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| !style="background:#eed; padding:0.3em; text-align:center;"|Alternative names
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| |Toxic liver disease<br />
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| Toxin induced liver disease<br />
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| Drug induced liver disease<br />
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| Drug induced liver damage<br />
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| Hepatogenous poisoning
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| |style="padding:0.1em; font-size:0.9em; background-color:#eed;"|'''Subordinate terms'''
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| |Toxic hepatitis<br />
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| Toxin induced hepatitis<br />
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| Drug induced hepatitis<br />
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| Drug-induced hepatic necrosis<br />
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| Drug induced hepatic fibrosis<br />
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| Drug induced hepatic granuloma<br />
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| Toxic liver disease with hepatitis<br />
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| Toxic liver disease with cholestasis<br />
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| |}
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| {{Hepatotoxicity}} | | {{Hepatotoxicity}} |
| | {{See Also|Drug induced liver injury}} |
| | {{See Also|Hy's law}} |
| | '''For patient information on this topic click [[Hepatotoxicity (patient information)|here]].''' |
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| {{CMG}} | | {{CMG}} |
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| {{SK}} Toxic liver disease; Toxin induced liver disease; Drug induced liver disease; Drug induced liver damage; Hepatogenous poisoning | | {{SK}} Hepatogenous Poisoning; Toxic Liver Disease; Toxin-Induced Liver Disease; Toxic liver disease with cholestasis; Toxic liver disease with hepatitis |
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| ==Overview== | | ==[[Hepatotoxicity overview|Overview]]== |
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| '''Hepatotoxicity''' (from ''hepatic toxicity'') implies chemical-driven [[liver]] damage. The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents when taken in overdoses and sometime even when introduced within therapeutic ranges may injure the organ. Other chemical agents such as those used in laboratories and industries, natural chemicals (e.g. [[microcystin]]s) and herbal remedies can also induce hepatotoxicity. Chemicals that cause liver injury are called [[hepatotoxin]]s.
| | ==[[Hepatotoxicity historical perspective|Historical Perspective]]== |
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| 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>
| | ==[[Hepatotoxicity classification|Classification]]== |
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| == Drug metabolism in liver == | | ==[[Hepatotoxicity pathophysiology|Pathophysiology]]== |
| [[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.
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| [[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. | | ==[[Hepatotoxicity causes|Causes]]== |
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| 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:
| | ==[[Hepatotoxicity differential diagnosis|Differentiating Hepatotoxicity from other Diseases]]== |
| :'''1. Genetic diversity:'''
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| 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.
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| {| style="padding:0.3em; float:right; margin-left:5px; border:1px solid #A3B1BF;background:#F0FFFF;"
| | ==[[Hepatotoxicity epidemiology and demographics|Epidemiology and Demographics]]== |
| |+ ''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>{{cite web |url=http://medicine.iupui.edu/flockhart/table.htm |title=P450 Table |accessdate=2007-09-29 |format= |work=}}</ref>''
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| !bgcolor="#D3D3D3"|Potent inducers !! bgcolor="#D3D3D3"|Potent inhibitors !! bgcolor="#D3D3D3"|Substrates
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| | [[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]]
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| |}
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| :'''2. Change in enzyme activity:'''
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| 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
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| by increasing its synthesis. Depending on inducing drug's half life, there is usually a delay before enzyme activity increases.<ref name="pmid17708140"/>
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| :'''3. Competitive inhibition:'''
| | ==[[Hepatotoxicity risk factors|Risk Factors]]== |
| 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.
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| == Mechanism of liver damage == | | ==[[Hepatotoxicity screening|Screening]]== |
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| {| style="background:#E0FFFF;float:right;padding:0.3em; float:right; margin-left:5px; border:1px solid #A3B1BF"
| | ==[[Hepatotoxicity natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| !bgcolor="#B0C4DE"|Factors influencing <br />drug induced hepatotoxicity<ref name="isbn0-443-06633-7">{{cite book |author=Keeffe, Emmet B; Friedman, Lawrence M. |title=Handbook of liver diseases |publisher=Churchill Livingstone |location=Edinburgh |year=2004 |pages=104-123 |isbn=0-443-06633-7 |oclc= |doi= |accessdate=2007-09-07}}</ref>
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| *Age
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| *Ethnicity and race
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| *Gender
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| *Nutritional status
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| *underlying liver disease
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| *Renal function
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| *Pregnancy
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| *Duration and dosage of drug
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| *Enzyme induction
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| *Drug- drug interaction
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| |}
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| Drugs continue to be taken off the market due to late discovery of hepatotoxicity. Due to its unique metabolism and close relationship with the [[gastrointestinal tract]], the liver is susceptible to injury from drugs and other substances. 75% of blood coming to the liver arrives directly from gastrointestinal organs and then spleen via [[Hepatic portal vein|portal vein]]s which bring drugs and xenobiotics in concentrated form. Several mechanisms are responsible for either inducing hepatic injury or worsening the damage process.
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| Many chemicals damage [[mitochondria]], an intracellular organelle that produce energy. Its dysfunction releases excessive amount of oxidants which in turn injures hepatic cells. Activation of some enzymes in the cytochrome P-450 system such as [[CYP2E1]] also lead to oxidative stress.<ref name="pmid11812920">{{cite journal |author=Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ |title=Mechanisms of hepatotoxicity |journal=Toxicol. Sci. |volume=65 |issue=2 |pages=166–76 |year=2002 |pmid=11812920 |doi= |doi=10.1093/toxsci/65.2.166}}</ref> Injury to [[hepatocyte]] and [[bile duct]] cells lead to accumulation of [[bile acid]] [[cholestasis|inside liver]]. This promotes further liver damage.<ref name="pmid9606808">{{cite journal |author=Patel T, Roberts LR, Jones BA, Gores GJ |title=Dysregulation of apoptosis as a mechanism of liver disease: an overview |journal=Semin. Liver Dis. |volume=18 |issue=2 |pages=105–14 |year=1998 |pmid=9606808 |doi=}}</ref> Non-[[parenchyma]]l cells such as [[Kupffer cell]]s, fat storing [[Hepatic stellate cell|stellate cell]]s and [[leukocyte]]s (i.e. [[neutrophil]] and [[monocyte]]) also have role in the mechanism.
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| == Adverse drug Reactions == | | ==Diagnosis== |
| [[Adverse drug reaction]]s are classified as type A (intrinsic or pharmacological) or type B (idiosyncratic).<ref>{{cite book |author=Davies, D. |title=Textbook of adverse drug reactions |publisher=Oxford University Press |location=Oxford [Oxfordshire] |year=1985 |pages= 18-45|isbn=0-19-261479-7 |oclc=12558288 |doi=}}</ref>Type A drug reaction accounts for 80% of all toxicities.<ref name="pmid9554902">{{cite journal |author=Pirmohamed M, Breckenridge AM, Kitteringham NR, Park BK |title=Adverse drug reactions |journal=BMJ |volume=316 |issue=7140 |pages=1295–8 |year=1998 |pmid=9554902 |doi=}}</ref>
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| [[Medication|Drugs]] or toxins that have a '''pharmacological''' (type A) hepatotoxicity are those that have ''predictable'' [[dose-response curve]]s (higher concentrations cause more liver damage) and well characterized mechanisms of toxicity such as directly damaging liver tissue or blocking a metabolic process. As in the case of [[Acetaminophen]] overdose, this type of injury occurs shortly after some threshold for toxicity is reached. | | [[Hepatotoxicity history and symptoms|History and Symptoms]] | [[Hepatotoxicity physical examination|Physical Examination]] | [[Hepatotoxicity laboratory findings|Laboratory Findings]] | [[Hepatotoxicity x ray|X Ray]] | [[Hepatotoxicity CT|CT]] | [[Hepatotoxicity MRI|MRI]] | [[Hepatotoxicity ultrasound|Ultrasound]] | [[Hepatotoxicity other imaging findings|Other Imaging Findings]] | [[Hepatotoxicity other diagnostic studies|Other Diagnostic Studies]] |
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| [[Idiosyncratic drug reaction|'''Idiosyncratic''']] (type B) injury occurs without warning; when agents cause ''non-predictable'' hepatotoxicity in susceptible individuals which is not related to dose and has variable latency period.<ref name="pmid352664">{{cite journal |author=Zimmerman HJ |title=Drug-induced liver disease. |journal=Drugs |volume=16 |issue=1 |pages=25-45 |year=1978 |pmid=352664 |doi= |doi=10.2165/00003495-197816010-00002}}</ref> This type of injury does not have a clear dose-response or temporal relationship, and most often do not have predictive models. Idiosyncratic hepatotoxicity has led to the withdrawal of several drugs from market even after rigorous clinical testing as part of the FDA approval process; [[Troglitazone]] (Rezulin) and [[trovafloxacin]] (Trovan) are two prime examples of idiosyncratic hepatotoxins.
| | ==Treatment== |
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| == Patterns of injury==
| | [[Hepatotoxicity medical therapy|Medical Therapy]] | [[Hepatotoxicity surgery|Surgery]] | [[Hepatotoxicity primary prevention|Primary Prevention]] | [[Hepatotoxicity secondary prevention|Secondary Prevention]] | [[Hepatotoxicity cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Hepatotoxicity future or investigational therapies|Future or Investigational Therapies]] |
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| {| style="padding:0.3em; float:right; margin-left:5px; border:1px solid #A3B1BF;background:#E0FFFF;"
| | ==Case Studies== |
| |+ ''Patterns of drug-induced liver disease''
| | [[Hepatotoxicity case study one|Case #1]] |
| !bgcolor="#B0C4DE"|Type of injury: !! bgcolor="#B0C4DE"|Hepatocellular !! bgcolor="#B0C4DE"|Cholestatic!!bgcolor="#B0C4DE"|Mixed
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| ![[ALT]]
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| | ≥ Twofold rise|| Normal||≥ Twofold rise
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| ![[Alkaline phosphatase|ALP]]
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| |Normal ||≥ Twofold rise||≥ Twofold rise
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| !ALT: ALP ratio
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| |High, ≥5|| Low, ≤2||2-5
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| !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>
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| |[[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]]
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| |}
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| 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.
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| Specific [[Morphology (biology)|histo-pathological]] patterns of liver injury from drug induced damage are discussed below.
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| '''Zonal Necrosis'''
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| 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]].
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| :Causes:
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| :[[Acetaminophen|Acetaminophen (Tylenol)]], [[carbon tetrachloride]]
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| '''[[Hepatitis]]'''
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| 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.
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| :Causes:
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| :(a) Viral hepatitis like: [[Halothane]], [[Isoniazid]], [[Phenytoin]]
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| :(b) Focal hepatitis: [[Aspirin]]
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| :(c) Chronic hepatitis: [[Methyldopa]], [[Diclofenac]]
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| '''[[Cholestasis]]'''
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| 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).
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| :Causes:
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| :(a) Bland: [[Combined oral contraceptive pill|Oral contraceptive pills]], [[anabolic steroid]], [[Androgens]]
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| :(b) Inflammatory: [[Allopurinol]], [[Co-amoxiclav]], [[Carbamazepine]]
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| :(c) Ductal: [[Chlorpromazine]], [[flucloxacillin]]
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| '''[[Steatosis]]'''
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| 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:
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| :(a) Microvesicular: [[Aspirin]] ([[Reye's syndrome]]), [[Ketoprofen]], [[Tetracycline]]
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| :(b) Macrovesicular: [[Acetamenophen]], [[methotrexate]]
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| :(c) Phospholipidosis: [[Amiodarone]], [[Total parenteral nutrition]]
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| '''[[Granuloma]]'''
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| 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.
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| : Causes:
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| :[[Allopurinol]], [[Phenytoin]], [[Isoniazid]], [[Quinine]], [[Penicillin]], [[Quinidine]]
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| '''Vascular lesions'''
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| They result from injury to the vascular endothelium.
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| :Causes:
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| :[[Venoocclusive disease]]: Chemotherapeutic agents, bush tea
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| :[[Peliosis hepatis]]: anabolic steroid
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| :[[Budd-Chiari syndrome|Hepatic vein thrombosis]]: Oral contraceptives
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| '''[[Neoplasm]]'''
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| Neoplasms have been described with prolonged exposure to some medications or toxins. Hepatocellular carcinoma, angiosarcoma and liver adenomas are the ones usually reported.
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| :Causes:
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| :[[Vinyl chloride]], [[Combined oral contraceptive pill]],[[Anabolic steroid]], [[Arsenic]], [[Thorotrast]]
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| == Clinical assessment ==
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| [[Image:Aseessement of hepatotoxicity.png|thumb|left|Algorithm for suspected drug induced hepatic toxicity]]
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| This remains a major challenge in clinical practice due to lack of reliable markers.<ref name="pmid17230599">{{cite journal |author=Andrade RJ, Robles M, Fernández-Castañer A, López-Ortega S, López-Vega MC, Lucena MI |title=Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists |journal=World J. Gastroenterol. |volume=13 |issue=3 |pages=329–40 |year=2007 |pmid=17230599 |url=http://www.wjgnet.com/1007-9327/13/329.asp|doi=}}</ref> Many other conditions lead to similar clinical as well as pathological picture. To diagnose hepatotoxicity, a causal relationship between the use of the toxin or drug and subsequent liver damage has to be established, but might be difficult, especially when idiosyncratic reaction is suspected.<ref>{{cite journal |author=Arundel C, Lewis JH |title=Drug-induced liver disease in 2006 |journal=Curr. Opin. Gastroenterol. |volume=23 |issue=3 |pages=244–54 |year=2007 |pmid=17414839 |doi=10.1097/MOG.0b013e3280b17dfb}}</ref> Simultaneous use of multiple drugs may add to the complexity. As in acetaminophen toxicity, well established dose dependent pharmacological hepatotoxicity is easier to spot. Several clinical scales such as [[Council for International Organizations of Medical Sciences|CIOMS]]/RUCAM scale and Maria and Victorino criteria have been proposed to establish causal relationship between offending drug and liver damage. [[CIOMS/RUCAM scale]] involves a scoring system which categorizes the suspicion into "definite or highly probable" (score > 8), “probable” (score 6-8), “possible” (score 3-5), “unlikely” (score 1-2) and “excluded” (score ≤ 0). In clinical practice physicians put more emphasis on the presence or absence of similarity between the biochemical profile of the patient and known biochemical profile of the suspected toxicity ( e.g. cholestatic damage in [[Co-amoxiclav|amoxycillin-clauvonic acid]] ).<ref name="pmid17230599"/>
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| == Treatment and prognosis ==
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| In most cases liver function will return to normality if offending drug is stopped early. However in acetamenophen toxicity initial insult can be fatal. In most instances supportive treatment is all that is required. However in fulminant hepatic failure from drug induced hepatotoxicity may require liver transplantation. In the past glucocorticoides in allergic features and ursodeoxycholic acid in cholestatic pictures had been used, but there is no good evidence to support their effectiveness.
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| An elevation in serum bilirubin level of more that 2 times ULN with associated transaminase rise is an ominous sign. This indicates severe hepatotoxicity and is likely to lead to mortality in 10% to 15% of patients, especially if the offending drug is not stopped ([[Hy's Law]]).<ref name="pmid14768020">{{cite journal |author=Reuben A |title=Hy's law |journal=Hepatology |volume=39 |issue=2 |pages=574–8 |year=2004 |pmid=14768020 |doi=10.1002/hep.20081}}</ref><ref name="pmid16618822">{{cite journal |author=Arora N, Goldhaber SZ |title=Anticoagulants and transaminase elevation |journal=Circulation |volume=113 |issue=15 |pages=e698–702 |year=2006 |pmid=16618822 |doi=10.1161/CIRCULATIONAHA.105.603100}}</ref> This is due to the fact that it requires significant damage to the liver to impair bilirubin excretion, hence minor impairment (in the absence of biliary obstruction or [[Gilbert syndrome]]) would not lead to jaundice. Other poor predictors of outcome are old age, female sex, high [[Aspartate transaminase|AST]].<ref>{{cite journal |author=Andrade RJ, Lucena MI, Kaplowitz N, ''et al'' |title=Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry |journal=Hepatology |volume=44 |issue=6 |pages=1581–8 |year=2006 |pmid=17133470 |doi=10.1002/hep.21424}}</ref><ref>{{cite journal |author=Björnsson E, Olsson R |title=Outcome and prognostic markers in severe drug-induced liver disease |journal=Hepatology |volume=42 |issue=2 |pages=481–9 |year=2005 |pmid=16025496 |doi=10.1002/hep.20800}}</ref>
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| == Drugs withdrawn for hepatotoxicity ==
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| [[Troglitazone]], [[bromfenac]], [[trovafloxacin]], ebrotidine, [[nimesulide]], [[nefazodone]] and [[ximelagatran]].<ref name="pmid17230599"/><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>
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| == Specific drug or toxin==
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| ====Acetaminophen ====
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| [[Image:Paracetamol-rod-povray.png|thumb|Acetaminophen (3D structure) overdose is the most common cause of drug induced liver disease]]
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| [[Acetaminophen]] (paracetamol, also known by the brand name Tylenol and Panadol) is usually well tolerated in prescribed dose but overdose is the most common cause of drug induced liver disease and [[acute liver failure]] worldwide,<ref name="isbn0-443-06633-7"/> which is one of the most painful experiences patients report. Reports of death from accute hepatotoxicity have been reported to be as low as 2.5 grams over a 24 hour period. Damage to the liver is not due to the drug itself but to a toxic metabolite (''N''-acetyl-''p''-benzoquinone imine NAPQI, or NABQI) which is produced by cytochrome P450 enzymes in the liver.<ref name="pmid15345657">{{cite journal |author=Wallace JL |title=Acetaminophen hepatotoxicity: NO to the rescue |journal=Br. J. Pharmacol. |volume=143 |issue=1 |pages=1–2 |year=2004 |pmid=15345657 |doi=10.1038/sj.bjp.0705781}}</ref> In normal circumstances this metabolite is detoxified by conjugating with [[glutathione]] in phase 2 reaction. In overdose large amount of NAPQI is generated which overwhelm the detoxification process and lead to damage to liver cells. [[Nitric oxide]] also plays role in inducing toxicity.<ref>{{cite journal |author=James LP, Mayeux PR, Hinson JA |title=Acetaminophen-induced hepatotoxicity |journal=Drug Metab. Dispos. |volume=31 |issue=12 |pages=1499–506 |year=2003 |pmid=14625346 |doi=10.1124/dmd.31.12.1499}}</ref> The risk of liver injury is influenced by several factors including the dose ingested, concurrent alcohol or other drug intake, interval between ingestion and antidote etc. The dose toxic to liver is quite variable and is lower in chronic alcoholics. Measurement of blood level is important in assessing prognosis, higher level predicting worse prognosis. Administration of [[Acetylcysteine]], a precursor of glutathione, can limit the severity of the liver damage by capturing the toxic NAPQI. Those who develop [[acute liver failure]] can still recover spontaneously, but may require transplantation if poor [[prognostic]] signs such as [[encephalopathy]] or [[coagulopathy]] is present (see [[King's College Criteria]]).
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| ==== Nonsteroidal anti-inflammatory drugs ====
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| Although individual analgesics rarely induce liver damage, due to their widespread use NSAIDs have emerged as a major group of drugs exhibiting hepatotoxicity. Both dose dependent and idiosyncratic reactions have been documented.<ref>{{cite journal |author=Manov I, Motanis H, Frumin I, Iancu TC |title=Hepatotoxicity of anti-inflammatory and analgesic drugs: ultrastructural aspects |journal=Acta Pharmacol. Sin. |volume=27 |issue=3 |pages=259–72 |year=2006 |pmid=16490160 |doi= |doi=10.1111/j.1745-7254.2006.00278.x}}</ref> Aspirin and [[phenylbutazone]] are associated with intrinsic hepatotoxicity; idiosyncratic reaction has been associated with ibuprofen, sulindac, phenylbutazone, piroxicam, diclofenac and indomethacin.
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| ==== Glucocorticoids ====
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| Glucocorticoids are so named due to their effect on carbohydrate mechanism. they promote glycogen storage in liver. Enlarged liver is a rare side effect of long term steroid use in children.<ref name="pmid3944744">{{cite journal |author=Iancu TC, Shiloh H, Dembo L |title=Hepatomegaly following short-term high-dose steroid therapy |journal=J. Pediatr. Gastroenterol. Nutr. |volume=5 |issue=1 |pages=41–6 |year=1986 |pmid=3944744 |doi=}}</ref> The classical effect of prolonged use both in adult and [[paediatric]] population is steatosis.<ref>
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| {{cite book
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| | last =Alpers DH | first = Sabesin SM| authorlink = | coauthors =Schiff L, Schiff ER, editors.
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| | title =Diseases of the liver | publisher =JB Lippincott | date =1982 | location =Philadelphia | pages =813-45 | url = | doi = | id =
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| | isbn = }}
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| </ref>
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| ==== Isoniazid ====
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| Isoniazide (INH) is one of the most commonly used drug for tuberculosis; it is associated with mild elevation of liver enzymes in up to 20% of patients and severe hepatotoxicity in 1-2% of patients.<ref name="pmid10215642">{{cite journal |author=Sarich TC, Adams SP, Petricca G, Wright JM |title=Inhibition of isoniazid-induced hepatotoxicity in rabbits by pretreatment with an amidase inhibitor |journal=J. Pharmacol. Exp. Ther. |volume=289 |issue=2 |pages=695–702 |year=1999 |pmid=10215642 |doi=}}</ref>
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| ==== Natural products ====
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| Example: Amanita mushroom, particularly the [[destroying angel]]s, aflatoxins
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| ==== Industrial toxin ====
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| Example: Arsenic, Carbon tetraChloride, Vinyl Chloride
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| ====Herbal and alternative remedies====
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| Ackee fruit, Bajiaolian, Camphor, Copaltra, Cycasin, Kava, Pyrrolizidine alkaloids, Horse chestnut leaf, Valerian, Comfrey (often used in herbal tea)<ref name="pmid15264453">{{cite journal |author=Pak E, Esrason KT, Wu VH |title=Hepatotoxicity of herbal remedies: an emerging dilemma |journal=Progress in transplantation (Aliso Viejo, Calif.) |volume=14 |issue=2 |pages=91–6 |year=2004 |pmid=15264453 |doi=}}</ref>
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| *Chinese herbal remedies:
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| :Jin Bu Huan, Ma-huang, Sho-wu-pian
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| <gallery>
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| Image:Amanita muscaria (fly agaric).JPG|Fly agaric (''Amanita muscaria'') is one of the natural products toxic to the liver
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| Image:Horse chestnut leaf.jpg|Horse chestnut leaf
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| Image:Akee.jpg|Ackee fruit
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| Image:Saint johns wart flowers.jpg|Saint John's wort Induces Cytochrome P-450 enzyme
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| </gallery>
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| ==Related Chapters== | | ==Related Chapters== |
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| * [[Reye's syndrome]] | | * [[Reye's syndrome]] |
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| ==References==
| | [[Category:Disease]] |
| {{reflist|2}}
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| [[Category:Toxicology]] | |
| [[Category:Gastroenterology]] | | [[Category:Gastroenterology]] |
| [[Category:Hepatology]] | | [[Category:Hepatology]] |