Liver Disease Caused by Anesthetics, Toxins, and Herbal Preparations

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CHAPTER 87 Liver Disease Caused by Anesthetics, Toxins, and Herbal Preparations

Although halothane hepatitis is now largely of historical interest, it holds an important place in the annals of causality assessment in drug-induced liver disease.1 In contrast with the largely unpredictable hepatotoxicity seen with more modern anesthetics and most other medicinal agents (as discussed in Chapter 86), liver damage caused by occupationally and environmentally encountered chemical compounds and other toxins often is more predictable, dose related, and predominantly cytotoxic in nature.14 Industrial exposure to hepatotoxic chemicals is a less frequent occupational hazard today than in the past, but reports of toxicity from chemical agents, as well as metals, adulterated cooking oils, and botanical toxins, have not disappeared.3,4 Additionally, the use of complementary and alternative medicine (CAM) preparations continues to increase, and reports of liver injury from potentially hepatotoxic herbal and weight loss products continue to appear (see Chapter 127).5,6 Anesthetics, herbal products, mushrooms, and other toxins continue to account for a substantial percentage of emergency liver transplants for acute liver failure.7


The volatile inhalational anesthetics in current use are derivatives of some of the most potent chemical hepatotoxins developed for medicinal purposes. Chloroform, the original haloalkane anesthetic, has long been abandoned but remains an important experimental hepatotoxin, as does carbon tetrachloride (another chlorinated aliphatic hydrocarbon), which found use as an early vermifuge and is still employed as a household reagent in some parts of the world.1,8 Halothane (fluothane), introduced in the 1950s as a safer, nonexplosive alternative to ether, is a haloalkane compound that produced a well-described but rare syndrome of acute hepatotoxicity, usually after repeat exposure.9 The anesthetics that followed-methoxyflurane, enflurane, isoflurane—all have been implicated as a cause of similar injury, albeit less commonly for enflurane and isoflurane than for halothane; even fewer instances have been reported for the newest agents, sevoflurane and desflurane,10,11 because of their proportionally lower degree of metabolism.12 Halothane is no longer being produced in the United States but continues to be employed in other countries13 and is a case study in the elucidation of immunologic-mediated liver injury.14


The retrospective National Halothane Study, cited in the past as the basis for exonerating halothane as a cause of hepatotoxicity,15 is now considered flawed.1 Nearly 1000 cases of halothane hepatotoxicity were reported worldwide during the 1960s and 1970s.1,9,16 A fairly uniform clinical picture of postoperative fever, eosinophilia, jaundice, and hepatic necrosis occurred a few days to weeks after administration of anesthesia, usually after repeat exposure to halothane, and the case-fatality rate was high (Table 87-1). Rare cases of halothane-induced liver injury were reported after workplace exposure among anesthesiologists, surgeons, nurses, and laboratory staff and after halothane sniffing for “recreational” use; in affected persons, antibodies to trifluoroacetylated (TFA) proteins were demonstrated, indicating previous exposure.17

Table 87-1 Clinicopathologic Features of Halothane Hepatitis


ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

Two types of postoperative liver injury have been associated with halothane. A minor form is seen in 10% to 30% of patients, in whom mild asymptomatic elevations in serum alanine aminotransferase (ALT) levels develop between the first and tenth postoperative days; the risk of hepatotoxicity is higher after two or more exposures to halothane than with subsequent use of alternative agents such as enflurane, isoflurane, and desflurane. Evidence of immune activation is lacking in these patients,18 in whom the ALT elevations generally are rapidly reversible. The major form of halothane-induced hepatotoxicity is a rare, dose-independent, severe hepatic drug reaction with elements of immunoallergy and metabolic idiosyncrasy (see Table 87-1). After an initial exposure to halothane, the frequency of this form of toxicity is only approximately 1 per 10,000,19 but the rate increases to approximately 1 per 1000 after two or more exposures, especially when the anesthetic agent is readministered within a few weeks.1 Typically, zone 3 (centrilobular) hepatic necrosis is seen histologically.20 The case-fatality rate ranged from 14% to 71% in the pre-liver transplantation era.1

Risk Factors for Halothane Hepatitis

Host-related risk factors for halothane hepatitis are listed in Table 87-2. The reaction is rare in childhood11; patients younger than 10 years of age represent only about 3% of the total, and cases in persons younger than 30 years account for less than 10%.11,16 The disease tended to be more severe in persons older than 40 years of age. Two thirds of cases have been in women, and repeat exposure to halothane (especially within a few weeks or months) is documented in as many as 90% of cases.1 The time between exposures can be as long as 28 years.21 After repeat exposure, hepatitis is earlier in onset and more severe. Obesity is another risk factor, possibly because of storage of halothane in body fat. The induction of cytochrome P450 (CYP) enzymes (especially CYP2E1) that metabolize halothane to its toxic intermediate has been produced experimentally with phenobarbital, alcohol, and isoniazid; valproate inhibits and phenytoin has no specific effect on halothane hepatotoxicity.1 Inhibition of CYP2E1 by administration of a single dose of disulfiram has been suggested as a means of preventing halothane hepatitis—by inhibiting the production of the metabolite responsible for neoantigen formation.22

Table 87-2 Risk Factors for Halothane Hepatitis


CYP2E1, cytochrome P450 2E1.

Familial predisposition to halothane-induced liver injury has been reported in closely related family members.23 Serum antibodies to volatile anesthetics have been found in pediatric anesthesiologists,17 who, like patients with halothane hepatitis, had higher levels of serum autoantibodies to CYP2E1 and to endoplasmic reticulum protein (ERp58) than those found in general anesthesiologists and control subjects who had never been exposed to inhalational anesthetics. The autoantibodies are not thought to have a role in pathogenesis.1


In a study of 77 cases of halothane hepatitis reviewed by the Armed Forces Institute of Pathology,20 various degrees of liver injury were seen, depending on the severity of the reaction. Massive or submassive necrosis involving zone 3 was present in all autopsy specimens, whereas biopsy material revealed a broader range of injury—from spotty necrosis in about one third of cases to zone 3 necrosis in two thirds. The zone 3 injury is sharply demarcated, and the inflammatory response is less severe than in acute viral hepatitis.


Halothane injury occurs by one or more of three potential mechanisms: hypersensitivity, production of hepatotoxic metabolites, and hypoxia, in decreasing order of importance.1 Evidence for the role of hypersensitivity is found in the increased susceptibility and shortened latency after repeat exposure, the hallmark symptoms and signs of drug allergy (fever, rash, eosinophilia, and granuloma formation), and the detection of neoantigens and antibodies. Halothane oxidation yields trifluoroacetylchloride, which acts on hepatocyte proteins to produce neoantigens that are responsible for the major form of injury. By contrast, reductive pathways produce free radicals that can act as reactive metabolites that may have a role in causing minor injury. A unifying hypothesis set forth by Zimmerman1 suggests that halothane injury most likely is the result of immunologic enhancement of zone 3 necrosis produced by the reductive metabolite(s). Accordingly, the hepatotoxic potential of halothane depends on the susceptibility of the patient and on factors that promote production of hepatotoxic or immunogenic metabolites.1 A protective role for zinc pretreatment has been proposed based on studies in rats.24

Course and Outcome

Mortality rates for halothane hepatitis were high in early series; since then, successful treatment has been achieved with liver transplantation in many patients.13 When spontaneous recovery occurs, symptoms usually resolve within 5 to 14 days, and recovery is complete within several weeks.1 Immunosuppressive agents have only rarely been reported to improve the outcome.11 It is doubtful that halothane causes chronic hepatitis.1 Adverse prognostic factors include age older than 40 years, obesity, severe coagulopathy, serum bilirubin level greater than 20 mg/dL, and a shorter interval to onset of jaundice.1,16,19


The likelihood that individual haloalkane anesthetics will cause liver injury appears to be related to the extent to which they are metabolized by hepatic CYP enzymes: 20% to 30% for halothane, greater than 30% for methoxyflurane, 2% for enflurane, 1% for sevoflurane, and 0.2% or less for isoflurane and desflurane.12 Accordingly, the estimated frequency of hepatitis from the newer agents is much less than that for halothane (Table 87-3).

Methoxyflurane caused hepatotoxicity and a high frequency of nephrotoxicity that led to its withdrawal.25 Enflurane caused a clinical syndrome similar to that for halothane, with the onset of fever within 3 days and jaundice in 3 to 19 days after anesthesia26,27; the estimated incidence of enflurane-induced liver injury was about 1 in 800,000 exposed patients.10

Despite its low rate of metabolism,12 numerous instances of isoflurane-associated liver injury have been reported.2830 In one case, cross-sensitivity was suspected 22 years after an initial exposure to enflurane.29 TFA liver proteins have been detected in patients with suspected isoflurane liver toxicity.30

The newest haloalkane anesthetics, desflurane and sevoflurane, appear to be nearly free of adverse hepatic effects. Desflurane undergoes minimal biotransformation and was not associated with the development of TFA antibodies in exposed rats.12 Only isolated reports of liver injury in patients receiving desflurane anesthesia have been published.31 The biotransformation of sevoflurane also is minimal, and only rare reports have implicated this agent in postoperative hepatic dysfunction.32 Ether, nitrous oxide, and cyclopropane apparently are devoid of significant hepatotoxic potential because of their lack of halogen moieties.1


From 25% to 75% of patients undergoing surgery experience postoperative hepatic dysfunction, ranging from mild elevations in liver biochemical tests to hepatic failure; jaundice has been reported in nearly 50% of patients with underlying cirrhosis in the postoperative period (see Chapter 20).33 Patients undergoing upper abdominal surgical procedures are at highest risk of postoperative liver dysfunction, as well as pancreatitis, cholecystitis, and bile duct injury because of impaired blood flow to the liver.33 Table 87-4 lists many causes of postoperative jaundice and hepatic dysfunction, broadly divided into hepatocellular injury, cholestasis, and indirect hyperbilirubinemia. Drugs that may cause hepatoxicity in this setting include antibiotics (e.g., erythromycin, telithromycin, amoxicillin-clavulanate, trimethoprim-sulfamethoxazole) and the halogenated anesthetics discussed earlier; most produce injury by hypersensitivity mechanisms within one to two weeks of administration.1,2 Table 87-5 contrasts the features of halogenated anesthetic-induced hepatitis, ischemic hepatitis (shock liver) (see Chapter 83), and cholestatic injury (see Chapter 86) in the early postoperative period.

Table 87-4 Causes of Postoperative Hepatic Dysfunction


ALT, alanine aminotransferase; G6PD, glucose-6-phosphate dehydrogenase; NASH, nonalcoholic steatohepatitis.



Among tens of thousands of chemical compounds in commercial and industrial use, several hundred are listed as causing liver injury by the National Institute for Occupational Safety and Health (NIOSH), as published in their Pocket Guide to Chemical Hazards.34 The National Library of Medicine also maintains a database of chemical toxins in its Toxicology and Environmental Health Information Program (TEHIP).35

Toxic exposure to chemical agents occurs most often from inhalation or absorption by the skin and less often from absorption by the gastrointestinal tract after oral ingestion or through a parenteral route. Because most chemical toxins are lipid soluble, when absorbed they can easily cross biological membranes to reach their target organ(s), including the liver.3,4 Hepatotoxic chemical exposure (as with carbon tetrachloride and phosphorus) usually results in an acute cytotoxic injury that typically consists of three distinct phases, similar to those observed after an acetaminophen overdose or ingestion of toxic mushrooms (Table 87-6).1,3 Less commonly, acute cholestatic injury may occur.36 Many chemicals (e.g., vinyl chloride) also are carcinogenic, and hepatic malignancies have been part of the clinicopathologic spectrum of chemical injury (Table 87-7).37 Although liver injury is the dominant toxicity for some agents, hepatic damage may be only one facet of more generalized toxicity for other agents.3

Table 87-7 Clinicopathologic Spectrum of Chemical Hepatotoxins

Acute Injury

Microvesicular Steatosis

Cholestasis Subacute Injury Necrosis Trinitrotoluene Sinusoidal Obstruction Syndrome Pyrrolizidine alkaloids, arsenic, thorium dioxide Toxic Cirrhosis Peliosis Hepatis Dioxin Chronic Injury Cirrhosis Chloroaliphatics, trinitrotoluene, arsenic, pyrrolizidine alkaloids Hepatoportal sclerosis Arsenic, vinyl chloride Neoplasia Hepatocellular carcinoma Arsenic, aflatoxins, thorium dioxide Angiosarcoma Vinyl chloride, thorium dioxide, arsenic Hemangioendothelioma Arsenic

Data from references 1, 3, 4, 36, and 37.

Carbon Tetrachloride and Other Chlorinated Aliphatic Hydrocarbons

Carbon tetrachloride (CCl4) is a classic example of a zone 3 hepatotoxin that causes necrosis leading to hepatic failure (see Table 87-6). Injury is mediated by its metabolism to a toxic trichloromethyl radical catalyzed by CYP2E1.7,38 Alcohol potentiates the injury through induction of this cytochrome.1 Most cases have been the result of industrial or domestic accidents, such as inhalation of CCl4-containing dry cleaning fluids that are used as household reagents or ingestion of these compounds by alcoholics who mistake them for potable beverages.1 At the cellular level, direct damage to cellular membranes results in leakage of intracellular enzymes and electrolytes, leading in turn to calcium shifts and lipid peroxidation.8 Hepatic steatosis develops as a result of triglyceride accumulation caused by haloalkylation-dependent inhibition of lipoprotein micelle transport out of the hepatocyte.38 CCl4 is more toxic than other haloalkanes and haloalkenes because toxicity correlates inversely with the level of bond dissociation energy, number of halogen atoms, and chain length (Table 87-8).1,38 In older series, complete clinical and histologic recovery from CCl4-induced liver damage was the rule with modest exposures, but supervening acute tubular necrosis and gastrointestinal hemorrhage were associated with a case-fatality rate of 10% to 25%.1,3 Activation of endonucleases, causing chromosomal damage and mutations, may result in carcinogenesis.38

Table 87-8 Relative Hepatotoxicity of Haloalkane Compounds

Carbon tetrachloride ++++
Tetrachlorethane ++++
Chloroform ++
Trichloroethylene + to ++
1,1,2-Trichloroethane + to ++
Tetrachloroethylene +
1,1,1-Trichloroethane +
Dichloromethane ±
Dibromomethane ±

Scale from ++++, maximal injury to −, trivial or no injury.

Data from references 1 and 3.

Chloroform remains an important experimental hepatotoxin, although its use as an anesthetic has long been abandoned (see later).1,3 Hepatic injury, including chronic hepatitis, has been reported with 1,1,1-trichloroethane.39

Hydrochlorofluorocarbons (HCFCs) have been associated with liver injury in several industrial workers exposed to dichlorotrifluoroethane (HCFC 123) and 1-chlorotetraflu-oroethane (HCFC 124), both of which are metabolized to reactive trifluoroacetyl halide intermediates similar to those implicated in halothane toxicity.40 Zone 3 necrosis is present on liver biopsy specimens, and autoantibodies against CYP2E1 or P58 are detected in the serum of many affected persons. As with halothane, liver toxicity may be potentiated by ethanol.41

Vinyl Chloride and Other Chlorinated Ethylenes

In the past, exposure to vinyl chloride monomer (VCM), or monochloroethylene, occurred in polymerization plants where vinyl chloride was heated to form polyvinyl chloride (PVC) in the manufacture of plastics; the toxic gas containing VCM was inhaled in this process.1 Vinyl chloride is ubiquitous in the environment and has been estimated by the Environmental Protection Agency to exist in at least 10% of toxic waste sites.4 Although PVC appears to be nontoxic, long-term exposure to VCM has led to chronic liver injury, including nodular subcapsular fibrosis, sinusoidal dilatation, peliosis hepatis, and periportal fibrosis associated with portal hypertension.1,3 Nonalcoholic fatty liver disease, including lipogranulomas, has been described in more than 50% of nonobese chemical workers with high exposure levels to VCM; some of these workers continued to have nonalcoholic steatohepatitis up to six years later.42

Vinyl chloride is carcinogenic. Angiosarcoma develops after a mean latency of 25 years after exposure; the risk is related to the duration and extent of contact.43 Alcohol appears to enhance the hepatocarcinogenicity of vinyl chloride, in rodents and possibly in humans, by inducing CYP2E1, which converts vinyl chloride to a toxic or carcinogenic metabolite (e.g., 2-chloroethylene oxide).1 A history of vinyl chloride exposure was found in 15% to 25% of all cases of hepatic angiosarcoma reported in the late 1970s,3 and strict hygienic measures instituted in 1974 have resulted in a marked decrease in the frequency of angiosarcoma since then; however, persons with the highest exposure still have a four-fold increased risk of developing periportal hepatic fibrosis, which may be a precursor of angiosarcoma.44 Persons previously exposed to vinyl chloride should undergo regular clinical examination for early detection of liver tumors, and those with known chronic liver disease or high levels of exposure should undergo regular hepatic imaging. Persons who work in PVC plants should undergo regular monitoring of liver biochemical test levels, and those with persistent abnormalities should be removed from workplace exposure.44 High serum levels of hyaluronic acid were correlated with the development of angiocarcinoma in 26 of 82 workers occupationally exposed to PVC in Kentucky.45

Nonhalogenated Organic Compounds

Benzene has been associated with minor hepatic injury in animals. Toluene led to steatosis and necrosis in a “glue sniffer”46 and has been associated with acute fatty liver of pregnancy; it caused elevations in serum gamma glutamyl transpeptidase levels after industrial exposure. Xylene can cause mild hepatic steatosis, and styrene (vinyl benzene) has led to elevated serum aminotransferase levels after prolonged exposure.

Trinitrotoluene and Other Nitroaromatic Compounds

Trinitrotoluene (TNT), or nitroglycerin, was first observed to be hepatotoxic during World War I, when severe acute and subacute hepatic necrosis developed in munitions workers in England, Germany, and the United States; the case-fatality rate was more than 25%.1,3 The frequency of hepatotoxicity during World War II was lower, with approximately 1 in 500 workers affected, but the estimated frequencies of methemoglobinemia and aplastic anemia were 50 times higher.3 Subacute hepatic necrosis followed two to four months of regular exposure to TNT. Percutaneous absorption was the major source of exposure. In some patients, rapidly progressive liver failure and death occurred within days to months, with massive hepatic necrosis at autopsy. In others, the subacute injury progressed over several months to micronodular cirrhosis and portal hypertension. The relatively low incidence of injury suggests that formation of a toxic metabolite was involved.1 Nitrobenzene and dinitrobenzene also were observed to be hepatotoxic during World War I. As with TNT, excessive exposure led to methemoglobinemia.

Polychlorinated Biphenyls and Other Halogenated Aromatic Compounds

Polychlorinated biphenyls (PCBs) are mixtures of trichloro-, tetrachloro-, pentachloro-, and hexachloro-derivatives of biphenyls, naphthalenes, and triphenyls that are used in the manufacture of electrical transformers, condensers, capacitors, insulating materials for electrical cables, and industrial fluids. Acute and chronic hepatotoxicity from PCB exposure seen during World War II resembled that caused by TNT.3,4 Inhalation of toxic fumes released by the melting of PCBs and chloronaphthalene mixtures during soldering of electrical materials was the most common means of exposure.1 The severity of liver injury correlated with the number of chlorine molecules.3 Liver damage appeared as early as seven weeks after ongoing exposure and was accompanied by anorexia, nausea, and edema of the face and hands. Acne-like skin lesions (chloracne) usually preceded hepatic injury. Once jaundice appeared, death occurred within two weeks in fulminant cases, which were characterized by massive necrosis (so-called acute yellow atrophy), or after one to three months in the subacute form. Cirrhosis developed in some persons who survived the acute injury.1

Polybrominated biphenyls (PBBs) appear to be even more toxic than PCBs. Consumption of milk and meat from livestock given feed mistakenly contaminated by a PBB has led to hepatomegaly and minor elevations in liver enzyme levels in exposed persons.3

Miscellaneous Chemical Compounds

Dimethylformamide is a solvent used in the synthetic resin and leather industries that causes dose-related massive hepatic necrosis in animals48 and is capable of producing focal hepatic necrosis and microvesicular steatosis in humans.3 Most persons exposed for more than one year have symptomatic disease that slowly resolves when they are removed from the workplace. Disulfiram-like symptoms can occur.49

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