halogenated inhalational anesthetics are the most commonly used agents for induction and maintenance of general anesthesia . the choice of anesthetic depends on many factors including ease of administration , cost , availability and permissibility of their effects . for more than 50 years chloroform the original halogenated anesthetic abandoned for a long period is indicated to be hepatotoxic by different studies ( 1 , 2 ) . halothane , introduced in 1950s as a safer alternative for chloroform , causes a well - documented syndrome of acute hepatotoxicity as well . these agents are also shown to cause similar injury , but less than halothane ( 3 ) . fortunately , fewer cases of hepatotoxicity have been reported for the newest agents , desflurane and sevoflurane ( 4 ) . most hypotheses on the mechanism of halogenated anesthetics - induced hepatic injury are based on the production of metabolites causing immunoallergic reaction in patients . all of these anesthetics undergo biotransformation , primarily involving cytochrome p-450 2e1 ( cyp 2e1 ) ( 5 ) . the likelihood that each halogenated inhalational anesthetic causes liver injury correlates with the extent to which it is metabolized by this cytochrome ( 20% to 30% for halothane , 2% for enflurane , 1% for sevoflurane , and 0.2% or less for isoflurane and desflurane ) and the metabolic products ( 5 ) . in this study , we aimed to review available literature documenting the mechanism and extent by which these agents cause liver injuries . electronic search was performed by searching several databases ( pubmed , google scholar , scopus , index copernicus , ebsco and the cochrane database ) using the keywords including  inhalational anesthetics  and  liver injury  ;  inhalational anesthetics  and  hepatotoxicity  ;  volatile anesthetics  and  liver injury  ;  volatile anesthetics  and  hepatotoxicity  ; for the period of 1966 to 2013 . all randomized clinical trials , case series , case report and meta - analysis studies with the above mentioned contents were included in review process . totally , 247 articles were found in primary search , from which 52 articles were eligible and enrolled in this study . halothane is a classic form of halogenated anesthetics , which was introduced in 1956 and rapidly became the most commonly used agent for general anesthesia . within a few years of its introduction , cases of halothane - induced liver injuries were reported . in 1969 , the national institutes of health ( nih ) organized an epidemiological study on 250000 cases of halothane administration , which revealed an incidence of fatal hepatic necrosis of about 1 in 35000 individuals ( 6 - 8 ) . concerns about its hepatotoxicity eliminated the use of this anesthetic for adults in the united states and many other countries . two types of postoperative liver injuries have been reported to be associated with halothane administration . twenty percent of patients receiving halothane anesthesia show a mild injury characterized by nausea , lethargy and fever . the first is a transient elevation of liver enzymes , alanine aminotransferase ( alt ) and aspartate aminotransferase ( ast ) , which remain elevated for one to two weeks following halothane exposure and resolve without treatment ( 9 ) . halothane associated hypoxia is indicated to be due to alteration in the hepatic oxygen demand and supply relationship ( 10 , 11 ) . mild hepatic injury appears to result from direct toxic effect of halothane on hepatic cells ; however , evidence of immune activation is lacking in this type . the other form of liver damage after halothane exposure is severe acute hepatitis with histological findings of massive hepatic necrosis . this form is dose - independent and rare , occurring in approximately 1/15000 cases after initial exposure , but in about 1/1000 cases after repeated exposures ( 12 - 15 ) . the severe type of injury is associated with acute elevations in alt and ast levels ( 5 to 50 fold ) and onset of jaundice within 2 to 14 days of halothane administration . there is strong evidence that the severe type of liver injury is mediated by the patient 's own immune system . approximately 60% to 80% of inhaled halothane is eliminated unchanged through the lungs , but about 20% of it undergoes metabolism either in an oxidative ( by cyp2e1 and cyp2a6 ) or reductive ( by cytochrome cyp2a6 and cyp3a4 ) pathways . halothane oxidation leads to production of trifluoroacetic acid ( tfa ) , which acts on hepatocyte proteins to produce trifluoroacetylated components . it is indicated that serum of patients with a clinical diagnosis of halothane - induced hepatitis contains circulating immunoglobulin g ( igg ) , reacting with liver microsomal trifluoroacetylated proteins ( 16 ) . repeated halothane exposure stimulates the immune response , increasing the incidence of hepatitis , fever , rash , arthralgia , and peripheral eosinophilia ( 17 , 18 ) . hepatic injury due to immune response is severe and even sometimes fatal ( 19 ) . on the other hand , reductive pathways of halothane metabolism produce free radicals that can act as reactive metabolites causing minor injury . different risk factors have been suggested to increase the incidence of halothane - induced hepatotoxicity . this injury tends to be more severe in persons older than 40 years as they account for 80% of cases . repeated exposure to halothane ( especially within a few weeks or months ) is documented in as many as 90% of cases . obesity is another risk factor , possibly because of accumulation of halothane in adipose tissue . induction of cyp2e1 by phenobarbital , alcohol , and isoniazid are all risk factors for halothane hepatitis ( 20 - 22 ) . however , halothane is no longer used in many developed countries but continues to be used in some developing countries . after halothane , other halogenated anesthetics , including enflurane ( 1972 ) , isoflurane ( 1979 ) , desflurane ( 1993 ) and sevoflurane ( 1995 ) have been introduced . compared to halothane , these agents have the advantage of fewer metabolisms by the cyp2e1 system , which suggests less adverse effects on liver , following their administration ( 23 , 24 ) . as it has a slow onset of action , it is used largely to maintain anesthesia after induction with other agents . enflurane became available in 1972 and is still in use , although less widely than other more modern halogenated agents . clinically apparent , very rare cases of severe hepatic injury from enflurane have been reported . like halothane , enflurane is metabolized by the microsomal drug - metabolizing enzyme cyp2e1 to a trifluoroacetylated reactive intermediate , which is capable of binding to multiple intracytoplasmic proteins , forming potentially immunogenic adducts . as the tfa adducts induced antibodies can be detected in patients with enflurane , as well as halothane , it is suggested that the mechanism of enflurane - induced liver injury resembles the mechanism of halothane hepatotoxicity . however , the incidence of enflurane - induced hepatotoxicity appears to be less compared to halothane . as with halothane hepatotoxicity , this injury is marked by acute elevations in serum alt ( 5- to 50-fold ) and appearance of jaundice 2 to 21 days after the operation and anesthesia ( 25 - 27 ) . isoflurane , an isomer of enflurane , is a widely used anesthetic agent with rapid onset of action and rapid dispersal . it was approved in 1979 and widely accepted as a safer agent with less risk of hepatotoxicity . since its release by the food and drug administration , controversy has existed about the extent to which isoflurane is capable of producing hepatotoxic effects ( 3 ) . this agent is suggested to be less hepatotoxic compared to halothane and enflurane ; however , there are few case reports , describing fetal hepatotoxicity following single exposure to isoflurane ( 3 , 28 , 29 ) . the mechanism of isoflurane hepatotoxicity is suspected to be similar to that of halothane and associated with production of reactive intermediates . similar to previously described agents , desflurane is metabolized to a small but variable extent by the microsomal drug - metabolizing enzyme cyp2e1 to a tfa reactive intermediate , which is capable of binding to multiple intracytoplasmic proteins , forming potentially immunogenic adducts . occurrence of hepatic injury following desflurane anesthesia was once thought to be rare . however , case reports reporting complications related to the use of this anesthetic continue to be accumulated ( 30 - 35 ) . interestingly , in addition to circulating anti - tfa antibodies ( 4 , 5 ) , such as those associated with halothane or isoflurane , recently autoantibodies to cyp2e1 and 58 kda endoplasmic reticulum protein ( erp58 ) , have been reported after desflurane anesthesia ( 30 ) . the presence of these antibodies suggests the induction of heterogeneous immune complexes following desflurane exposure . sevoflurane has many desirable clinical properties , including a nonpungent odor and low solubility in blood , which provides rapid induction and recovery . studies have indicated that its administration is not associated with elevated alt and ast levels ( 29 ) . in contrast with older halogenated anesthetics , sevoflurane metabolism has not resulted in the formation of tfa ; hence , hepatotoxic potential of sevoflurane is considered to be low ( 36 , 37 ) . a unique compound of sevoflurane metabolism , hexafluoroisopropanol ( hfip ) has significantly less protein binding capability than tfa . in addition , hfip does not accumulate and rapidly undergoes phase ii biotransformation , specifically glucuronidation , to form hfip - glucuronide . this compound is mostly excreted in the urine within 12 hours after anesthesia and is not detectable beyond 2 days ( 38 - 40 ) . this is in contrast to previous anesthetics , where tfa is detectable in urine for up to 12 days after 75 minutes of anesthesia ( 41 - 43 ) . however , sevoflurane has a low hepatotoxic potential as described in the current available literature ( 8 , 44 , 45 ) . as apparently , sevoflurane is unlikely to cause severe postoperative hepatic injury and is an ideal anesthetic for patients with previous exposure to other halogenated anesthetics or hepatic disease ( 46 - 48 ) . sevoflurane seems to be the best anesthetic choice in large size surgeries and liver transplants , intervention in which postoperative liver dysfunction could have harmful effects on patients . interestingly , new studies demonstrated that sevoflurane pretreatment even exerts a protective effect on hepatic ischemia / reperfusion injury , which is a common problem in hepatic surgery ( 47 , 49 , 50 ) . anesthesia - induce hepatotoxicity is a diagnosis of exclusion , so that ruling out other causes is essential . clinical features similar to anesthesia - induced liver injury can be caused by acute viral hepatitis , exacerbation of previous chronic liver disease , hemolysis after blood transfusion , liver damage due to hypoxia ( caused by vasoconstriction , shock , hypoxia , cardiac arrest ischemia ) , hypotension or liver damage due to other hepatotoxic drugs ( antibiotics , antidepressants , phenothiazines , phenytoin , anticoagulants ) . for instance , from a histopathological point of view , centrolobular necrosis with mild cholestasis and fatty infiltration are associated with both hepatic necrosis due to halothane and hepatic necrosis caused by viruses . furthermore , an operation per se may cause changes in liver function regardless of the type of anesthesia . using anamnestic or serological tests together with clinical and epidemiological criteria would be helpful to distinguish anesthesia - induced hepatitis from other causes of hepatitis . features of anesthesia - induced hepatitis include high fever onset day 3 to 14 , incidence of jaundice 1 - 2 days after fever , presence of no viral antibodies , latent period less than 15 days , recent exposure in 80% of cases , leukocytosis with eosinophilia ( 20% following halothane but rare in viral hepatitis ) , fulminant course ( 40% mortality vs. 1% for viral ) and two times higher incidence in females . halothane is a classic form of halogenated anesthetics , which was introduced in 1956 and rapidly became the most commonly used agent for general anesthesia . within a few years of its introduction , cases of halothane - induced liver injuries were reported . in 1969 , the national institutes of health ( nih ) organized an epidemiological study on 250000 cases of halothane administration , which revealed an incidence of fatal hepatic necrosis of about 1 in 35000 individuals ( 6 - 8 ) . concerns about its hepatotoxicity eliminated the use of this anesthetic for adults in the united states and many other countries . two types of postoperative liver injuries have been reported to be associated with halothane administration . twenty percent of patients receiving halothane anesthesia show a mild injury characterized by nausea , lethargy and fever . the first is a transient elevation of liver enzymes , alanine aminotransferase ( alt ) and aspartate aminotransferase ( ast ) , which remain elevated for one to two weeks following halothane exposure and resolve without treatment ( 9 ) . halothane associated hypoxia is indicated to be due to alteration in the hepatic oxygen demand and supply relationship ( 10 , 11 ) . mild hepatic injury appears to result from direct toxic effect of halothane on hepatic cells ; however , evidence of immune activation is lacking in this type . the other form of liver damage after halothane exposure is severe acute hepatitis with histological findings of massive hepatic necrosis . this form is dose - independent and rare , occurring in approximately 1/15000 cases after initial exposure , but in about 1/1000 cases after repeated exposures ( 12 - 15 ) . the severe type of injury is associated with acute elevations in alt and ast levels ( 5 to 50 fold ) and onset of jaundice within 2 to 14 days of halothane administration . there is strong evidence that the severe type of liver injury is mediated by the patient 's own immune system . approximately 60% to 80% of inhaled halothane is eliminated unchanged through the lungs , but about 20% of it undergoes metabolism either in an oxidative ( by cyp2e1 and cyp2a6 ) or reductive ( by cytochrome cyp2a6 and cyp3a4 ) pathways . halothane oxidation leads to production of trifluoroacetic acid ( tfa ) , which acts on hepatocyte proteins to produce trifluoroacetylated components . it is indicated that serum of patients with a clinical diagnosis of halothane - induced hepatitis contains circulating immunoglobulin g ( igg ) , reacting with liver microsomal trifluoroacetylated proteins ( 16 ) . repeated halothane exposure stimulates the immune response , increasing the incidence of hepatitis , fever , rash , arthralgia , and peripheral eosinophilia ( 17 , 18 ) . hepatic injury due to immune response is severe and even sometimes fatal ( 19 ) . on the other hand , reductive pathways of halothane metabolism produce free radicals that can act as reactive metabolites causing minor injury . different risk factors have been suggested to increase the incidence of halothane - induced hepatotoxicity . this injury tends to be more severe in persons older than 40 years as they account for 80% of cases . repeated exposure to halothane ( especially within a few weeks or months ) is documented in as many as 90% of cases . obesity is another risk factor , possibly because of accumulation of halothane in adipose tissue . induction of cyp2e1 by phenobarbital , alcohol , and isoniazid are all risk factors for halothane hepatitis ( 20 - 22 ) . however , halothane is no longer used in many developed countries but continues to be used in some developing countries . after halothane , other halogenated anesthetics , including enflurane ( 1972 ) , isoflurane ( 1979 ) , desflurane ( 1993 ) and sevoflurane ( 1995 ) have been introduced . compared to halothane , these agents have the advantage of fewer metabolisms by the cyp2e1 system , which suggests less adverse effects on liver , following their administration ( 23 , 24 ) . as it has a slow onset of action , it is used largely to maintain anesthesia after induction with other agents . enflurane became available in 1972 and is still in use , although less widely than other more modern halogenated agents . . clinically apparent , very rare cases of severe hepatic injury from enflurane have been reported . like halothane , enflurane is metabolized by the microsomal drug - metabolizing enzyme cyp2e1 to a trifluoroacetylated reactive intermediate , which is capable of binding to multiple intracytoplasmic proteins , forming potentially immunogenic adducts . as the tfa adducts induced antibodies can be detected in patients with enflurane , as well as halothane , it is suggested that the mechanism of enflurane - induced liver injury resembles the mechanism of halothane hepatotoxicity . however , the incidence of enflurane - induced hepatotoxicity appears to be less compared to halothane . as with halothane hepatotoxicity , this injury is marked by acute elevations in serum alt ( 5- to 50-fold ) and appearance of jaundice 2 to 21 days after the operation and anesthesia ( 25 - 27 ) . isoflurane , an isomer of enflurane , is a widely used anesthetic agent with rapid onset of action and rapid dispersal . it was approved in 1979 and widely accepted as a safer agent with less risk of hepatotoxicity . since its release by the food and drug administration , controversy has existed about the extent to which isoflurane is capable of producing hepatotoxic effects ( 3 ) . this agent is suggested to be less hepatotoxic compared to halothane and enflurane ; however , there are few case reports , describing fetal hepatotoxicity following single exposure to isoflurane ( 3 , 28 , 29 ) . the mechanism of isoflurane hepatotoxicity is suspected to be similar to that of halothane and associated with production of reactive intermediates . similar to previously described agents , desflurane is metabolized to a small but variable extent by the microsomal drug - metabolizing enzyme cyp2e1 to a tfa reactive intermediate , which is capable of binding to multiple intracytoplasmic proteins , forming potentially immunogenic adducts . however , case reports reporting complications related to the use of this anesthetic continue to be accumulated ( 30 - 35 ) . interestingly , in addition to circulating anti - tfa antibodies ( 4 , 5 ) , such as those associated with halothane or isoflurane , recently autoantibodies to cyp2e1 and 58 kda endoplasmic reticulum protein ( erp58 ) , have been reported after desflurane anesthesia ( 30 ) . the presence of these antibodies suggests the induction of heterogeneous immune complexes following desflurane exposure . sevoflurane has many desirable clinical properties , including a nonpungent odor and low solubility in blood , which provides rapid induction and recovery . studies have indicated that its administration is not associated with elevated alt and ast levels ( 29 ) . in contrast with older halogenated anesthetics , sevoflurane metabolism has not resulted in the formation of tfa ; hence , hepatotoxic potential of sevoflurane is considered to be low ( 36 , 37 ) . a unique compound of sevoflurane metabolism , hexafluoroisopropanol ( hfip ) has significantly less protein binding capability than tfa . in addition , hfip does not accumulate and rapidly undergoes phase ii biotransformation , specifically glucuronidation , to form hfip - glucuronide . this compound is mostly excreted in the urine within 12 hours after anesthesia and is not detectable beyond 2 days ( 38 - 40 ) . this is in contrast to previous anesthetics , where tfa is detectable in urine for up to 12 days after 75 minutes of anesthesia ( 41 - 43 ) . however , sevoflurane has a low hepatotoxic potential as described in the current available literature ( 8 , 44 , 45 ) . as apparently , sevoflurane is unlikely to cause severe postoperative hepatic injury and is an ideal anesthetic for patients with previous exposure to other halogenated anesthetics or hepatic disease ( 46 - 48 ) . sevoflurane seems to be the best anesthetic choice in large size surgeries and liver transplants , intervention in which postoperative liver dysfunction could have harmful effects on patients . interestingly , new studies demonstrated that sevoflurane pretreatment even exerts a protective effect on hepatic ischemia / reperfusion injury , which is a common problem in hepatic surgery ( 47 , 49 , 50 ) . enflurane is a widely used halogenated inhalational anesthetic . as it has a slow onset of action , it is used largely to maintain anesthesia after induction with other agents . enflurane became available in 1972 and is still in use , although less widely than other more modern halogenated agents . approximately 2% of enflurane undergoes hepatic metabolism compared to 20 - 30% of halothane . clinically apparent like halothane , enflurane is metabolized by the microsomal drug - metabolizing enzyme cyp2e1 to a trifluoroacetylated reactive intermediate , which is capable of binding to multiple intracytoplasmic proteins , forming potentially immunogenic adducts . as the tfa adducts induced antibodies can be detected in patients with enflurane , as well as halothane , it is suggested that the mechanism of enflurane - induced liver injury resembles the mechanism of halothane hepatotoxicity . however , the incidence of enflurane - induced hepatotoxicity appears to be less compared to halothane . as with halothane hepatotoxicity , this injury is marked by acute elevations in serum alt ( 5- to 50-fold ) and appearance of jaundice 2 to 21 days after the operation and anesthesia ( 25 - 27 ) . isoflurane , an isomer of enflurane , is a widely used anesthetic agent with rapid onset of action and rapid dispersal . it was approved in 1979 and widely accepted as a safer agent with less risk of hepatotoxicity . since its release by the food and drug administration , controversy has existed about the extent to which isoflurane is capable of producing hepatotoxic effects ( 3 ) . this agent is suggested to be less hepatotoxic compared to halothane and enflurane ; however , there are few case reports , describing fetal hepatotoxicity following single exposure to isoflurane ( 3 , 28 , 29 ) . the mechanism of isoflurane hepatotoxicity is suspected to be similar to that of halothane and associated with production of reactive intermediates . similar to previously described agents , desflurane is metabolized to a small but variable extent by the microsomal drug - metabolizing enzyme cyp2e1 to a tfa reactive intermediate , which is capable of binding to multiple intracytoplasmic proteins , forming potentially immunogenic adducts . occurrence of hepatic injury following desflurane anesthesia was once thought to be rare . however , case reports reporting complications related to the use of this anesthetic continue to be accumulated ( 30 - 35 ) . interestingly , in addition to circulating anti - tfa antibodies ( 4 , 5 ) , such as those associated with halothane or isoflurane , recently autoantibodies to cyp2e1 and 58 kda endoplasmic reticulum protein ( erp58 ) , have been reported after desflurane anesthesia ( 30 ) . the presence of these antibodies suggests the induction of heterogeneous immune complexes following desflurane exposure . sevoflurane has many desirable clinical properties , including a nonpungent odor and low solubility in blood , which provides rapid induction and recovery . studies have indicated that its administration is not associated with elevated alt and ast levels ( 29 ) . in contrast with older halogenated anesthetics , sevoflurane metabolism has not resulted in the formation of tfa ; hence , hepatotoxic potential of sevoflurane is considered to be low ( 36 , 37 ) . a unique compound of sevoflurane metabolism , hexafluoroisopropanol ( hfip ) has significantly less protein binding capability than tfa . in addition , hfip does not accumulate and rapidly undergoes phase ii biotransformation , specifically glucuronidation , to form hfip - glucuronide . this compound is mostly excreted in the urine within 12 hours after anesthesia and is not detectable beyond 2 days ( 38 - 40 ) . this is in contrast to previous anesthetics , where tfa is detectable in urine for up to 12 days after 75 minutes of anesthesia ( 41 - 43 ) . however , sevoflurane has a low hepatotoxic potential as described in the current available literature ( 8 , 44 , 45 ) . as apparently , sevoflurane is unlikely to cause severe postoperative hepatic injury and is an ideal anesthetic for patients with previous exposure to other halogenated anesthetics or hepatic disease ( 46 - 48 ) . sevoflurane seems to be the best anesthetic choice in large size surgeries and liver transplants , intervention in which postoperative liver dysfunction could have harmful effects on patients . interestingly , new studies demonstrated that sevoflurane pretreatment even exerts a protective effect on hepatic ischemia / reperfusion injury , which is a common problem in hepatic surgery ( 47 , 49 , 50 ) . anesthesia - induce hepatotoxicity is a diagnosis of exclusion , so that ruling out other causes is essential . clinical features similar to anesthesia - induced liver injury can be caused by acute viral hepatitis , exacerbation of previous chronic liver disease , hemolysis after blood transfusion , liver damage due to hypoxia ( caused by vasoconstriction , shock , hypoxia , cardiac arrest ischemia ) , hypotension or liver damage due to other hepatotoxic drugs ( antibiotics , antidepressants , phenothiazines , phenytoin , anticoagulants ) . for instance , from a histopathological point of view , centrolobular necrosis with mild cholestasis and fatty infiltration are associated with both hepatic necrosis due to halothane and hepatic necrosis caused by viruses . furthermore , an operation per se may cause changes in liver function regardless of the type of anesthesia . using anamnestic or serological tests together with clinical and epidemiological criteria would be helpful to distinguish anesthesia - induced hepatitis from other causes of hepatitis . features of anesthesia - induced hepatitis include high fever onset day 3 to 14 , incidence of jaundice 1 - 2 days after fever , presence of no viral antibodies , latent period less than 15 days , recent exposure in 80% of cases , leukocytosis with eosinophilia ( 20% following halothane but rare in viral hepatitis ) , fulminant course ( 40% mortality vs. 1% for viral ) and two times higher incidence in females . halogenated anesthesia - induced liver injury has been well documented in available literature . beginning with halothane in the 1950s , however , postoperative liver injury was soon recognized , especially in patients re - exposed to halothane . hepatitis followed by halothane anesthesia has high morbidity and mortality rates and survived patients may require a liver transplantation . next generation of halogenated anesthetics including enflurane , isoflurane , desflurane , and sevoflurane have different molecular structures and are associated with less hepatotoxicity ; however , rare instances of acute liver injury have been reported with all of these agents . the pattern of liver injury described with the newer halogenated anesthetics ( enflurane , isoflurane and desflurane ) has resembled that of halothane mechanism and evidence of autoimmune response to trifluoroacetylated liver proteins has been identified in patients serum . a history of anesthesia - induced hepatitis is a reason to avoid subsequent exposure to halothane or other halogenated anesthetics , since crossed immunity can rarely occur . unlike other halogenated anesthetics , sevoflurane is not metabolized to hepatotoxic trifluoroacetylated proteins ; however , very few reports have described liver injury after sevoflurane exposure . in spite of the fact that anesthesia - induced liver injury is not a common occurrence , we should be aware of the association between the disease and the use of halogenated anesthetics .