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__NOTOC__
#redirect [[Drug induced liver injury]]
{{Drug-induced hepatitis}}
{{CMG}}
 
 
==Overview==
More than 900 drugs have been implicated in causing liver injury<ref name="isbn0-8385-1551-7">{{cite book |author=Friedman, Scott E.; Grendell, James H.; McQuaid, Kenneth R. |title=Current diagnosis & treatment in gastroenterology |publisher=Lang Medical Books/McGraw-Hill |location=New York |year=2003 |pages=p664-679 |isbn=0-8385-1551-7 |oclc= |doi=}}</ref> and it is the most common reason for a drug to be withdrawn from the market. Chemicals often cause [[subclinical]] injury to liver which manifests only as abnormal [[Liver function tests|liver enzyme tests]]. Drug induced liver injury is responsible for 5% of all hospital admissions and 50% of all [[acute liver failure]]s.<ref name="isbn1-56053-618-7">{{cite book |author=McNally, Peter F. |title=GI/Liver Secrets: with STUDENT CONSULT Access |publisher=C.V. Mosby |location=Saint Louis |year= |pages= |isbn=1-56053-618-7 |oclc= |doi=}}</ref><ref>{{cite journal |author=Ostapowicz G, Fontana RJ, Schiødt FV, ''et al'' |title=Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States |journal=Ann. Intern. Med. |volume=137 |issue=12 |pages=947–54 |year=2002 |pmid=12484709 |doi=}}</ref>
 
==Pathophysiology==
 
===A- Pathophysiologic mechanisms===
 
The pathophysiologic mechanisms of hepatotoxicity are still being explored and include both hepatocellular and extracellular mechanisms. The following are some of the mechanisms that have been described:
 
====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 P<sub>450</sub> 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.
 
===B- Drug toxicity mechanisms===
 
The classic division of drug reactions is into at least 2 major groups,
 
# Drugs that directly affect the liver
# Drugs that mediate an immune response.
 
====Hypersensitivity====
 
Phenytoin is a classic, if not common, cause of hypersensitivity reactions. The response is characterized by fever, rash, and eosinophilia and 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).
 
== Drug metabolism in liver ==
[[Image:Hepatic drug metabolism.png|thumb|left|Drug metabolism in liver: transferases are : glutathione, sulfate, acetate, glucoronic acid. P<sub>450</sub> is cytochrome P<sub>450</sub> enzymes. 3 different pathways are depicted for Drugs A, B and C.]]
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).<ref>{{cite book |author=Donald Blumenthal; Laurence Brunton; Keith Parker; Lazo, John S.; Iain Buxton |title=Goodman and Gilman's Pharmacological Basis of Therapeutics Digital Edition |publisher=McGraw-Hill Professional |location= |year= |pages= |isbn=0-07-146804-8 |oclc= |doi=}}</ref> 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 metabolised by phase 2 directly. Phase 1 reaction involves [[oxidation]], [[Reduction (chemistry)|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 [[enzyme]]s 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 [[isoform]]s, six of them metabolize 90% of drugs.<ref name="isbn0-7487-6011-3">{{cite book |author=Skett, Paul; Gibson, G. Gordon |title=Introduction to drug metabolism |publisher=Nelson Thornes Publishers |location=Cheltenham, UK |year=2001 |pages= |isbn=0-7487-6011-3 |oclc= |doi=}}</ref><ref name="pmid17708140">{{cite journal |author=Lynch T, Price A |title=The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects |journal=American family physician |volume=76 |issue=3 |pages=391–6 |year=2007 |pmid=17708140 |doi=}}</ref> 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.
 
{| style="padding:0.3em; float:right; margin-left:5px; border:1px solid #A3B1BF;background:#F0FFFF;"
|+ ''Cytochrome P-450 enzyme induction and inhibition<ref name="pmid17708140"/><ref name="isbn1-58562-111-0">{{cite book |author=Jessica R. Oesterheld; Kelly L. Cozza; Armstrong, Scott |title=Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, Ugts, P-Glycoproteins |publisher=American Psychiatric Association |location=Washington, DC |year= |pages=167-396 |isbn=1-58562-111-0 |oclc= |doi=}}</ref><ref>Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). http://medicine.iupui.edu/flockhart/table.htm. Accessed [29-09-2007]</ref>''
!bgcolor="#D3D3D3"|Potent inducers !! bgcolor="#D3D3D3"|Potent inhibitors !! bgcolor="#D3D3D3"|Substrates
|-
| [[Rifampicin]], [[Carbamazepine]], <br />[[Phenobarbital]], [[Phenytoin]], <br />([[St John's wort]]), || [[Amiodarone]], [[cimetidine]], <br />[[ciprofloxacin]], [[fluconazole]],<br /> [[fluoxetine]], [[erythromycin]], <br />[[isoniazid]], [[diltiazem]] ||[[Caffeine]], [[clozapine]],<br /> [[omeprazole]], [[losartan]],<br />[[theophylline]]
|}
:'''2. Change in enzyme activity:'''
Many substances can influence  P-450 enzyme mechanism. Drugs interact with the enzyme family in several ways.<ref name="pmid9469685">{{cite journal |author=Michalets EL |title=Update: clinically significant cytochrome P-450 drug interactions |journal=Pharmacotherapy |volume=18 |issue=1 |pages=84–112 |year=1998 |pmid=9469685 |doi=}}</ref> 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.<ref name="pmid17708140"/>
 
:'''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 injury==
 
{| style="padding:0.3em; float:right; margin-left:5px; border:1px solid #A3B1BF;background:#E0FFFF;"
|+ ''Patterns of drug-induced liver disease''
!bgcolor="#B0C4DE"|Type of injury: !! bgcolor="#B0C4DE"|Hepatocellular !! bgcolor="#B0C4DE"|Cholestatic!!bgcolor="#B0C4DE"|Mixed
|-
![[ALT]]
| ≥ Twofold rise|| Normal||≥ Twofold rise
|-
![[Alkaline phosphatase|ALP]]
|Normal ||≥ Twofold rise||≥ Twofold rise
|-
!ALT: ALP ratio
|High, ≥5|| Low, ≤2||2-5
|-
!Examples<ref name="pmid16710915">{{cite journal |author=Mumoli N, Cei M, Cosimi A |title=Drug-related hepatotoxicity |journal=N. Engl. J. Med. |volume=354 |issue=20 |pages=2191-3; author reply 2191-3 |year=2006 |pmid=16710915 |doi=}}</ref>
|[[Acetaminophen]]<br />[[Allopurinol]]<br />[[Amiodarone]]<br />[[HAART]]<br />[[NSAID]]||[[Anabolic steroid]]<br />[[Chlorpromazine]]<br />[[Clopidogrel]]<br />[[Erythromycin]]<br />[[Hormonal contraception]]||[[Amitryptyline]],<br />[[Enalapril]]<br />[[Carbamazepine]]<br />[[Sulphonamide]]<br />[[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) [[alanine transferase|ALT]] level more than three times of upper limit of normal (ULN), (b) [[alkaline phosphatase|ALP]] level more than twice ULN, or (c) total bilirubin level more than twice ULN when associated with increased ALT or ALP.<ref>{{cite journal |author=Bénichou C |title=Criteria of drug-induced liver disorders. Report of an international consensus meeting |journal=J. Hepatol. |volume=11 |issue=2 |pages=272–6 |year=1990 |pmid=2254635 |doi=}}</ref><ref name="pmid16710915"/> 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 [[Morphology (biology)|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 [[Alanine transaminase|ALT]] and severe disturbance of liver function leading to [[acute liver failure]].
:Causes:
:[[Acetaminophen|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 [[lymphocyte|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: [[Combined oral contraceptive pill|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
:[[Budd-Chiari syndrome|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]]
 
==Risk Factors==
 
* 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 - [[Salicylate]]s, [[valproic acid]]
* [[Liver disease]]: In general, patients with chronic liver disease are not uniformly at increased risk of hepatic injury. Although the total cytochrome P<sub>450</sub> 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, blacks and Hispanics may be more susceptible to isoniazid (INH) toxicity. The rate of metabolism is under the control of P<sub>450</sub> enzymes and can vary from individual to individual.
 
==List of Drugs that can cause Hepatitis==
 
===Drug that Effect Cytochrome P<sub>450</sub>===
 
====Inducers====
 
*[[Carbamazepine]]
*[[Ethanol]]
*[[Glucocorticoids]]
*[[Griseofulvin]]
*[[Omeprazole]] - Induces P<sub>450</sub> 1A2
*[[Phenobarbital]]
*[[Phenytoin]]
*[[Primidone]]
*[[Quinine]]
*[[Rifampin]]
 
====Inhibitors====
*[[Amiodarone]]
*[[Cimetidine]]
*[[Erythromycin]]
*Grape fruit
*[[Isoniazid]]
*[[Ketoconazole]]
*[[Metronidazole]]
*[[Omeprazole]] - Inhibits P<sub>450</sub> 2C8
*[[Quinidine]]
*[[Sulfonamide]]s
 
== Drugs withdrawn for hepatotoxicity ==
[[Troglitazone]], [[bromfenac]], [[trovafloxacin]], ebrotidine, [[nimesulide]], [[nefazodone]] and [[ximelagatran]].<ref>PMID 17230599</ref> <ref name="pmid10687025">{{cite journal |author=Shah RR |title=Drug-induced hepatotoxicity: pharmacokinetic perspectives and strategies for risk reduction |journal=Adverse drug reactions and toxicological reviews |volume=18 |issue=4 |pages=181–233 |year=1999 |pmid=10687025 |doi=}}</ref>
 
==Diagnosis==
 
===History and symptoms===
:* [[fever]]
:* [[jaundice]]
:* [[nausea]]
:* [[rash]] or itchy red [[hives]] on skin
:* [[vomiting]]
:* [[decreased appetite]]
:* [[flu]]-like symptoms
:* [[joint pain]]
:* sore muscles
 
===Diagnostic Tests===
* [[CBC]]
* [[Alkaline phosphatase]]
* [[AST]] / [[serum glutamic oxaloacetic transaminase]] ([[SGOT]])
* [[ALT]] / [[serum glutamic pyruvate transaminase]] ([[SGPT]])
* [[Albumin]]
* [[Gammaglobulin]]
* [[Prothrombin time]] after [[vitamin K]]
* [[Anti-mitochondrial antibody]] ([[AMA]])
* [[Anti smooth muscle antibody]] ([[ASMA]])
* [[Urinalysis]]
* [[Electrolyte]]s
* Drug levels
* [[Ultrasonography]]
* [[CT]]
* [[MRI]]
* [[Liver biopsy]]
 
==Differential Diagnosis==
 
* [[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]]
 
==Treatment==
 
There is no specific treatment for drug-induced hepatitis other than stopping the drug that is causing the problem.
 
Bed rest during the acute phase of the disease is essential part of the therapy, when the symptoms are most severe. If significant [[nausea]] and [[vomiting]] occur, fluids given through a vein may be needed.
 
Patients with [[acute hepatitis]] should avoid physical exertion, alcohol, [[acetaminophen]], and any other substances that are harmful to the liver.
 
==References==
{{Reflist|2}}
 
==See Also==
 
* [[Hepatotoxicity]]
 
 
 
[[Category:Gastroenterology]]
 
{{WH}}
{{WS}}

Latest revision as of 20:47, 2 June 2016