New ALT Reference Intervals for Children and Adults

Background Rationale for Changing ALT Reference Intervals Serum liver chemistry tests provide a useful and cost-effective evaluation The high specificity of ALT for liver damage makes accurate population- of liver function. They are ordered regularly for individuals who are as- based reference intervals critical for medical decisionmaking; however, ymptomatic — for routine screening, blood banking, and physical exami- reference intervals for serum ALT vary widely among laboratories. Often nations to obtain life insurance — as well as for inpatients with medical or the reference subjects used for reference interval studies were not well surgical issues unrelated to liver fuction.1 The most commonly used serum defined and may have included subjects with subclinical liver disease. liver chemistry tests are alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, alkaline phosphatase, prothrombin time, One study (that included more than 6000 total subjects) carefully selected serum albumin, γ-glutamyltransferase (GGT), bile acids, 5′-nucleotidase, certain subjects with low risk for subclinical liver disease and found the and lactate dehydrogenase.1 upper limits for normal ALT to be as low as 30 U/L for males and 19 U/L for females.3 In addition, ALT activity in patients with viral hepatitis, who One of the major markers of hepatocellular damage is ALT.1 ALT activity achieved sustained virologic response, was often below 30 U/L. This occurs predominantly in the liver; however, significant activity also occurs suggests that necroinflammatory activity was present before treatment at 3 in the kidneys, heart, skeletal muscle, pancreas, spleen, and lung tissue. ALT levels above 30 U/L. A recent review of new developments in the Consequently, elevated levels of ALT may indicate myocardial infarction, evaluation of patients with chronic hepatitis B reported that ALT levels of 4 hepatic disease, muscular dystrophy, and organ damage.1,2 Parenchymal 45 U/L or lower were associated with higher HBV antigen seroclearance. liver disease is the most common reason for elevated ALT, since ALT is Guidelines from the National Academy of Clinical Biochemistry indicated more liver-specific than elevated AST.1,2 that a value of 45 U/L in men is a clinically useful upper limit of reference intervals for ALT.5 Evaluation of Elevated ALT Levels In 2010, included in the American Gastroenterology Association publica- The American Gastroenterology Association categorizes elevations in tion, Clinical Gastroenterology and Hepatology, was an important study ALT levels depending on the magnitude of elevation (see below) in order on the proper cut-off values for the reliable detection of chronic pediatric to narrow the differential diagnosis for the possible cause of liver damage.1 liver disease. The authors found that the upper limits of ALT used in chil- Mild elevation (less than five times the upper limit of the refer- dren’s hospitals is usually set too high and does not reliably detect chronic ence interval). Common etiology may be1: liver disease in children and suggested the upper limits for children 12 to • Chronic hepatitis B or C 17 years old be 26 U/L for boys and 22 U/L for girls.6 • Acute viral hepatitis (A – E, EBV, CMV) New Reference Intervals • Steatosis/steatohepatitis Recently, LabCorp conducted an internal study of ALT reference intervals • Hemochromatosis that included more than 260,000 male and female subjects. The results • Medications/toxins demonstrated a close correlation to other investigations. The new ALT ref- • Autoimmune hepatitis erence intervals are calculated as below.7 qw

• α1-Antitrypsin deficiency Gender Age Range (Years) ALT (U/L) • Wilson’s disease • Celiac disease 0 – 11 <29 • Alcohol-related liver injury Female 12 – 17 <25 • Cirrhosis ≥18 <33 (Nonhepatic reasons: hemolysis, myopathy, thyroid disease, strenu- 0 – 11 <30 ous exercise.) Male 12 – 17 – <31 Severe elevation (greater than 15 times the upper limit of the refer- ≥18 <45 ence interval). Common etiology may be1: References • Acute viral hepatitis (A – E, herpes) 1. Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology Medications/toxins 2002 Oct; 123(4):1367-1384. • 2. ALT. Roche Diagnostics. Package insert, V 8 English. 2005-04 • Ischemic hepatitis 3. Fried MW. Hepatitis C infection with normal liver chemistry tests. Clin Gastroenterol Hepatol. 2008 May; 6(5):503-505. • Autoimmune hepatitis 4. Tujios SR, Lee WM. New advances in chronic hepatitis B. Curr Opin Gastroenterol. 2012 May; Wilson’s disease 28(3):193-197. Available at: http://www.medscape.com/viewarticle/762771. Accessed June 5, 2012. • 5. Dufour DR, Lott JA, Nolte FS, et al. Diagnosis and monitoring of hepatic injury. Performance charac- • Acute bile duct obstruction teristics of laboratory tests. Clin Chem. 2000 Dec; 46(12):2027-2049. 6. Schwimmer JB, Dunn W, Norman GJ, et al. SAFETY Study: Alanine aminotransferase cutoff val- • Acute Budd-Chiari syndrome ues are set too high for reliable detection of pediatric chronic liver disease. Gastroenterology. 2010 Apr; 138(4):1357-1364. • Hepatic artery ligation 7. LabCorp internal data on file. Clinical and Laboratory Evaluation of Mild Elevations of Serum ALT and/or AST

Elevated ALT and/or AST (less than five times the upper limit of the reference interval)

History and Physical Examination Repeat ALT and/or AST if observational Persistently (Subsequent evaluation if one or more approach is deemed appropriate1,2 elevated diagnostic considerations are likely); Discontinue hepatotoxic medications.1,2 Suspicion of liver disease1,2 Evaluate other liver chemistry test results: bilirubin, alkaline phosphtase, prothrombin time, albumin, CBC with Therapeutic lifestyle modification: discontinue Normal test results, platelets, hepatitis A, B, and C alcohol, stop hepatotoxic medications, weight loss, asymptomatic, no hepatic serology tests, iron TIBC, ferritin1,2 1,2 diabetes control; monitor liver chemistry tests decomposition

Positive viral Normal Abnormal Normal test results, hepatitis serology suspicion of autoimmune hepatitis, Wilson’s disease, α - Consider ultrasound and 1 Observation1,2 antitrypsin deficiency, celiac Follow current guidelines for the serologic evaluation: ANA, disease smooth muscle antibody, management of acute and chronic viral hepatitis; if HCV is diagnosed, ceruloplasmin, α1-antitrypsin, celiac disease serology tests1 consider noninvasive assessment Normal of liver status if if biopsy is contraindicated (HCV FibroSURE test)3

Abnormal On iron supplementation: serology discontinue iron supplements, Elevated ferritin, discontinue alcohol1,2 TIBC > 45% Further evaluation for autoimmune hepatitis, Wilson’s disease, α -antitrypsin Repeat liver chemistry tests, fasting 1 1,2 No iron supplementation1,2 deficiency, or celiac disease1,2 serum iron, TIBC, ferritin

Observation1,2 Normal Abnormal Test for HFE genotype1,2,4

Signs of fatty infiltration during Evaluate for non-HFE-related iron Normal or C282Y ultrasonography overload disease; monitor liver heterozygous homozygous function tests2,4

Evaluate for steatohepatitis (nonalchoholic fatty liver disease; consider noninvasive assessment of Persistent ALT Follow current hematochromatosis liver fibrosis if biopsy is contraindicated elevation, management guidelines; monitor liver (NASH FibroSURE test)3,7 TIBC > 50%, function tests, ferritin2,4 elevated ferritin

AST > ALT with history of alcohol abuse Persistent ALT and/or Consider liver biopsy1,2,4 AST elevation, ferritin > 1000 μg/L

Consider noninvasive assessment of liver fibrosis if liver biopsy is contraindicated (ASH FibroSURE test)3,7 Persistently elevated Evaluate for cholestatic and/or alkaline phosphatase with infiltrative liver disease2 elevation in either bilirubin, GGT, AST > ALT with no or 5’ nucleotidase history of alcohol abuse

In the absence of nonhepatic Low serum albumin, Evaluate for possible cirrhosis or etiologies, evaluate for elevated prothrombin time, drug-included liver injury; possible cirrhosis2,5 low platelets exclude nonhepatic cause, such as hemolytic states and myopathic process2

References 1. American Gastroenterological Association medical position statement: Evaluation of liver chemistry tests. Gastroenterology. 2002; 123:1364-1366. 2. Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology. 2002 Oct; 123(4):1367-1384. 3. LabCorp. Directory of Services and Interpretive Guide. 2012. Available at: https://www.labcorp.com/wps/portal/provider/testmenu. Accessed January 22, 2013. 4. Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS; American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011 Jul; 54(1):328-343. 5. Dufour DR, Lott JA, Nolte FS, Gretch DR, Koff RS, Seeff LB. Diagnosis and monitoring of hepatic injury. II. Recommendations for use of laboratory tests in screening, diagnosis, and monitoring. Clin Chem. 2000 Dec;46(12):2050-68. 6. Balas B, Ali R, Cusi K. Non-alcoholic steatohepatitis—An endocrine disorder. US Endocrine Dis. 2007; 79-84.