Clinical UM Guideline

This document addresses laboratory testing of gamma glutamyl transferase (GGT) in blood.

Medically Necessary:

GGT testing using blood is considered medically necessary for any of the following indications:

1. To differentiate between sources of elevated alkaline phosphatase activity; or
2. To evaluate liver function, injury or disease in individuals with at least one of the following:
   1. Known or suspected hepatobiliary disease; or
   2. Alcohol use disorder; or
   3. Substance use disorder; or
   4. Therapy with medication that has potentially toxic effects on the liver; or
   5. Exposure to hepatotoxins; or
   6. Infections that may cause liver injury (for example, viral hepatitis, amoebiasis, tuberculosis, and similar infections); or
   7. Pancreatic disease; or
   8. Gastrointestinal disease; or
   9. Liver transplantation; or
   10. Primary or secondary malignant neoplasms; or
   11. Diseases or conditions known to have liver involvement (for example, diabetes mellitus, sarcoidosis, amyloidosis, disorders of iron and mineral metabolism, lupus, hypertension, heart failure).

Not Medically Necessary:

GGT testing using blood is considered not medically necessary when the above criteria are not met.

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Medically Necessary:

When services are Not Medically Necessary:
For the procedure code listed above, for all other diagnoses not listed.

Gamma glutamyl transferase (GGT), also known as gamma glutamyl transpeptidase, is an enzyme found throughout the body but predominantly in the liver. It is a cell membrane protein produced in the cells lining the bile duct system in the liver. Normally GGT plays an important role in reducing oxidative stress by facilitating generation of glutathione, a potent antioxidant. GGT also aids in the detoxification of drugs and other xenobiotics in the liver. When the liver is injured, GGT may leak from damaged cells into the bloodstream.

Since the 1960s, measurement of GGT in blood has been used to assess liver function and injury (Brennan, 2022). GGT is commonly measured in either blood serum or plasma. Generally, the higher the level of GGT, the greater the level of damage to the liver. Liver conditions that can cause elevated GGT include hepatitis, cholestasis, and cirrhosis. Hepatitis is often associated with infection by viruses, bacteria or parasites but can also be caused by exposure to liver toxins. The highest levels of GGT are usually seen in patients with cholestasis due to bile duct strictures or stones. Cirrhosis is commonly associated with alcohol use disorder. Even in the absence of cirrhosis, GGT levels tend to be higher in people who regularly drink alcohol, compared with people who drink in moderation or only on occasion. GGT levels may be used to monitor alcohol-drinking habits and follow the evolution of alcoholic liver disease (Neuman, 2020).

GGT is very sensitive for the diagnosis of liver injury, although it has poor specificity in identifying particular causes. GGT is abnormally high in the majority of individuals with liver disease irrespective of pathogenesis. However, other extra-hepatic diseases and conditions can also contribute to elevated GGT such as pancreatitis, diabetes mellitus, obesity, malnutrition, hypertension, stroke, and chronic obstructive pulmonary disease (Brennan, 2022; Koenig, 2015; Neuman, 2020).

GGT is associated with the metabolic syndrome (MetS) and is often elevated in individuals with nonalcoholic fatty liver disease (NAFLD) (Neuman, 2020). MetS consists of obesity, hypertension, impaired glucose tolerance and hyperlipidemia; NAFLD is the hepatic manifestation of MetS. Additional organ systems are involved in NAFLD related to other components of MetS including kidney, gastrointestinal, and cardiovascular systems. Elevated GGT can be associated with risk to all of these systems including chronic kidney disease, end stage renal disease, chronic intestinal disorders, coronary heart disease and chronic heart failure (Ess, 2011; Lee, 2020; Ndrepepa, 2018; Neuman, 2020; Shen, 2017; Voss, 2021).

Primary and secondary forms of liver cancer can be associated with increased GGT (Whitfield, 2001). In healthy adults, an elevated serum GGT is associated with a higher risk of many cancers, especially liver cancer (Strasak, 2008; Mok, 2016). Elevated GGT may also be an indicator of an increased risk of other cancers including prostate, breast, esophageal and colorectal (Choi, 2017; Hong, 2020; Van Hemelrijck, 2011). There is evidence that GGT is a prognostic biomarker in individuals with cancer, with elevated serum GGT predicting worse outcomes (Ma, 2014; Takemura, 2021; Yin, 2013).

GGT is used as a biomarker to monitor liver function after transplant. Early elevated serum GGT after liver transplantation is associated with improved survival (Alkozai, 2014). Trends in GGT levels have been reported to be useful in detection of rejection of transplanted livers (Hickman, 1994).

Increased GGT can be an indicator of drug-induced liver injury (Weber, 2021). Anticonvulsant drugs such as phenytoin, phenobarbitone, carbamazepine and valproic acid are associated with elevated GGT. Other types of drugs such as the diuretic furosemide, the gastric acid reducer cimetidine, anti-acne medication isotretinoin, and barbiturates can likewise elevate GGT (Brennan, 2022). The commonly used pain reliever acetaminophen can cause liver toxicity and increase GGT levels as well (Ahlers, 2011; McClain, 1999). Some drugs used recreationally or by people with substance use disorder can also lead to liver injury and increased liver enzymes, including cannabis, kratom, cocaine and anabolic steroids (Fernandes, 2019; Silva, 1991; Solimini, 2017; Watkins, 2021).

Exposure to a wide range of environmental chemicals such as the fungicide hexachlorobenzene and the insecticide DDT can produce increased serum GGT (Whitfield, 2001). Heavy metals including lead, mercury, cadmium and copper can prompt significant increases in GGT (Yorita Christensen, 2013). Studies of people exposed to polychlorinated biphenyls (PCBs) have reported increases in GGT that are suggestive of liver damage.

Since the GGT test alone cannot diagnose a specific cause of liver disease, it is usually performed in conjunction with other liver function tests. The British Society of Gastroenterology recommends that “Initial investigation for potential liver disease should include bilirubin, albumin, alanine aminotransferase (ALT), alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT), together with a full blood count if not already performed within the previous 12 months. (level 2b, grade B)” (Newsome, 2018).

Bone disease and liver disease can both lead to elevated levels of ALP. A GGT test along with an ALP test can help distinguish between these disorders. High levels of both enzymes together likely indicate liver disease, while high levels of ALP and low or normal GGT indicate a probable bone disorder. The 2017 guideline of the American College of Gastroenterology for Evaluation of Abnormal Liver Chemistries (Kwo, 2017) states that “To confirm hepatic origin of alkaline phosphatase, the canalicular enzyme GGT may be measured. An elevated GGT suggests that the alkaline phosphatase elevation is of hepatic origin.”

Canalicular: Pertaining to the thin capillaries that carry bile in the liver.

Cirrhosis: Scarring of the liver.

Cholestasis: Reduced or stopped bile flow usually due to bile duct obstruction.

Glutathione: A tripeptide made from the amino acids glycine, cysteine and glutamic acid that is found in all mammalian tissues and is responsible for oxidative stress mitigation.

Hepatitis: Inflammation of the liver.

Hepatobiliary: Pertaining to the liver, bile ducts, or gallbladder.

Xenobiotic: A chemical substance that is foreign to the body such as pesticides, food additives, industrial chemicals and environmental pollutants.

Peer Reviewed Publications:

1. Ahlers SJGM, van Gulik L, van Dongen EPA, et al. Aminotransferase levels in relation to short-term use of acetaminophen four grams daily in postoperative cardiothoracic patients in the intensive care unit. Anaesth Intens Care. 2011; 39:1056-1063.
2. Alkozai EM, Lisman T, Porte RJ, Nijsten MW. Early elevated serum gamma glutamyl transpeptidase after liver transplantation is associated with better survival. F1000Res. 2014; 3:85.
3. Brennan PN, Dillon JF, Tapper EB. Gamma-Glutamyl Transferase (γ-GT) - an old dog with new tricks? Liver Int. 2022; 42(1):9-15.
4. Choi YJ, Lee DH, Han KD, et al. Elevated serum gamma-glutamyltransferase is associated with an increased risk of oesophageal carcinoma in a cohort of 8,388,256 Korean subjects. PLoS One. 2017; 12(5):e0177053.
5. Ess M, Mussner-Seeber C, Mariacher S, et al. γ-Glutamyltransferase rather than total bilirubin predicts outcome in chronic heart failure. J Card Fail. 2011; 17(7):577-584.
6. Fernandes CT, Iqbal U, Tighe SP, Ahmed A. Kratom-induced cholestatic liver injury and its conservative management. J Investig Med High Impact Case Rep. 2019; 7:2324709619836138.
7. Fu SJ, Zhao Q, Ji F, et al. Elevated preoperative serum gamma-glutamyl transpeptidase predicts poor prognosis for hepatocellular carcinoma after liver transplantation. Sci Rep. 2016; 6:28835.
8. Hickman PE, Lynch SV, Potter JM, et al. Gamma glutamyl transferase as a marker of liver transplant rejection. Transplantation 1994; 57:1278-1280.
9. Hong TC, Yang HC, Chen CL, et al. Relationship between serum gamma-glutamyl transferase level and colorectal adenoma. PLoS One. 2020; 15(10):e0240445.
10. Koenig G, Seneff S. Gamma-glutamyltransferase: a predictive biomarker of cellular antioxidant inadequacy and disease risk. Dis Markers. 2015; 2015:818570.
11. Lee DY, Han K, Yu JH, et al. Gamma-glutamyl transferase variability can predict the development of end-stage of renal disease: a nationwide population-based study. Sci Rep. 2020; 10(1):11668.
12. Ma H, Zhang L, Tang B, et al. γ-Glutamyltranspeptidase is a prognostic marker of survival and recurrence in radiofrequency-ablation treatment of hepatocellular carcinoma. Ann Surg Oncol. 2014; 21(9):3084-3089.
13. McClain CJ, Price S, Barve S, et al. Acetaminophen hepatotoxicity: an update. Curr Gastroenterol Rep. 1999; 1:42-49.
14. Mok Y, Son DK, Yun YD, et al. γ-Glutamyltransferase and cancer risk: the Korean cancer prevention study. Int J Cancer. 2016; 138:311-319.
15. Ndrepepa G, Colleran R, Kastrati A. Gamma-glutamyl transferase and the risk of atherosclerosis and coronary heart disease. Clin Chim Acta. 2018; 476:130-138.
16. Neuman MG, Malnick S, Chertin L. Gamma glutamyl transferase - an underestimated marker for cardiovascular disease and the metabolic syndrome. J Pharm Pharm Sci. 2020; 23(1):65-74.
17. Shen ZW, Xing J, Wang QL, et al. Association between serum γ-glutamyltransferase and chronic kidney disease in urban Han Chinese: a prospective cohort study. Int Urol Nephrol. 2017; 49(2):303-312.
18. Silva MO, Roth D, Reddy KR, et al. Hepatic dysfunction accompanying acute cocaine intoxication. J Hepatol. 1991; 12:312-315.
19. Solimini R, Rotolo MC, Mastrobattista L, et al. Hepatotoxicity associated with illicit use of anabolic androgenic steroids in doping. Eur Rev Med Pharmacol Sci. 2017; 21(1 Suppl):7-16.
20. Strasak AM, Rapp K, Brant LJ, et al. Association of gamma-glutamyltransferase and risk of cancer incidence in men: a prospective study. Cancer Res. 2008; 68:3970-3977.
21. Takemura K, Board PG, Koga F. A systematic review of serum γ-glutamyltransferase as a prognostic biomarker in patients with genitourinary cancer. Antioxidants (Basel). 2021; 10(4):549.
22. Van Hemelrijck M, Jassem W, Walldius G, et al. Gamma-glutamyltransferase and risk of cancer in a cohort of 545,460 persons - the Swedish AMORIS study. Eur J Cancer. 2011; 47:2033-2041.
23. Voss J, Schneider CV, Kleinjans M, et al. Hepatobiliary phenotype of individuals with chronic intestinal disorders. Sci Rep. 2021; 11(1):19954.
24. Watkins PB, Church RJ, Li J, Knappertz V. Cannabidiol and abnormal liver chemistries in healthy adults: results of a phase I clinical trial. Clin Pharmacol Ther. 2021; 109(5):1224-1231.
25. Weber S, Allgeier J, Denk G, Gerbes AL. Marked increase of gamma-glutamyltransferase as an indicator of drug-induced liver injury in patients without conventional diagnostic criteria of acute liver injury. Visc Med. 2022; 38:223-228.
26. Whitfield JB. Gamma glutamyl transferase. Crit Rev Clin Lab Sci. 2001; 38(4):263-355.
27. Yin X, Zheng SS, Zhang BH, et al. Elevation of serum γ-glutamyltransferase as a predictor of aggressive tumor behaviors and unfavorable prognosis in patients with intrahepatic cholangiocarcinoma: analysis of a large monocenter study. Eur J Gastroenterol Hepatol. 2013; 25(12):1408-1414.
28. Yorita Christensen KL, Carr C, Sanyal AJ, Gennings C. Multiple classes of environmental chemicals are associated with liver disease: NHANES 2003–2004. Int J Hyg Environ Health. 2013; 216(6):703-709.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Centers for Medicare and Medicaid Services (CMS). Local Coverage Determination (LCD): MolDX: Biomarkers in Cardiovascular Risk Assessment.
   • LCD L36129. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=36129&ver=50&keyword=Gamma%20Glutamyl%20Transferase&keywordType=starts&areaId=all&docType=F&contractOption=all&sortBy=relevance&bc=1. Accessed on February 5, 2024.
   • LCD L36139. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=36139&ver=29&keyword=Gamma%20Glutamyl%20Transferase&keywordType=starts&areaId=all&docType=F&contractOption=all&sortBy=relevance&bc=1. Accessed on February 5, 2024.
   • LCD L36358. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=36358&ver=36&keyword=Gamma%20Glutamyl%20Transferase&keywordType=starts&areaId=all&docType=F&contractOption=all&sortBy=relevance&bc=1. Accessed on February 5, 2024.
   • LCD L36362. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=36362&ver=31&keyword=Gamma%20Glutamyl%20Transferase&keywordType=starts&areaId=all&docType=F&contractOption=all&sortBy=relevance&bc=1. Accessed on February 5, 2024.
   • LCD L36523. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=36523&ver=31&keyword=Gamma%20Glutamyl%20Transferase&keywordType=starts&areaId=all&docType=F&contractOption=all&sortBy=relevance&bc=1. Accessed on February 5, 2024.
2. Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017; 112:18-35.
3. Newsome PN, Cramb R Davison SM, et al. British Society of Gastroenterology. Guidelines on the management of abnormal liver blood tests. Gut. 2018; 67(1):6-19.

1. American Association for Clinical Chemistry. GGT Blood Test (Gamma Glutamyl Transferase/ Transpeptidase). Last modified September 29, 2022. Available at: https://www.testing.com/tests/gamma-glutamyl-transferase-ggt/. Accessed on February 5, 2024.
2. National Library of Medicine. Medical Tests. Gamma-glutamyl Transferase (GGT) Test. Last updated November 16, 2021. Available at: https://medlineplus.gov/lab-tests/gamma-glutamyl-transferase-ggt-test/. Accessed on February 5, 2024.

γ-glutamyltransferase
gamma glutamyl transferase
gamma glutamyl transpeptidase

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Federal and State law, as well as contract language, and Coverage Guidelines take precedence over Clinical UM Guidelines. We reserve the right to review and update Clinical UM Guidelines periodically. Clinical guidelines approved by the Medical Policy & Technology Assessment Committee are available for general adoption by plans or lines of business for consistent review of the medical necessity of services related to the clinical guideline when the plan performs utilization review for the subject. Due to variances in utilization patterns, each plan may choose whether to adopt a particular Clinical UM Guideline. To determine if review is required for this Clinical UM Guideline, please contact the customer service number on the member's card.

Alternatively, commercial or FEP plans or lines of business which determine there is not a need to adopt the guideline to review services generally across all providers delivering services to Plan’s or line of business’s members may instead use the clinical guideline for provider education and/or to review the medical necessity of services for any provider who has been notified that his/her/its claims will be reviewed for medical necessity due to billing practices or claims that are not consistent with other providers, in terms of frequency or in some other manner.

No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan.

© CPT Only – American Medical Association