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Elevated Serum Aminotransferases

Educational Objective
To understand how to interpret the results of diagnostic tests and apply them clinically.
1 Credit CME

A previously healthy 50-year-old woman presented with 3 weeks of fatigue, nausea, dark urine, pruritus, and scleral icterus. She was treated for Graves disease approximately 20 years previously and had no known family history of autoimmune disease. She reported rare alcohol use, no consumption of herbal products, no new medications, and no illicit drug use. She had no known viral exposures, recent vaccinations, or recent travel. On examination, she was jaundiced and had epigastric abdominal discomfort, but no edema or encephalopathy. Results of blood testing for hepatitis A, B, and C and COVID-19 polymerase chain reaction testing were negative. Findings of abdominal ultrasonography with Doppler were normal. Laboratory data are shown in the Table.

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D. Request an expedited liver biopsy

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are intracellular enzymes in hepatocytes. Although ALT exists exclusively in the cytoplasm, AST is found in the cytoplasm and mitochondria.1,2 AST is also present in muscles, the kidneys, and the brain; therefore, ALT is more specific for hepatocellular injury. The normal serum AST:ALT ratio is approximately 1. Serum aminotransferase activity is determined by spectrophotometric assays that measure changes in light intensity in a solution, and accurate measurement may be impaired by lipemia, hemolysis, or marked bilirubinemia.

In 2021, the upper reference limits for ALT were redefined as 42 U/L in men and 30 U/L in women.3 For children, the 97th percentile ranges from 30 to 38 U/L in boys and 24 to 32 U/L in girls.4 Metabolic risk factors (including adiposity and hypertension) are associated with higher ALT levels,3 and median ALT and AST levels rise with increasing body mass index classes, likely due to non–alcohol-related fatty liver disease.5 The 2022 Medicare reimbursement rate for serum aminotransferase testing is approximately $5.00 for each enzyme tested. Many liver diseases, such as viral hepatitis or autoimmune hepatitis, present with elevated AST and ALT due to hepatocyte membrane damage and release of these enzymes into the blood (Figure). Aminotransferase levels are typically mildly to moderately elevated (eg, 1.5 to 5 times the upper limit of normal) in non–alcohol-related fatty liver disease, chronic untreated viral hepatitis, acute Budd-Chiari syndrome, acute fatty liver of pregnancy, alcohol-related hepatitis, and cirrhosis. Patients with alcohol-related hepatitis often have serum AST:ALT ratios greater than or equal to 2. Cirrhosis is typically associated with an AST:ALT ratio greater than 1, reflecting reduced hepatocyte production of ALT and impaired clearance of AST by liver sinusoidal cells.

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Article Information

Corresponding Author: Gideon M. Hirschfield, MB, BChir, PhD, Toronto Centre for Liver Disease, Lily and Terry Horner Chair in Autoimmune Liver Disease Research, University of Toronto, 200 Elizabeth St, Toronto, ON M5G 2C4, Canada (gideon.hirschfield@uhn.ca).

Conflict of Interest Disclosures: Dr Hirschfield reported receiving personal fees for consultancy from Intercept Pharma, Cymabay, Genfit, Roche, Pliant, High Tide, Mirum, and GlaxoSmithKline outside the submitted work. No other disclosures were reported.

References
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Kasarala  G , Tillmann  HL .  Standard liver tests.   Clin Liver Dis (Hoboken). 2016;8(1):13-18. doi:10.1002/cld.562PubMedGoogle ScholarCrossref
2.
Kwo  PY , Cohen  SM , Lim  JK .  ACG Clinical Guideline: evaluation of abnormal liver chemistries.   Am J Gastroenterol. 2017;112(1):18-35. doi:10.1038/ajg.2016.517PubMedGoogle ScholarCrossref
3.
Valenti  L , Pelusi  S , Bianco  C ,  et al.  Definition of healthy ranges for alanine aminotransferase levels: a 2021 update.   Hepatol Commun. 2021;5(11):1824-1832. doi:10.1002/hep4.1794PubMedGoogle ScholarCrossref
4.
Bussler  S , Vogel  M , Pietzner  D ,  et al.  New pediatric percentiles of liver enzyme serum levels (alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase): effects of age, sex, body mass index, and pubertal stage.   Hepatology. 2018;68(4):1319-1330. doi:10.1002/hep.29542PubMedGoogle ScholarCrossref
5.
Marchesini  G , Avagnina  S , Barantani  EG ,  et al.  Aminotransferase and gamma-glutamyltranspeptidase levels in obesity are associated with insulin resistance and the metabolic syndrome.   J Endocrinol Invest. 2005;28(4):333-339. doi:10.1007/BF03347199PubMedGoogle Scholar
6.
Newsome  PN , Cramb  R , Davison  SM ,  et al.  Guidelines on the management of abnormal liver blood tests.   Gut. 2018;67(1):6-19. doi:10.1136/gutjnl-2017-314924PubMedGoogle ScholarCrossref
7.
Tran  AN , Lim  JK .  Care of the patient with abnormal liver test results.   Ann Intern Med. 2021;174(9):ITC129-ITC144. doi:10.7326/AITC202109210PubMedGoogle ScholarCrossref
8.
Mack  CL , Adams  D , Assis  DN ,  et al.  Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American Association for the Study of Liver Diseases.   Hepatology. 2020;72(2):671-722. doi:10.1002/hep.31065PubMedGoogle ScholarCrossref
9.
Galvin  Z , McDonough  A , Ryan  J , Stewart  S .  Blood alanine aminotransferase levels >1,000 IU/l: causes and outcomes.   Clin Med (Lond). 2015;15(3):244-247. doi:10.7861/clinmedicine.15-3-244PubMedGoogle ScholarCrossref
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