Letter to the editor
Hepatotoxicity of anesthetic gases
Wiebke Albrecht1
1Leibniz Research Centre for Working Environment and Human Factors
EXCLI J 2020;19:Doc1052
Dear Editor,
Recently, Masoud Neghab and colleagues published an article about liver enzymes in operating room personnel exposed to anesthetic gases (Neghab et al., 2020[13]). In the United States about 200,000 health care workers may be exposed to anesthetic gases (OSHA, 2000[15]). Possible adverse effects discussed in the context of exposure to anesthetic gases are hepatotoxicity (Safari et al., 2014[16]; Nicoll et al., 2012[14]; Iaizzo et al., 1990[9]) and nephrotoxicity (Jafari et al., 2018[10]). Neghab and colleagues studied 52 exposed and 52 non-exposed individuals (Neghab et al., 2020[13]). The exposed subjects showed relatively high mean urinary concentrations of 176 ppm, 5.0 ppm and 15.0 ppm nitrous oxide, isoflurane and sevoflurane (Neghab et al., 2020[13]). The authors report statistically significant increases in the liver enzymes aspartate aminotransferase, alanine aminotransferase and glutathione-S-transferase α as well as the kidney damage marker kidney injury molecule-1 compared to non-exposed individuals. It should, however, be considered that the exposure associated increase of liver enzymes was small. For example, aspartate aminotransferase increased from 19.8 ± 11.8 in non-exposed to 24.8 ± 13.2 U/L in exposed individuals (Neghab et al., 2020[13]). The corresponding activities for alanine aminotransferase were 20.8 ± 14.7 and 29.8 ± 20.7, respectively.
Currently, numerous studies are performed to study hepatotoxicity in vitro, e.g. using primary human hepatocytes (Godoy et al., 2013[4]; Albrecht et al., 2019[1]; Gu et al., 2018[7]; Grinberg et al., 2014[6], 2018[5]). In animal models often the toxic solvent CCl4 (Hoehme et al., 2010[8]; Ghallab et al., 2016[2]) or acetaminophen (Ghallab et al., 2019[3]; Leist et al., 2017[12]) are used to study hepatotoxicity. In human liver diseases as well as in animal studies with experimental, e.g. cholestatic liver damage, a much higher increase of liver enzymes is observed (Ghallab et al., 2019[3]; Vartak et al., 2016[17]; Jansen et al., 2017[11]) compared to the present study (Neghab et al., 2020[13]). The authors of the present study (Neghab et al., 2020[13]) critically discuss if the very small increase of liver enzymes is of pathophysiological relevance or if it can be compensated without consequences. The work of Neghab and colleagues represents a valuable contribution to the long-standing question if occupational exposure to anesthetic gases causes an increased risk of hepatotoxicity. Further analyses of exposed individuals are required and a specific focus should be given to studies with a long-term follow-up to learn if operating room personnel exposed to anesthetic gases has an increased risk to develop chronic liver diseases.
Conflict of interest
The author declares no conflict of interest.
References
1.
Albrecht W, Kappenberg F, Brecklinghaus T, Stoeber R, Marchan R, Zhang M, et al. Prediction of human drug-induced liver injury (DILI) in relation to oral doses and blood concentrations. Arch Toxicol. 2019;93:1609-37. doi: 10.1007/s00204-019-02492-92.
Ghallab A, Cellière G, Henkel SG, Driesch D, Hoehme S, Hofmann U, et al. Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases. J Hepatol. 2016;64:860-71. doi: 10.1016/j.jhep.2015.11.0183.
Ghallab A, Myllys M, Holland CH, Zaza A, Murad W, Hassan R, et al. Influence of liver fibrosis on lobular zonation. Cells. 2019;8:1556. doi: 10.3390/cells81215564.
Godoy P, Hewitt NJ, Albrecht U, Andersen ME, Ansari N, Bhattacharya S, et al. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol. 2013;87:1315-530. doi: 10.1007/s00204-013-1078-55.
Grinberg M, Stöber RM, Albrecht W, Edlund K, Schug M, Godoy P, et al. Toxicogenomics directory of rat hepatotoxicants in vivo and in cultivated hepatocytes. Arch Toxicol. 2018;92:3517-33. doi: 10.1007/s00204-018-2352-36.
Grinberg M, Stöber RM, Edlund K, Rempel E, Godoy P, Reif R, et al. Toxicogenomics directory of chemically exposed human hepatocytes. Arch Toxicol. 2014;88:2261-87. doi: 10.1007/s00204-014-1400-x7.
Gu X, Albrecht W, Edlund K, Kappenberg F, Rahnenführer J, Leist M, et al. Relevance of the incubation period in cytotoxicity testing with primary human hepatocytes. Arch Toxicol. 2018;92:3505-15. doi: 10.1007/s00204-018-2302-0 8.
Hoehme S, Brulport M, Bauer A, Bedawy E, Schormann W, Hermes M, et al. Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Proc Natl Acad Sci U S A. 2010;107:10371-6. doi: 10.1073/pnas.09093741079.
Iaizzo PA, Seewald MJ, Powis G, Van Dyke RA. The effects of volatile anesthetics on Ca++ mobilization in rat hepatocytes. Anesthesiology. 1990;72:504–9. doi: 10.1097/00000542-199003000-0001910.
Jafari A, Jafari F, Mohebbi I. Effects of occupational exposure to trace levels of halogenated anesthetics on the liver, kidney, and oxidative stress parameters in operating room personnel. Toxin Rev. 2018;2018:1–10.11.
Jansen PL, Ghallab A, Vartak N, Reif R, Schaap FG, Hampe J, et al. The ascending pathophysiology of cholestatic liver disease. Hepatology. 2017;65:722-38. doi: 10.1002/hep.2896512.
Leist M, Ghallab A, Graepel R, Marchan R, Hassan R, Bennekou SH, et al. Adverse outcome pathways: opportunities, limitations and open questions. Arch Toxicol. 2017;91:3477-505. doi: 10.1007/s00204-017-2045-313.
Neghab M, Amiri F, Soleimani E, Yousefinejad S, Hassanzadeh J. Toxic responses of the liver and kidneys following occupational exposure to anesthetic gases. EXCLI J. 2020;19:418-29. doi: 10.17179/excli2019-191114.
Nicoll A, Moore D, Njoku D, Hockey B. Repeated exposure to modern volatile anaesthetics may cause chronic hepatitis as well as acute liver injury. BMJ Case Reports. 2012;2012:bcr2012006543. doi: 10.1136/bcr-2012-00654315.
OSHA, Occupational Safety and Health Administration. Anesthetic gases: Guidelines for workplace exposures. Washington, DC: U. S. Dept. of Labour, OSHA;2000. [20 Oct 2019]. Available from: https://www.osha.gov/dts/osta/anestheticgases/16.
Safari S, Motavaf M, Siamdoust SAS, Alavian SM. Hepatotoxicity of halogenated inhalational anesthetics. Iran Red Crescent Med J. 2014;16:e20153. doi: 10.5812/ircmj.20153 17.
Vartak N, Damle-Vartak A, Richter B, Dirsch O, Dahmen U, Hammad S, et al. Cholestasis-induced adaptive remodeling of interlobular bile ducts. Hepatology. 2016;63:951-64. doi: 10.1002/hep.28373