting drugs may cause more injury than shorter-acting drugs.
• Gender: Although the reasons are unknown, hepatic drug reactions are more common in females.
• Genetic factors: A unique gene encodes each P-450 protein. Genetic differences in the P-450 enzymes can result in abnormal reactions to drugs, including idiosyncratic reactions. Debrisoquine is an antiarrhythmic drug that undergoes poor metabolism because of abnormal expression of P-450-II-D6. This can be identified by polymerase chain reaction amplification of mutant genes. This has led to the possibility of future detection of persons who can have abnormal reactions to a drug.
• Host factors that may enhance susceptibility to drugs, possibly inducing liver disease:

• AIDS – Dapsone, trimethoprim-sulfamethoxazole
• Diabetes mellitus – Methotrexate, niacin
• Fasting or malnutrition – Acetaminophen
• Female – Halothane, nitrofurantoin, sulindac
• Hepatitis C – Ibuprofen, ritonavir, flutamide
• Large body mass index / obesity – Halothane
• Male – Amoxicillin-clavulanic acid (Augmentin)
• Old age – Acetaminophen, halothane, INH, amoxicillin-clavulanic acid
• Preexisting liver disease – Niacin, tetracycline, methotrexate
• Renal failure – Tetracycline, allopurinol
• Young age – Salicylates, valproic acid

• Liver disease: In general, patients with chronic liver disease are not uniformly at increased risk of hepatic injury. Although the total cytochrome P₄₅₀ is reduced, some may be affected more than others. The modification of doses in persons with liver disease should be based on the knowledge of the specific enzyme involved in the metabolism. Patients with HIV infection who are co-infected with hepatitis B or C virus are at increased risk for hepatotoxic effects when treated with antiretroviral therapy. Similarly, patients with cirrhosis are at increased risk of decompensation by toxic drugs.
• Other comorbidities: Persons with AIDS, persons who are malnourished, and persons who are fasting may be susceptible to drug reactions because of low glutathione stores.
• Race: Some drugs appear to have different toxicities based on race. For example, African Americans and Hispanics may be more susceptible to isoniazid (INH) toxicity. The rate of metabolism is under the control of P₄₅₀ enzymes and can vary from individual to individual.

• Carbamazepine
• Ethanol
• Glucocorticoids
• Griseofulvin
• Omeprazole (Induces P₄₅₀ 1A2)
• Phenobarbital
• Phenytoin
• Primidone
• Quinine
• Rifampin

• Amiodarone
• Cimetidine
• Erythromycin
• Grape fruit
• Isoniazid
• Ketoconazole
• Metronidazole
• Omeprazole (Inhibits P₄₅₀ 2C8)
• Quinidine
• Sulfonamides

• Troglitazone
• Bromfenac
• Trovafloxacin
• Ebrotidine
• Nimesulide
• Nefazodone
• Ximelagatran

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rachita Navara, M.D. [2]

General screening guidelines for drug induced liver injury do not exist. However, certain specific guidelines have been established for drugs associated with a high incidence of severe liver injury, e.g. methotrexate.^[1] These guidelines remain controversial.

Periodic screening of serum alanine aminotransferase is sometimes initiated for drugs associated with a high incidence of liver injury, at provider discretion.^[2]

However, because frequent laboratory monitoring is often not possible for both patients and providers, compliance with any drug-specific surveillance guidelines is variable and drug-specific guidelines remain controversial. This is largely because the significance of a mildly elevated serum alanine aminotransferase is unclear and may result in inappropriate drug withdrawal in patients who would otherwise adapt to ongoing use of the inciting drug.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rachita Navara, M.D. [2]

The clinical course of drug induced liver injury varies based on causative drug.^[1] There is a hallmark latent period between the initiation of the drug (“the challenge”) and the development of either symptoms or, more commonly, asymptomatic elevations in serum alanine aminotransferase. Liver injury typically recurs if the drug is reintroduced in the future, often with greater severity that could be life-threatening. Prompt withdrawal of the offending drug leads to complete resolution in 90% of patients, with no long-term sequelae.

There is a hallmark latent period between the initiation of the drug (“the challenge”) and the development of either symptoms or, more commonly, asymptomatic elevations in serum alanine aminotransferase. Once the diagnosis of drug induced liver injury is established and the inciting drug is withdrawn, the “dechallenge” or clinical improvement is relatively immediate. Liver injury typically recurs if the drug is reintroduced in the future, often with greater severity that could be life-threatening.

The main complication that can develop as a result of drug induced liver injury is chronic liver failure in 5-10% of patients, particularly if they have preexisting liver disease. Up to 10% of patients with drug induced liver injury do not survive the initial injury or require liver transplantation. Overall, complications are dependent on the inciting drug and patient risk factors.

Prompt withdrawal of the offending drug leads to complete resolution in 90% of patients, with no long-term sequelae.