Case Con feyence of the University of Florida Series Editors: A. Joseph Layon, MD
??
Michael E. Mahla, MD Jerome H. Modell, MD
??
Postoperative Elevation of Serum Transaminases following Isoflurane Anesthesia Jayne T. Gunza, MD,* Annette G. Pashayan, MD-f Department ville, FL.
of Anesthesiology,
University of Florida College of Medicine, Gaineb-
Comment by Mark E. Mailliard, MD,* Gary L. Davis, MD5 Halogenated inhalational anesthetics have been implicated in hepatotoxicity. Halothane hepatitis results from the biotransformation of the drug to a metabolite that binds to liver proteins, which creates a hapten, which, in turn, causes an immunologic response in the liver. Case reports of hepatic injury resulting from isoflurane, which has a decreased biotransformation compared with that of halothane, have received much criticism. We describe a patient who had elevated liver enzymes and a positive trifluoroacetyl antibody titer following an anesthetic regimen that included isoflurane. *Resident in Anesthesiology tAssociate
Professor
of Anesthesiology
PAssociate Professor of Medicine and Director, tobiliary Diseases, Division of Gastroenterology, Nutrition
Diseases,
for publication for publication
are selected and edited at the DeUniversity of Florida College of
December 2, 1991; March 12, 1992.
revised
0 1992 Butterworth-Heinemann 1. Clin. Anesth. 4:336-341, 1992.
336
Introduction Halogenated drugs have been associated with hepatic dysfunction.r-3 Case reports of isoflurane causing liver injury have received much criticism. We describe a patient who had elevated liver enzymes and a positive trifluoroacetyl (TFA) antibody titer after an anesthetic regimen that included isoflurane.
J. Clin. Anesth., vol. 4, July/August 1992
Case Report History
Section of HepaHepatology, and
Address reprint requests to Editorial Office, Department of Anesthesiology, Box J-254, J. Hillis Miller Health Center, Gainesville, FL 32610-0254, USA.
Received accepted
volatile-isoflurane: biotransformation, fluorometabolites; complications; hepatotoxicity; liver; toxicity, hepatic; trifluoroacetate.
and Neurosurgery
SAssistant Professor of Medicine, Section of Hepatobiliary Division of Gastroenterology, Hepatology, and Nutrition
Case Conference presentations partment of Anesthesiology, Medicine.
Keywords: Anesthetics,
manuscript
and Physical
Examination
A 42-year-old, 54-kg woman with a history of chronic low back and left leg pain was scheduled for elective surgery to place a spinal cord stimulator. She had undergone three previous operative procedures on her back: an L4-5 discectomy in 1985, subsequent wound exploration for drainage of a staphylococcal infection, and an L5-Sl discectomy in 1987. She also had undergone a cholecystectomy in 1965 and an appendectomy in 1967. She reported no complications from previous anesthetics, at least one of which consisted of isoflurane, sufentanil, and atracurium. The patient had experienced mild epigastric pain in the past that required treatment with cimetidine. On admission, she had occasional hand and ankle
Elevation of ~erurn transaminases: Gztnza and Pushayan
edema unrelated to congestive heart failure or renal disease. She smoked an occasional cigarette and drank one or two alcoholic beverages per week. Medications included ibuprofen 600 mg, hydrochlorothiazide 50 mg every day, and amitriptyline 50 mg. She also took a commercial combination of acetaminophen 500 mglhydrocodone 5 mg (Vicodin), 1 tablet every 6 hours as needed for pain. She reported allergies to vancomycin, which caused hives and difficulty breathing, and acetaminophenloxycodone (Tylox), which caused nausea and vomiting. The patient’s physical examination was unremarkable, and preoperative laboratory data showed normal serum transaminases. Her hepatitis A IgM antibody was positive, compatible with an infection in the past; her hepatitis B antigens were negative. Operative
overshadowed incisional pain and was only partially lieved by morphine 7 mg IV. She did not experience
Course and Recovery
The patient received lorazepam 1 mg orally the evening before surgery. She was brought to the operating room the following morning as the first case of the day, and routine monitors were placed. Following preoxygenation, anesthesia was induced with intravenous (IV) sufentanil 10 pg, thiopental sodium 200 mg, and atracurium 30 mg and was maintained with nitrous oxide in oxygen (0,) and isoflurane. The mass spectrometer indicated that maximal end-tidal isoflurane was 0.69% and halothane and enflurane were 0. The procedure, which was performed with the patient in the prone position, lasted approximately 1 hour and was uneventful. During the anesthetic, heart rate (HR) and mean arterial pressure remained within 20% of their preoperative levels. Endtidal partial pressure of carbon dioxide was stable at 30 mmHg, and arterial oxygen saturation by pulse oximetry (SpO,) was 98% to 100% with mechanical ventilation. At the end of the case, residual neuromuscular blockade was reversed with atropine 1 mg and neostigmine 4 mg. After the patient awoke, she was extubated and taken to the recovery room in stable condition. Approximately 45 minutes after arrival in the recovery room, the patient experienced severe epigastric and left upper quadrant pain. The pain was so severe that it
Results of Liver Function Tests for a Woman Who Had Elevated Serum Transaminases after an Operation
Table 1.
Test
Total protein (g/dl) Albumin (g/dl) Total bilirubin (mgidl) Direct bilirubin (mg/dl) Alkaline phosphatase
(W/L)
AST (ML) ALT (IU/L) LDH (W/L) *Normal
re-
any nausea or vomiting, dyspnea, or chest pain. On examination, she had decreased bowel sounds but no point tenderness, rebound pain, or abdominal distention. Vital signs remained stable, with blood pressure around lOO/ 65 mmHg, HR 70 to 80 beats per minute, respiration 20 to 25 breaths per minute, and SpO, 98% with 40% 0, by face mask. An electrocardiogram taken at this time was unchanged from previous tracings. Chest roentgenogram was unremarkable except for a moderate gastric air bubble, and abdominal roentgenogram (kidneys, ureters, and bladder) showed no free air or other acute changes. We placed a nasogastric sump tube, which partially relieved the symptoms. When the patient returned to the ward, she had moderate discomfort. This slowly resolved over several days of bed rest and nasogastric suction. Postoperative laboratory studies were positive for elevation of serum transaminases (Table I). The day after the surgical procedure, serum glutamic oxaloacetic transaminase peaked at 492 IU/L (normal is less than 40 IU/L), and serum glutamic pyruvic transaminase peaked at 774 IU/L (normal is less than 40 IUIL). Serum amylase, creatinine phosphatase, and alkaline phosphatase were normal. Lactate dehydrogenase was increased slightly to 298 IU/L (normal is less than 200 IUIL). Serum bilirubin increased modestly, but never beyond the normal range, and the patient did not become jaundiced. Serologic markers for acute infectious hepatitis were negative, including hepatitis B surface antigen and B core antigen, hepatitis A IgM antibody, Epstein-Barr IgM antibody, and cytomegalovirus IgM antibody. The patient’s urine remained clear, and a screen for urine porphyrins was negative. Esophagoscopy and gastroscopy performed 4 days after anesthesia showed several healing ulcers and mild gastritis. Our consultant gastroenterologist considered the patient’s condition most compatible with drug-induced hepatitis, with concurrent epigastric pain due to gastritis and ulcers. The abdominal pain resolved and serum transaminases decreased during the week after the operation. The spinal cord stimulator, which was unsuccessful in relieving the patient’s
Normal Values*
Before Operation
6 to 8 3 to 5 0.1 to 1.0
6.8 4.4
0.3 0.1 69 25 23 131
0 30 0 0 60
to to to to to
0.3 120 40 40 200
Recovery Room
Day after Operation 1
2
3
4
7
9
35
5.5
4.9
4.9
5.8
4.8
7.4
3.2
3.2
3.6
3.0
0.8
0.4
0.7
0.5
3.7 0.4
4.8
0.4
6.9 4.2 0.3
6.1
3.6 0.1 62 54
0.3 89 492
0.1 81 146
0.4 99 59
0.2 84 42
42 152
774 298
477 143
408 151
253 136
0.1 126 25 164 159
0.1 114 30 94 117
0.4 co.1 80 20 25 167
values for laboratory.
AST = serum
ghtamic
oxaloacetic
transaminase;
ALT = serum glutamic pyruvic transaminase;
LDH = lactate
dehydrogenase,
J. Clin. Anesth., vol. 4, July/August
1992
337
Case Reports
back and leg pain, was removed 1 week after the initial procedure under local anesthesia. One month after discharge, the patient’s gastrointestinal symptoms had largely resolved, and her liver function studies, including serum transaminases, were normal (Table I). A serum titer for TFA antibodies obtained at this visit was positive at 1:700. A second titer obtained 4 months after the anesthetic was positive at 1:400. Discussion Pathophysiology Hepatic blood flow is diminished by all anesthetic techniques in proportion to the decrease in systemic arterial pressure.” Surgical trauma or positioning also can lows hepatic blood fl0w.j Resulting ischemia could be potentiated by an anesthetic-induced decrease in hepatic blood flow and could result in hepatic dysfunction. Although occasional case reports have implicated barbiturates and opiates, they are generally considered unlikely to cause liver dysfunction.” Halogenated drugs have been associated with postoperative hepatic injury. Halothane, enflurane, methoxyflurane, and isoflurane each have been implicated in causing hepatic dysfunction ranging from slightly elevated hepatic enzymes to massive necrosis resulting in death.‘-3.7 That isoflurane can cause an immune-mediated response similar to that caused by halothane is a controversial topic at this time. Although rare. the possibility theoretically exists. Because halothane and isoflurane each produce TFA acid as a metabolic by-product, cross-sensitivity is a concern.” Halothane, the most widely studied of the volatile drugs, appears capable of producing two clinically distinct forms of hepatitis: a mild form and one that is potentially lethal. 9 The mild hepatic reaction usually manifests soon after anesthesia and is detected by increased serum transaminase levels.1o Although the mechanism is unclear, this reaction may be due to the intermediates produced in the reductive metabolism of halothane. Factors that may predispose a patient to this type of halothane hepatitis include toxic metaholites,” and number of exposures,‘:l.lJ hypoxia, 12 the duration status.11 The second form of obesity, 15 and nutritional hepatic dysfunction is a more severe disease and is thought to be immune mediated because testing often detects TFA. This severe form has a delayed onset of 5 to 10 days, is difficult to demonstrate in animals, is associated with repeated anesthetic administration, and is far less common than the mild hepatitis. Despite clinically distinct presentations, a common mechanism of an anesthetic metabolism-induced immune response may link all hepatic dysfunction associated with volatile halogenated drugs.” Theoretically, crosssensitization may exist among the three volatile drugs halothane, enflurane, and isoflurane. These drugs all have the potential for producing metabolites that can alter liver proteins, which makes them immunogenic.” Oxidative metabolism of halothane produces TFA chlorideI”, metabolism of enflurane, or isoflurane also 33%
.J. Clin. Anesth.,
vol. 4, July/August
1992
results in .I-FA, although at lower levels.1 1 -I‘f~r Io~~I frequency of hepatotoxicity caused by enflurane or isoflurane exposure may be due solelv to the different rates of metabolism of ;he drugs compared with that of’ halothane.x,g Skeptics of this explanation, who refute thf mechanism as proof by analog),, seek other causes ot postoperative hepatic dysfunction.l;m 1” The halothane metabolite TFR chloride, acting as hapten, binds covalentlv to liver proteins, which therr function as antigens .to induce antibody production.’ lil,?‘i.L’The l enzyme-linked immunosorbent assa! (ELISA), with trifuoroacetylated albumin as the representative antigen, can detect antibodies resulting from metabolism of- volatile anesthetics. Although there was one report of a 12%) false-positive rate with this VLSI,21 healthy anesthesiologists with chronic low-dose exposure to halothane, as well as patients who have had halothane anesthesia without liver damage, generally do not tesl positive.” Ii The antibody generally is not present in patients who have hepatic dysfunction from other drugs. toxins, or viruses.“’ This anti-TFA antibody test appears to be specific for patients with halothane hepatitis; tite1.s may persist ibr 1 to :i years.’ Other drugs-for example, antibiotics---that at-e I’OIItinely used in treating patients perioperativelv may pia\ a part in this setting. Penicillin, carbenicillin. and anpicillin have been associated with asymptomatic, t‘ever‘sible elevation of’ serum transaminases.“’ Parenteral oxacillin also has resulted in rare cases 01 nausea and vomiting, elevation of serum transaminases. and liver tenderness.pi Neither liver dysfunction nor cholestatic ,jaundice”l have been reported after parenteral nafcillin. Doses CJ~ acetaminophen are recommended not to t:~teed 2.6 g/day with chronic use, as acute toxic doses havt been shown to produce hepatic necrosis.27 The induction of drug-metabolizing enzymes in the liver or the depletion of glutathione can enhance the toxicity of’acetaminophen and lead to hepatic damage. Critiqur qf thr CUM Our patient was considered to have sustained some drgree of hepatic in.jury because serum transaminases and lactate dehydrogenase were increased even though surgical tissue damage, as indicated by normal creatinine phosphokinase, was minimal. She did not have an abdominal procedure, and so she was not at risk for surgical trauma to the liver. However, she was pcisitioned prontl with bilateral chest rolls from the axillae to the iliac crests. which could have compressed the hepatir artery, the portal vein, or both and thus resulted in hepatic injury. More likely, however, two other processes occurred simultaneously. The first, accounting for acute onset of severe mid-epigastric and left upper quadrant abdominal pain, was gastritis as evidenced by upper endoscopy. The serond process was an acute elevation of serum transaminases without associated jaundice, which occurred the day after general anesthesia. This patient had no history of recent blood transfusions or contact with non-A, non-B hepatitis. The fre-
. Elevation of serum transaminasrs: Gunza and Pashayan
quency of postoperative non-A, non-B hepatitis is 3.3% in surgical patients not requiring blood transfusionz8 Thus, drug-induced hepatitis was a more likely diagnosis. Preoperatively, the patient had been taking acetaminophen with hydrocodone, amitriptyline, ibuprofen, and hydrochlorothiazide. Since the patient gave no indication of taking toxic doses of acetaminophenfhydrocodone, acetaminophen is not likely implicated in her postoperative elevation of liver enzymes. She was not tested, however, for serum acetaminophen level. Amitriptyline has been associated with rare instances of drug-induced hepatitis, including elevated liver enzymes and cholestatic jaundice.29 Our patient had discontinued this drug 10 days before surgery, so it is an unlikely cause of the acute change in her liver function studies. Both ibuprofen and hydrochlorothiazide are rarely associated with hepatic dysfunction,*” but since her preoperative liver function assays were all normal the day before the operative procedure, our patient’s hepatic problems were likely due to drugs administered the day of the intervention. The night before surgery, the patient received lorazepam 1 mg orally. Long-term therapy with
lorazepam has been associated with elevated lactate dehydrogenase levels, *g but a one-time dose is highly unlikely to result in elevated liver enzymes. Because our patient had elevated titers for the TFA antibody drawn 1 and 4 months after the exposure to isoflurane and no other discernible cause, we believe her elevated liver function tests were isoflurane induced. Despite the positive titers, the patient experienced only a brief elevation of serum transaminases, which resolved within 1 week of her general anesthetic. The patient had had five previous anesthetics, two of which included isoflurane. Unfortunately, it is not known whether she was ever exposed to halothane, because records of her 1965 and 1967 anesthetics were lost. Therefore, the possibility of cross-sensitization between halothane and isofluraneQJo cannot be substantiated in this case. Because halothane and isoflurane biotransformation produces the same metabolite, TFA acid, and this patient had positive titers, it is possible that she experienced isoflurane hepatotoxicity. Therefore, for this patient, the future use of halothane or isoflurane for anesthesia is not advisable.
Comment and Dr. Davis: Evaluation of postoperative or postanesthetic hepatic dysfunction requires attention to viral, ischemic, transfusion-associated, drug-induced, biliary, and septic etiologies.31 Clarification of the most likely cause is difbcult: operative and anesthetic records, medication history, and the temporal sequence of serologic evidence of hepatic dysfunction must be examined carefully. In many cases, the cause of the hepatic injury cannot be definitively characterized and is often attributed, by default, to the effects of anesthesia, surgical trauma, or tissue hypoxia. Such explanations may be appropriate, because minor abnormalities of liver tests are common after surgical procedures, particularly abdominal procedures. 3p Thus, in this case presentation and its subsequent discussion, the lack of an identifiable cause for this patient’s postoperative hepatitis raised the question of anesthetic-associated hepatic injury secondary to isoflurane. The patient had evidence of antibodies to the TFA halide metabolite of halothane. The clinical presumption with this patient is that these antibodies developed from a previous exposure to isoflurane. Despite the rarity of this complication, recent published clinical case reports of suspected isoflurane hepatotoxicity support the possibility that isoflurane can lead to hepatic injury similar to that caused by the other haloalkane anesthetics, enflurane and halothane.3.17,33.34 Anesthetic-induced hepatotoxicity should always be considered a potential explanation of hepatic dysfunction. Early, mild, and self-limited abnormalities of liver tests occur in 20% to 30% of those who undergo halothane anesthesia.3j The most severe dysfunction, known as halothane hepatitis, is an infrequent occurrence (1 in 3,500 to 35,000).Z6,“7 The exact mechanism of haloal-
Dr. Mailliard
kane-induced hepatic injury, however, remains speculative. Halothane hepatotoxicity may be related directly or indirectly to the formation of reactive drug metabolites.3fi,“7The risk of hepatotoxicity is thought to be much lower with halogenated anesthetic drugs such as enflurane and isoflurane because they are far less extensively metabolized. These drugs are metabolized by both reduction and oxidation pathways. With reduction, reactive free radicals that are highly cytotoxic to centrizonal hepatocytes form. This is usually a minor pathway for metabolism of these compounds, however, and in the case of isoflurane likely accounts for less than 1% of total metabolism.3R Furthermore, reactive metabolites have not been detected during isoflurane anesthesia despite the experimental condition of reduced 0, tension. Yet isoflurane has been shown to cause central hepatic necrosis in 35% to 80% of hypermetabolic rats under hypoxic conditions.3g,40 Certainly, reductive metabolites do not represent the whole story. The major metabolic pathway of halogenated anesthetics is through cytochrome P450-mediated oxidation.37 With oxidation, a reactive but far less toxic halide metabolite forms (TFA in the case of halothane or isoflurane), which covalently binds to and alters hepatic microsomal proteins. 36,37These altered hepatic proteins may be expressed on hepatocyte membranes and serve as neoantigens. The process of oxidative biotransformation and covalent binding of the metabolite to hepatocyte proteins occurs much less frequently with enflurane or isoflurane than with halothane.3Q Antibodies to TFA-protein complexes, found in the serum of patients with halothane or enflurane hepatitis, have led to the suspicion that the host immune response to drugJ, Clin. Anesth.,
vol. 4, July/August
1992
339
Ca.se Conference
induced neoantigens is instrumental in the pathogenesis of haloalkane anesthetic-induced hepatotoxicity.37 Although it appears that metabolite-hepatic protein binding universally occurs after halothane exposure, it is unclear why the complexes only occasionally result immunogenically in antibody formation. Possibilities include variability in the magnitude of metabolite formation, covalent binding, and membrane expression of neoantigens. Variability in immune response may relate to differences in antigen expression and processing, as well as immunoregulation. Regardless of the mechanism by which anti-‘I‘FA antibodies are produced, they may be important in identifying patients at risk for severe hepatotoxicity. Whether these antibodies are themselves critical to the pathogenesis of liver injury from antibody-dependent cytotoxicity is unproven. Unfortunately, ELBA tests for antibodies to TFA neoantigens, with TFA-albumin as the t.est antigen, have demonstrated that this test currently lacks
the specificity and sensitivity to make it other than an experimental diagnostic tooL2’ Purified TFA antigens might improve the predictive value of the ELISA test and allow identification of the majoritv of sensitized patients. In conclusion, a patient should unif-ormly undergo evaluation to identify the cause of hepatic injury. Druginduced disease should always be high on the differential diagnosis, but this cause is difficult to confirm. When evaluating the possibility of an unusual drug-induced liver injury such as that caused by halogenated anesthetics, rechallenging with the suspected drug may be the only absolute means of verification. However, the risk to the patient with rechallenge and the availabilit)of other therapeutic drugs have eliminated the need f&ithis potentially dangerous maneuver. Improved tests for anti-TFA antibodies may help identify those patients at risk for severe haloalkane hepatotoxlcq and promore safer anesthetic care for these patients.
Acknowledgments
13. Cal-ney FThl, Van Dyke RA: Halothane llrpatitis: cl cntltal review. .4n&h 4nal,q 1972;s 1: 135-42. 14. Dundee ,JW: Problems of multiple inhalation anaesthet,cs. HI 1 Anaesth 198 1:53(Suppl 1):63-X 15. Christ DD, Kenna JG, Satoh H, Pohl LK: knflul-ane metabolism produces covalently bound liver adducts recognized bv antibodies from patients with halothane hepatitis. An&ptzolo,q 1988;69:833-8.
We thank Burnell R. Brown, Jr., MD, PhD, of the Department of Anesthesiology, College of Medicine, University of Arizona Health Sciences Center, Tucson, Arizona, for performing the TFA anribody assay. Lynn Dirk provided editorial assistance.
References JK, Lecky JH, Nahrwold ML: Hepatocellular dys1. Denlinger function without jaundice after enflurane anesthesia. Anesthesiology 1974;41:86-7. GH: Hepatotoxicity af.ter methoxyflurane 2 Klein NC, Jefferies administration. _/AMA 1966; 197: 1037-9. TW, Straughen WJ: A report of hepatic necrosis and 3 Carrigan death following isoflurane anesthesia. Anesthesiology 1987;67: 581-3. AJ: Adverse effects of volatile anaes4 Brown BR Jr, Gandolfi thetics. BrJ Anaesth 1987;59: 14-23. in hepatic blood flow during anes5 Gelman SL: Disturbances thesia and surgery. Arch Surg 1976;111:881-3. BH, et al: Hepatic injury in6 Shingu K, Eger El 11, Johnson duced by anesthetic agents in rats. Anesth Analg 1983;62: 1405. 7. Subcommittee on the National Halothane Study: Summary of the National Halothane Study. JAMA 1969; 197:467-77. AK, Gandolfi AJ, Brown BR Jr: Immunological basis 8. Hubbard of anesthetic-induced hepatotoxicity. Anesthesiology 1988;69:8 147. and inhalation anesthetics: views 9. Brown BR Jr: Hepatotoxicity in the era of isoflurane. J Clin An&h 1989; 1:368-76. of anesthetic agents: toxic impli10. Van Dyke RA: Metabolism ,cations. Acta Anaesthesiol Stand 1982;75(Suppl):7-9. 11. McLain GE, Sipes IG, Brown BR Jr: An animal model of halothane hepatotoxicity: roles of enzyme induction and hypoxia. Anesthesiology 1979;51:321-6. SB, Goodman ZD, Ishak KG, Zimmerman HJ, Ire) 12. Benjamin NS: The morphologic spectrum of halothane-induced hepatic injury: analysis of 77 cases. Hepatology 1985;5: 1163-71.
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E’, Anderson DK, Fertans \:,J, Gillette JR, 16. Satoh I-I, Fukada Pohi LR: Immunological studies on the mechanism of halothane-induced hepatotoxicity: immunohistochemical evidencr of trifuoroacetylated hepatocytes. I Phnrmocol Sxp %I 1985;223:857-62. 17. Stoelting RK, Blitr CD, Cohen PJ, Merm KC;: llepatic dysfunction after isoflurane anesthesia. An& An& 1987;66: 147 -53. RK: Isoflurane and posroperative hepatic dysfuni 18. Stoelting tion [Editorial]. CnrlJ Anaesth 1987;34:223-6. DF, Eger EI 11: Repeated isoflurane anesthesia in 19. McLaughlin ;.patient with hepatic dysfunction. An&h Am/g 1984:63:775-20.
21.
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Vergani D, Mieli-Vergani G, 1ilberti A. er al: Anrlbodirs to rhe surface of halothane-altered rabbit hepatocytes in patients with severe halothane-associated hepatitis. N En@ ,I .ZIpd 1980; 303:66-71. Bunker JP, Forrest WH, Mosteller F, \jandarn LD. eds. .tcr/roncli Halothune Study.: A Study of the Pmsible ,4.c,ocmtzon Retzurerl Hulothane Anesthma and Postoperatzvr Hepatzr N~cro.src. Washington: U.S. Government Printing Office, 1969. Martin JL. Kenna ,I(;, Pohl LR: Antibody assays for the detection of patients sensitized LO halothane. iln~.~lh i\ntllg 1990;70:154-9. Kenna JC, Neuberger J, Williams R: An enzyme-linked immunosorbent assay for detection of antibodies against halothanraltered hepatocyte antigens. J Immunol Method 1984;75:3-14. Knirsch AK, Gralla EJ: Abnormal serum transaminase level5 after parenteral ampicillin and carbenicillin administration. X EnglJ Med 1970;282: 1081-2. Dismukes WE: Oxacillin-induced hepatic dyst’unction. /A&1:1 1973;226:861-3.
Elevation
26. Drug Information for the Health Care Professional. 27. 28. 29.
30.
31.
32. 33.
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ington: U.S. Government Printing Office, 1990:2181. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutzcs. 17th ed. New York: Macmillan, 1985:694. Dienstag JL: Non-A, non-B hepatitis. I: Recognition, epidemiology, and clinical features. Gastroenterology 1983;85:439-62. Drug Infomatzonfor the Health Care Professional. Vol. 1A. Washington: U.S. Government Printing Office, 1990:374, 506,614, 1236. Christ DD, Satoh H, Kenna JG, Pohl LR: Potential metabolic basis for enflurane hepatitis and the apparent cross-sensitization between enflurane and halothane. Drug Metab Dzspos 1988; 16: 135-40. Farrell GC: Postoperative hepatic dysfunction. In: Zakim D, Boyer TD, eds. Hepatology. Philadelphia: W.B. Saunders, 1990:869-90. Koff RG: Postoperative jaundice. Surg Clin North Am 1975;59:823-37. Brunt EM, White H, Marsh JW, Holtmann B, Peters M: Ful-
34. 35.
36. 37. 38.
39.
40.
of serum transaminases:
Gunza and Pashayan
minant hepatic failure after repeated exposure to isoflurane anesthesia. Hepatology 1991;13:1017-21, Zimmerman H: Even isoflurane. Hepatology 1991;13: 1251-3. Zimmerman HJ: Anesthetic agents. In: Zimmerman HJ, ed. Hepatotoxicity. New York: Appleton-Century-Crofts, 1978:37094. Neuberger J, Kenna JG: Halothane hepatitis: a model of immune-mediated drug hepatotoxicity. Clin Sci 1987;72:263-71. Kenna JG: The molecular basis of halothane-induced hepatitis. Biochem Sot Tran.s 1991;19:191-5. Holaday DA, Fiserova-Bergova V, Latto IP, Zumbiel MS: Resistance of isoflurane to biotransformation in man. Anesthesiology 1975;43:325-32. Van Dyke RA: Hepatic centrilobular necrosis in rats after exposure to halothane, enflurane, or isoflurane. Anesth Analg 1982;61:812-19. Berman ML, Kuhnert L, Phythyon JM, Holaday DA: Isoflurane and enflurane-induced hepatic necrosis in triiodothyronine-pretreated rats. Anesthesiology 1983;58:1-5.
J. Clin.
Anesth.,
vol. 4, July/August
1992
341
??
Michael E. Mahla, MD Jerome H. Modell, MD
??
Postoperative Elevation of Serum Transaminases following Isoflurane Anesthesia Jayne T. Gunza, MD,* Annette G. Pashayan, MD-f Department ville, FL.
of Anesthesiology,
University of Florida College of Medicine, Gaineb-
Comment by Mark E. Mailliard, MD,* Gary L. Davis, MD5 Halogenated inhalational anesthetics have been implicated in hepatotoxicity. Halothane hepatitis results from the biotransformation of the drug to a metabolite that binds to liver proteins, which creates a hapten, which, in turn, causes an immunologic response in the liver. Case reports of hepatic injury resulting from isoflurane, which has a decreased biotransformation compared with that of halothane, have received much criticism. We describe a patient who had elevated liver enzymes and a positive trifluoroacetyl antibody titer following an anesthetic regimen that included isoflurane. *Resident in Anesthesiology tAssociate
Professor
of Anesthesiology
PAssociate Professor of Medicine and Director, tobiliary Diseases, Division of Gastroenterology, Nutrition
Diseases,
for publication for publication
are selected and edited at the DeUniversity of Florida College of
December 2, 1991; March 12, 1992.
revised
0 1992 Butterworth-Heinemann 1. Clin. Anesth. 4:336-341, 1992.
336
Introduction Halogenated drugs have been associated with hepatic dysfunction.r-3 Case reports of isoflurane causing liver injury have received much criticism. We describe a patient who had elevated liver enzymes and a positive trifluoroacetyl (TFA) antibody titer after an anesthetic regimen that included isoflurane.
J. Clin. Anesth., vol. 4, July/August 1992
Case Report History
Section of HepaHepatology, and
Address reprint requests to Editorial Office, Department of Anesthesiology, Box J-254, J. Hillis Miller Health Center, Gainesville, FL 32610-0254, USA.
Received accepted
volatile-isoflurane: biotransformation, fluorometabolites; complications; hepatotoxicity; liver; toxicity, hepatic; trifluoroacetate.
and Neurosurgery
SAssistant Professor of Medicine, Section of Hepatobiliary Division of Gastroenterology, Hepatology, and Nutrition
Case Conference presentations partment of Anesthesiology, Medicine.
Keywords: Anesthetics,
manuscript
and Physical
Examination
A 42-year-old, 54-kg woman with a history of chronic low back and left leg pain was scheduled for elective surgery to place a spinal cord stimulator. She had undergone three previous operative procedures on her back: an L4-5 discectomy in 1985, subsequent wound exploration for drainage of a staphylococcal infection, and an L5-Sl discectomy in 1987. She also had undergone a cholecystectomy in 1965 and an appendectomy in 1967. She reported no complications from previous anesthetics, at least one of which consisted of isoflurane, sufentanil, and atracurium. The patient had experienced mild epigastric pain in the past that required treatment with cimetidine. On admission, she had occasional hand and ankle
Elevation of ~erurn transaminases: Gztnza and Pushayan
edema unrelated to congestive heart failure or renal disease. She smoked an occasional cigarette and drank one or two alcoholic beverages per week. Medications included ibuprofen 600 mg, hydrochlorothiazide 50 mg every day, and amitriptyline 50 mg. She also took a commercial combination of acetaminophen 500 mglhydrocodone 5 mg (Vicodin), 1 tablet every 6 hours as needed for pain. She reported allergies to vancomycin, which caused hives and difficulty breathing, and acetaminophenloxycodone (Tylox), which caused nausea and vomiting. The patient’s physical examination was unremarkable, and preoperative laboratory data showed normal serum transaminases. Her hepatitis A IgM antibody was positive, compatible with an infection in the past; her hepatitis B antigens were negative. Operative
overshadowed incisional pain and was only partially lieved by morphine 7 mg IV. She did not experience
Course and Recovery
The patient received lorazepam 1 mg orally the evening before surgery. She was brought to the operating room the following morning as the first case of the day, and routine monitors were placed. Following preoxygenation, anesthesia was induced with intravenous (IV) sufentanil 10 pg, thiopental sodium 200 mg, and atracurium 30 mg and was maintained with nitrous oxide in oxygen (0,) and isoflurane. The mass spectrometer indicated that maximal end-tidal isoflurane was 0.69% and halothane and enflurane were 0. The procedure, which was performed with the patient in the prone position, lasted approximately 1 hour and was uneventful. During the anesthetic, heart rate (HR) and mean arterial pressure remained within 20% of their preoperative levels. Endtidal partial pressure of carbon dioxide was stable at 30 mmHg, and arterial oxygen saturation by pulse oximetry (SpO,) was 98% to 100% with mechanical ventilation. At the end of the case, residual neuromuscular blockade was reversed with atropine 1 mg and neostigmine 4 mg. After the patient awoke, she was extubated and taken to the recovery room in stable condition. Approximately 45 minutes after arrival in the recovery room, the patient experienced severe epigastric and left upper quadrant pain. The pain was so severe that it
Results of Liver Function Tests for a Woman Who Had Elevated Serum Transaminases after an Operation
Table 1.
Test
Total protein (g/dl) Albumin (g/dl) Total bilirubin (mgidl) Direct bilirubin (mg/dl) Alkaline phosphatase
(W/L)
AST (ML) ALT (IU/L) LDH (W/L) *Normal
re-
any nausea or vomiting, dyspnea, or chest pain. On examination, she had decreased bowel sounds but no point tenderness, rebound pain, or abdominal distention. Vital signs remained stable, with blood pressure around lOO/ 65 mmHg, HR 70 to 80 beats per minute, respiration 20 to 25 breaths per minute, and SpO, 98% with 40% 0, by face mask. An electrocardiogram taken at this time was unchanged from previous tracings. Chest roentgenogram was unremarkable except for a moderate gastric air bubble, and abdominal roentgenogram (kidneys, ureters, and bladder) showed no free air or other acute changes. We placed a nasogastric sump tube, which partially relieved the symptoms. When the patient returned to the ward, she had moderate discomfort. This slowly resolved over several days of bed rest and nasogastric suction. Postoperative laboratory studies were positive for elevation of serum transaminases (Table I). The day after the surgical procedure, serum glutamic oxaloacetic transaminase peaked at 492 IU/L (normal is less than 40 IU/L), and serum glutamic pyruvic transaminase peaked at 774 IU/L (normal is less than 40 IUIL). Serum amylase, creatinine phosphatase, and alkaline phosphatase were normal. Lactate dehydrogenase was increased slightly to 298 IU/L (normal is less than 200 IUIL). Serum bilirubin increased modestly, but never beyond the normal range, and the patient did not become jaundiced. Serologic markers for acute infectious hepatitis were negative, including hepatitis B surface antigen and B core antigen, hepatitis A IgM antibody, Epstein-Barr IgM antibody, and cytomegalovirus IgM antibody. The patient’s urine remained clear, and a screen for urine porphyrins was negative. Esophagoscopy and gastroscopy performed 4 days after anesthesia showed several healing ulcers and mild gastritis. Our consultant gastroenterologist considered the patient’s condition most compatible with drug-induced hepatitis, with concurrent epigastric pain due to gastritis and ulcers. The abdominal pain resolved and serum transaminases decreased during the week after the operation. The spinal cord stimulator, which was unsuccessful in relieving the patient’s
Normal Values*
Before Operation
6 to 8 3 to 5 0.1 to 1.0
6.8 4.4
0.3 0.1 69 25 23 131
0 30 0 0 60
to to to to to
0.3 120 40 40 200
Recovery Room
Day after Operation 1
2
3
4
7
9
35
5.5
4.9
4.9
5.8
4.8
7.4
3.2
3.2
3.6
3.0
0.8
0.4
0.7
0.5
3.7 0.4
4.8
0.4
6.9 4.2 0.3
6.1
3.6 0.1 62 54
0.3 89 492
0.1 81 146
0.4 99 59
0.2 84 42
42 152
774 298
477 143
408 151
253 136
0.1 126 25 164 159
0.1 114 30 94 117
0.4 co.1 80 20 25 167
values for laboratory.
AST = serum
ghtamic
oxaloacetic
transaminase;
ALT = serum glutamic pyruvic transaminase;
LDH = lactate
dehydrogenase,
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1992
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Case Reports
back and leg pain, was removed 1 week after the initial procedure under local anesthesia. One month after discharge, the patient’s gastrointestinal symptoms had largely resolved, and her liver function studies, including serum transaminases, were normal (Table I). A serum titer for TFA antibodies obtained at this visit was positive at 1:700. A second titer obtained 4 months after the anesthetic was positive at 1:400. Discussion Pathophysiology Hepatic blood flow is diminished by all anesthetic techniques in proportion to the decrease in systemic arterial pressure.” Surgical trauma or positioning also can lows hepatic blood fl0w.j Resulting ischemia could be potentiated by an anesthetic-induced decrease in hepatic blood flow and could result in hepatic dysfunction. Although occasional case reports have implicated barbiturates and opiates, they are generally considered unlikely to cause liver dysfunction.” Halogenated drugs have been associated with postoperative hepatic injury. Halothane, enflurane, methoxyflurane, and isoflurane each have been implicated in causing hepatic dysfunction ranging from slightly elevated hepatic enzymes to massive necrosis resulting in death.‘-3.7 That isoflurane can cause an immune-mediated response similar to that caused by halothane is a controversial topic at this time. Although rare. the possibility theoretically exists. Because halothane and isoflurane each produce TFA acid as a metabolic by-product, cross-sensitivity is a concern.” Halothane, the most widely studied of the volatile drugs, appears capable of producing two clinically distinct forms of hepatitis: a mild form and one that is potentially lethal. 9 The mild hepatic reaction usually manifests soon after anesthesia and is detected by increased serum transaminase levels.1o Although the mechanism is unclear, this reaction may be due to the intermediates produced in the reductive metabolism of halothane. Factors that may predispose a patient to this type of halothane hepatitis include toxic metaholites,” and number of exposures,‘:l.lJ hypoxia, 12 the duration status.11 The second form of obesity, 15 and nutritional hepatic dysfunction is a more severe disease and is thought to be immune mediated because testing often detects TFA. This severe form has a delayed onset of 5 to 10 days, is difficult to demonstrate in animals, is associated with repeated anesthetic administration, and is far less common than the mild hepatitis. Despite clinically distinct presentations, a common mechanism of an anesthetic metabolism-induced immune response may link all hepatic dysfunction associated with volatile halogenated drugs.” Theoretically, crosssensitization may exist among the three volatile drugs halothane, enflurane, and isoflurane. These drugs all have the potential for producing metabolites that can alter liver proteins, which makes them immunogenic.” Oxidative metabolism of halothane produces TFA chlorideI”, metabolism of enflurane, or isoflurane also 33%
.J. Clin. Anesth.,
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1992
results in .I-FA, although at lower levels.1 1 -I‘f~r Io~~I frequency of hepatotoxicity caused by enflurane or isoflurane exposure may be due solelv to the different rates of metabolism of ;he drugs compared with that of’ halothane.x,g Skeptics of this explanation, who refute thf mechanism as proof by analog),, seek other causes ot postoperative hepatic dysfunction.l;m 1” The halothane metabolite TFR chloride, acting as hapten, binds covalentlv to liver proteins, which therr function as antigens .to induce antibody production.’ lil,?‘i.L’The l enzyme-linked immunosorbent assa! (ELISA), with trifuoroacetylated albumin as the representative antigen, can detect antibodies resulting from metabolism of- volatile anesthetics. Although there was one report of a 12%) false-positive rate with this VLSI,21 healthy anesthesiologists with chronic low-dose exposure to halothane, as well as patients who have had halothane anesthesia without liver damage, generally do not tesl positive.” Ii The antibody generally is not present in patients who have hepatic dysfunction from other drugs. toxins, or viruses.“’ This anti-TFA antibody test appears to be specific for patients with halothane hepatitis; tite1.s may persist ibr 1 to :i years.’ Other drugs-for example, antibiotics---that at-e I’OIItinely used in treating patients perioperativelv may pia\ a part in this setting. Penicillin, carbenicillin. and anpicillin have been associated with asymptomatic, t‘ever‘sible elevation of’ serum transaminases.“’ Parenteral oxacillin also has resulted in rare cases 01 nausea and vomiting, elevation of serum transaminases. and liver tenderness.pi Neither liver dysfunction nor cholestatic ,jaundice”l have been reported after parenteral nafcillin. Doses CJ~ acetaminophen are recommended not to t:~teed 2.6 g/day with chronic use, as acute toxic doses havt been shown to produce hepatic necrosis.27 The induction of drug-metabolizing enzymes in the liver or the depletion of glutathione can enhance the toxicity of’acetaminophen and lead to hepatic damage. Critiqur qf thr CUM Our patient was considered to have sustained some drgree of hepatic in.jury because serum transaminases and lactate dehydrogenase were increased even though surgical tissue damage, as indicated by normal creatinine phosphokinase, was minimal. She did not have an abdominal procedure, and so she was not at risk for surgical trauma to the liver. However, she was pcisitioned prontl with bilateral chest rolls from the axillae to the iliac crests. which could have compressed the hepatir artery, the portal vein, or both and thus resulted in hepatic injury. More likely, however, two other processes occurred simultaneously. The first, accounting for acute onset of severe mid-epigastric and left upper quadrant abdominal pain, was gastritis as evidenced by upper endoscopy. The serond process was an acute elevation of serum transaminases without associated jaundice, which occurred the day after general anesthesia. This patient had no history of recent blood transfusions or contact with non-A, non-B hepatitis. The fre-
. Elevation of serum transaminasrs: Gunza and Pashayan
quency of postoperative non-A, non-B hepatitis is 3.3% in surgical patients not requiring blood transfusionz8 Thus, drug-induced hepatitis was a more likely diagnosis. Preoperatively, the patient had been taking acetaminophen with hydrocodone, amitriptyline, ibuprofen, and hydrochlorothiazide. Since the patient gave no indication of taking toxic doses of acetaminophenfhydrocodone, acetaminophen is not likely implicated in her postoperative elevation of liver enzymes. She was not tested, however, for serum acetaminophen level. Amitriptyline has been associated with rare instances of drug-induced hepatitis, including elevated liver enzymes and cholestatic jaundice.29 Our patient had discontinued this drug 10 days before surgery, so it is an unlikely cause of the acute change in her liver function studies. Both ibuprofen and hydrochlorothiazide are rarely associated with hepatic dysfunction,*” but since her preoperative liver function assays were all normal the day before the operative procedure, our patient’s hepatic problems were likely due to drugs administered the day of the intervention. The night before surgery, the patient received lorazepam 1 mg orally. Long-term therapy with
lorazepam has been associated with elevated lactate dehydrogenase levels, *g but a one-time dose is highly unlikely to result in elevated liver enzymes. Because our patient had elevated titers for the TFA antibody drawn 1 and 4 months after the exposure to isoflurane and no other discernible cause, we believe her elevated liver function tests were isoflurane induced. Despite the positive titers, the patient experienced only a brief elevation of serum transaminases, which resolved within 1 week of her general anesthetic. The patient had had five previous anesthetics, two of which included isoflurane. Unfortunately, it is not known whether she was ever exposed to halothane, because records of her 1965 and 1967 anesthetics were lost. Therefore, the possibility of cross-sensitization between halothane and isofluraneQJo cannot be substantiated in this case. Because halothane and isoflurane biotransformation produces the same metabolite, TFA acid, and this patient had positive titers, it is possible that she experienced isoflurane hepatotoxicity. Therefore, for this patient, the future use of halothane or isoflurane for anesthesia is not advisable.
Comment and Dr. Davis: Evaluation of postoperative or postanesthetic hepatic dysfunction requires attention to viral, ischemic, transfusion-associated, drug-induced, biliary, and septic etiologies.31 Clarification of the most likely cause is difbcult: operative and anesthetic records, medication history, and the temporal sequence of serologic evidence of hepatic dysfunction must be examined carefully. In many cases, the cause of the hepatic injury cannot be definitively characterized and is often attributed, by default, to the effects of anesthesia, surgical trauma, or tissue hypoxia. Such explanations may be appropriate, because minor abnormalities of liver tests are common after surgical procedures, particularly abdominal procedures. 3p Thus, in this case presentation and its subsequent discussion, the lack of an identifiable cause for this patient’s postoperative hepatitis raised the question of anesthetic-associated hepatic injury secondary to isoflurane. The patient had evidence of antibodies to the TFA halide metabolite of halothane. The clinical presumption with this patient is that these antibodies developed from a previous exposure to isoflurane. Despite the rarity of this complication, recent published clinical case reports of suspected isoflurane hepatotoxicity support the possibility that isoflurane can lead to hepatic injury similar to that caused by the other haloalkane anesthetics, enflurane and halothane.3.17,33.34 Anesthetic-induced hepatotoxicity should always be considered a potential explanation of hepatic dysfunction. Early, mild, and self-limited abnormalities of liver tests occur in 20% to 30% of those who undergo halothane anesthesia.3j The most severe dysfunction, known as halothane hepatitis, is an infrequent occurrence (1 in 3,500 to 35,000).Z6,“7 The exact mechanism of haloal-
Dr. Mailliard
kane-induced hepatic injury, however, remains speculative. Halothane hepatotoxicity may be related directly or indirectly to the formation of reactive drug metabolites.3fi,“7The risk of hepatotoxicity is thought to be much lower with halogenated anesthetic drugs such as enflurane and isoflurane because they are far less extensively metabolized. These drugs are metabolized by both reduction and oxidation pathways. With reduction, reactive free radicals that are highly cytotoxic to centrizonal hepatocytes form. This is usually a minor pathway for metabolism of these compounds, however, and in the case of isoflurane likely accounts for less than 1% of total metabolism.3R Furthermore, reactive metabolites have not been detected during isoflurane anesthesia despite the experimental condition of reduced 0, tension. Yet isoflurane has been shown to cause central hepatic necrosis in 35% to 80% of hypermetabolic rats under hypoxic conditions.3g,40 Certainly, reductive metabolites do not represent the whole story. The major metabolic pathway of halogenated anesthetics is through cytochrome P450-mediated oxidation.37 With oxidation, a reactive but far less toxic halide metabolite forms (TFA in the case of halothane or isoflurane), which covalently binds to and alters hepatic microsomal proteins. 36,37These altered hepatic proteins may be expressed on hepatocyte membranes and serve as neoantigens. The process of oxidative biotransformation and covalent binding of the metabolite to hepatocyte proteins occurs much less frequently with enflurane or isoflurane than with halothane.3Q Antibodies to TFA-protein complexes, found in the serum of patients with halothane or enflurane hepatitis, have led to the suspicion that the host immune response to drugJ, Clin. Anesth.,
vol. 4, July/August
1992
339
Ca.se Conference
induced neoantigens is instrumental in the pathogenesis of haloalkane anesthetic-induced hepatotoxicity.37 Although it appears that metabolite-hepatic protein binding universally occurs after halothane exposure, it is unclear why the complexes only occasionally result immunogenically in antibody formation. Possibilities include variability in the magnitude of metabolite formation, covalent binding, and membrane expression of neoantigens. Variability in immune response may relate to differences in antigen expression and processing, as well as immunoregulation. Regardless of the mechanism by which anti-‘I‘FA antibodies are produced, they may be important in identifying patients at risk for severe hepatotoxicity. Whether these antibodies are themselves critical to the pathogenesis of liver injury from antibody-dependent cytotoxicity is unproven. Unfortunately, ELBA tests for antibodies to TFA neoantigens, with TFA-albumin as the t.est antigen, have demonstrated that this test currently lacks
the specificity and sensitivity to make it other than an experimental diagnostic tooL2’ Purified TFA antigens might improve the predictive value of the ELISA test and allow identification of the majoritv of sensitized patients. In conclusion, a patient should unif-ormly undergo evaluation to identify the cause of hepatic injury. Druginduced disease should always be high on the differential diagnosis, but this cause is difficult to confirm. When evaluating the possibility of an unusual drug-induced liver injury such as that caused by halogenated anesthetics, rechallenging with the suspected drug may be the only absolute means of verification. However, the risk to the patient with rechallenge and the availabilit)of other therapeutic drugs have eliminated the need f&ithis potentially dangerous maneuver. Improved tests for anti-TFA antibodies may help identify those patients at risk for severe haloalkane hepatotoxlcq and promore safer anesthetic care for these patients.
Acknowledgments
13. Cal-ney FThl, Van Dyke RA: Halothane llrpatitis: cl cntltal review. .4n&h 4nal,q 1972;s 1: 135-42. 14. Dundee ,JW: Problems of multiple inhalation anaesthet,cs. HI 1 Anaesth 198 1:53(Suppl 1):63-X 15. Christ DD, Kenna JG, Satoh H, Pohl LK: knflul-ane metabolism produces covalently bound liver adducts recognized bv antibodies from patients with halothane hepatitis. An&ptzolo,q 1988;69:833-8.
We thank Burnell R. Brown, Jr., MD, PhD, of the Department of Anesthesiology, College of Medicine, University of Arizona Health Sciences Center, Tucson, Arizona, for performing the TFA anribody assay. Lynn Dirk provided editorial assistance.
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