ACTIVITY DISCLAIMER. Liver Function Tests: Torn Between Two Livers DISCLOSURE. Learning Objectives. Audience Engagement System Step 1 Step 2 Step 3

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1 Liver Function Tests: Torn Between Two Livers Steven House, MD, FAAHPM, FAAFP ACTIVITY DISCLAIMER The material presented here is being made available by the American Academy of Family Physicians for educational purposes only. This material is not intended to represent the only, nor necessarily best, methods or procedures appropriate for the medical situations discussed. Rather, it is intended to present an approach, view, statement, or opinion of the faculty, which may be helpful to others who face similar situations. The AAFP disclaims any and all liability for injury or other damages resulting to any individual using this material and for all claims that might arise out of the use of the techniques demonstrated therein by such individuals, whether these claims shall be asserted by a physician or any other person. Every effort has been made to ensure the accuracy of the data presented here. Physicians may care to check specific details such as drug doses and contraindications, etc., in standard sources prior to clinical application. This material might contain recommendations/guidelines developed by other organizations. Please note that although these guidelines might be included, this does not necessarily imply the endorsement by the AAFP. DISCLOSURE Steven House, MD, FAAHPM, FAAFP It is the policy of the AAFP that all individuals in a position to control content disclose any relationships with commercial interests upon nomination/invitation of participation. Disclosure documents are reviewed for potential conflict of interest (COI), and if identified, conflicts are resolved prior to confirmation of participation. Only those participants who had no conflict of interest or who agreed to an identified resolution process prior to their participation were involved in this CME activity. All individuals in a position to control content for this activity have indicated they have no relevant financial relationships to disclose. Associate Professor, Department of Family and Geriatric Medicine, University of Louisville (UL) School of Medicine, Kentucky; Program Director, UL/Glasgow Family Medicine Residency, Kentucky. Dr. House is a graduate of the Mercer University School of Medicine (MUSM) in Macon, Georgia. He completed his family medicine residency at the Medical Center of Central Georgia, Macon. Dr. House has been working in undergraduate and graduate medical education since His areas of professional interest include evidence-based medicine, advance directives, and end-of-life care. The content of my material/presentation in this CME activity will not include discussion of unapproved or investigational uses of products or devices. Learning Objectives 1. Use a stepwise diagnostic approach to evaluate patients with elevated liver transaminase levels if the history and physical examination do not suggest a cause. Audience Engagement System Step 1 Step 2 Step 3 2. Develop a collaborative care plan that involves observation with lifestyle modification is appropriate if the initial history, physical examination, and workup do not suggest a cause of elevated liver transaminase levels. 3. Coordinate referral and follow-up in patients with unexplained elevation of liver transaminase levels for six months or more. 1

2 The Liver Responsible for: Detoxification Drug metabolism Prodrug activation Blood proteins, e.g., globulins, albumin Clotting factors Vitamin/mineral storage Glucose homeostasis Bile production Thousands of biochemical reactions Etc. "Gray1224" by Henry Vandyke Carter Henry Gray (1918) Anatomy of the Human Body Etc. Bartleby.com: Gray's Anatomy, Plate Licensed under Public Domain via Etc. Wikimedia Commons Accessed 8/7/ ARS Question 1 Which one of the following is the most specific for the liver? A. Aspartate transaminase (AST) B. Alkaline phosphatase (ALP) C. Alanine transaminase (ALT) D. Gamma-glutamyltransferase (GGT) E. Lactate dehydrogenase (LDH) Tests Bilirubin conjugated / unconjugated Aspartate transaminase (AST, formerly SGOT) Alanine transaminase (ALT, formerly SGPT) Gamma-glutamyl-transpeptidase (GGT) Alkaline phosphatase (ALP) Lactate dehydrogenase (LDH) 2

3 Liver & Biliary Tract Labs 1) Hepatocyte membrane integrity a) Transaminases (AST, ALT) b) Alk. phos., GGT 2) Measurement of the detoxifying and excretory functions of the hepatobiliary system a) Bilirubin b) Ammonia 3) Measurement of the synthetic capacity of the hepatocytes. a) Albumin / Prealbumin b) Coagulation factors ARS Question 2 You are evaluating a 46 year old obtunded male. Initial labs AST 180, ALT 80, ALP and bilirubin normal. No family is available for history. Based on this limited information, what do you suspect as one of your most likely diagnoses? A. Acetaminophen ingestion B. Alcohol intoxication C. Naproxen overdose D. Opioid overdose E. Bad night on call. Alanine transaminase (ALT) Liver, kidney, skeletal and cardiac muscle. ALT is more specific than AST. Cytosol only, but longer half-life. Transaminases Aspartate transaminase (AST) Liver, red blood cells, skeletal and cardiac muscle. Cytosol and mitochondria ALT and AST usually rise in tandem, but AST can rise out of proportion to ALT in chronic liver disease, especially from ethanol. Both are pyridoxine (B6) dependent, but ALT is more dependent, so B6 deficient alcoholics have greater impairment of ALT. 1 AST:ALT ratio >2 suggests alcoholic liver disease. AST:ALT ratio >4 could suggest Wilson disease Winter WE. The Liver and Biliary Tract. In: Laposata M, ed. Laboratory Medicine: The Diagnosis of Disease in the Clinical Laboratory, 2 nd edition. New York: McGraw Hill Education; 2014; Krier M, Ahmed A. The asymptomatic outpatient with abnormal liver function tests. Clin Liver Dis. 2009;13(2): Alkaline Phosphatase (ALP) In biliary tract, bone, ileum, and placenta. Increases more in biliary tract disease than AST and ALT. Isoenzyme fractionation possible, but GGT is generally more pragmatic for confirmation. [5 -nucleotidase (5 -NT) is also an option (institution specific)] Non-hepatic elevations: 1) Children 2-3x > adults due to growth. 2) Bone disease metastasis, Paget s, fractures 3) Hyperparathyroidism (vitamin D deficiency) 4) Ileal disease (celiac disease) 5) Third trimester from the placenta. Winter WE. The Liver and Biliary Tract. In: Laposata M, ed. Laboratory Medicine: The Diagnosis of Disease in the Clinical Laboratory, 2 nd edition. New York: McGraw Hill Education; 2014; Gamma-Glutamyltransferase (GGT) Found in liver, proximal convoluted tubule, pancreas, and intestine Not typically elevated in bone disease, so confirms hepatic origin of ALP. Combined elevations of ALP and GGT indicates biliary tract disease. GGT is induced by alcohol and anticonvulsants, so elevations not uncommon. Winter WE. The Liver and Biliary Tract. In: Laposata M, ed. Laboratory Medicine: The Diagnosis of Disease in the Clinical Laboratory, 2 nd edition. New York: McGraw Hill Education; 2014; Lactate Dehydrogenase (LDH) Five isoenzymes, but only LDH-5 is predominantly from the hepatocytes (and skeletal muscle) so not overly helpful. If LDH-5 is elevated, can check creatine kinase (CK). If CK is normal, LDH-5 is from liver, not skeletal muscle. Other tests are more practical than LDH fractionation, so no longer used. Winter WE. The Liver and Biliary Tract. In: Laposata M, ed. Laboratory Medicine: The Diagnosis of Disease in the Clinical Laboratory, 2 nd edition. New York: McGraw Hill Education; 2014;

4 ARS Question 3 A 40 year old asymptomatic female is seeing you as a new patient. Her employer provided a health fair for the employees, and she was told to see her doctor when lab results came back. Her BMI is 29, cholesterol 235, HDL 35, triglycerides 350, and fasting glucose 107. She had a mildly elevated ALT. She consumes 1-2 beers/day on average. If the ALT is accurate, what is your most likely diagnosis? A. Alcoholic liver disease B. Hepatitis B C. Hepatic steatosis D. Non-alcoholic steatohepatitis (NASH) E. Hemochromatosis ARS Question4 What is your next step? A. Ultrasound B. Hepatitis B antigen / Hepatitis C antibody tests C. CT scan D. Ferritin level E. Repeat liver panel in 2-4 weeks Enzymes Indicative of Liver Plasma Membrane Integrity Indicative of hepatocellular disease Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Lactate dehydrogenase (LDH) Indicative of biliary tract disease Alkaline phosphatase (ALP) Gamma-glutamyltransferase (GGT) 5 -Nucleotidase (5 -NT) Common Causes of Elevated Liver Transaminases, Clinical Clues, and Diagnostic Testing Less Common Causes of Elevated Liver Transaminases, Clinical Clues, and Diagnostic Testing ~31% of patients who have increased transaminases ~30% of US adults Oh RC, Hustead TR. Causes and Evaluation of Mildly Elevated Liver Transaminase Levels. Am Fam Physician. 2011;84(9): Reproduced with permission from Causes and Evaluation of Mildly Elevated Liver Transaminase Levels, November 1, 2011, Vol 84, No 9, issue of American Family Physician Copyright Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003;98(5): Oh RC, Hustead TR. Causes and Evaluation of Mildly Elevated Liver Transaminase Levels. Am Fam Physician. 2011;84(9): Reproduced with permission from Causes and Evaluation of Mildly Elevated Liver Transaminase Levels, November 1, 2011, Vol 84, No 9, issue of American Family Physician Copyright

5 Extrahepatic Causes of Elevated Liver Transaminases, Clinical Clues, and Diagnostic Testing Oh RC, Hustead TR. Causes and Evaluation of Mildly Elevated Liver Transaminase Levels. Am Fam Physician. 2011;84(9): Reproduced with permission from Causes and Evaluation of Mildly Elevated Liver Transaminase Levels, November 1, 2011, Vol 84, No 9, issue of American Family Physician Copyright Very Short List of Medications Associated with Elevation of Liver Transaminase Levels Analgesics Acetaminophen NSAIDs Allopurinol Methotrexate Antibiotic/Antiviral agents Isoniazid Pyrazinamide Rifampin Tetracyclines HAART Ketoconazole Navarro VJ, Senior JR. Drug related hepatotoxicity. N Engl J Med. 2006;354(7): Psychiatric meds Bupropion Risperidone SSRIs Trazodone Statins Anti-epileptics Valproic acid Cardiac meds Lisinopril, Losartan Amiodarone Omeprazole Acarbose Herbals (e.g., kava kava, germander) A Step-Wise Evaluation of Abnormal Liver Transaminase Levels Oh RC, Hustead TR. Causes and Evaluation of Mildly Elevated Liver Transaminase Levels. Am Fam Physician. 2011;84(9): Reproduced with permission from Causes and Evaluation of Mildly Elevated Liver Transaminase Levels, November 1, 2011, Vol 84, No 9, issue of American Family Physician Copyright 2011 Elevated ALT and AST levels (less than five times normal) History and physical examination* Discontinue hepatotoxic medication use and alcohol consumption Evaluate for metabolic syndrome (consider fasting lipid profile and glucose level) Consider repeat testing in 2 to 4 weeks Persistent or unexplained ALT and AST abnormalities Persistent or unexplained ALT and AST abnormalities Hepatitis C virus antibody testing Hepatitis B surface antigen testing Serum iron and ferritin levels, total iron binding capacity Fasting lipid profile and glucose level Consider ultrasonography Consider testing prothrombin time, measuring albumin level, and obtaining complete blood count with platelets Next slide Reproduced with permission from Causes and Evaluation of Mildly Elevated Liver Transaminase Levels, November 1, 2011, Vol 84, No 9, issue of American Family Physician Copyright Next slide Reproduced with permission from Causes and Evaluation of Mildly Elevated Liver Transaminase Levels, November 1, 2011, Vol 84, No 9, issue of American Family Physician Copyright

6 Negative or consistent w/ NAFLD The likelihood of elevated ALT was reduced by 70% through lifestyle modification [diet low saturated fats, high fiber and omega 3, calorie reduction, exercise (>150 mins./week), and modest weight loss (~2%). ** Reproduced with permission from Causes and Evaluation of Mildly Elevated Liver Transaminase Levels, November 1, 2011, Vol 84, No 9, issue of American Family Physician Copyright American Academy of Family Physicians. All Rights Reserved. **St. George A, Bauman A, Johnston A, et al. Effects of a lifestyle intervention in patients with abnormal liver enzymes and metabolic risk factors. J Gastroenterol Hepatol. 2008;24: Reproduced with permission from Causes and Evaluation of Mildly Elevated Liver Transaminase Levels, November 1, 2011, Vol 84, No 9, issue of American Family Physician Copyright Inpatient Evaluation Accuracy of Imaging in Identifying Hepatic Steatosis A request for inclusion of inpatient evaluation was sent to the AAFP. If asymptomatic and the H&P does not point to a cause, evaluation can begin inpatient and be continued outpatient. If H&P and/or other lab testing or imaging indicates, the 2 4 week repeat can be bypassed. If there is chronic disease or signs of hepatic decompensation, expedite evaluation +/ GI consultation. If testing is abnormal, obtain further testing as necessary. Reproduced with permission from Causes and Evaluation of Mildly Elevated Liver Transaminase Levels, November 1, 2011, Vol 84, No 9, issue of American Family Physician Copyright Table 2. Reproduced with permission from Causes and Evaluation of Mildly Elevated Liver Transaminase Levels, November 1, 2011, Vol 84, No 9, issue of American Family Physician Copyright 2011, Bohte AE, vanwerven JR, Bipat S, Stoker J. The diagnostic accuracy of US, CT, MRI and 1H MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta analysis. Eur Radiol. 2011;21(1): $ $$ How should I evaluate abnormal results? For Further Study 1. Oh RC, Hustead TR. Causes and Evaluation of Mildly Elevated Liver Transaminase Levels. Am Fam Physician. 2011;84(9): Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology. 2002;123(4): American Gastroenterological Association medical position statement: evaluation of liver chemistry tests. Gastroenterology. 2002;123(4): Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142: Wilkins T, Tadkod A, Hepburn I, Schade RR. Nonalcoholic Fatty Liver Disease: Diagnosis and Management. Am Fam Physician. 2013;88(1):

7 Thank You! Practice Recommendations 1) If your patient has elevated transaminases without obvious cause on H&P, repeat in 2-4 weeks (or 6-8 weeks of abstinence if drug or alcohol suspected). (SORT C) 1,2,5 2) If levels remain elevated, take a stepwise approach and consider a lipid panel and glucose / glycosylated hemoglobin if metabolic syndrome or non-alcoholic fatty liver disease is suspected (most common cause in US). Observation (~ 6 months) with lifestyle modification is appropriate if the initial evaluation does not suggest a cause.(sort C) 2,3,4,5 3) Consider referral to gastroenterologist: If unexplained elevations (~1.5 normal) persist > 6 months. (SORT C) 4,5 Evidence of hepatic dysfunction (elevated bilirubin or INR, decreased albumin). (SORT C) 4,5 When treatment beyond discontinuation of possible offending agent is required. (SORT C) 4,5 1. Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology. 2002;123(4): Morisco F, Pagliaro L, Caporaso N, et al. Consensus recommendations for managing asymptomatic persistent non virus, non alcohol related elevation of aminotransferase levels: suggestions for diagnostic procedures and monitoring. Dig Liver Dis. 2008;40(7): George A, Bauman A, Johnston A, et al. Effects of a lifestyle intervention in patients with abnormal liver enzymes and metabolic risk factors. J Gastroenterol Hepatol. 2008;24: Oh RC, Hustead TR. Causes and Evaluation of Mildly Elevated Liver Transaminase Levels. Am Fam Physician. 2011;84(9): American Gastroenterological Association Medical Position Statement: Evaluation of Liver Chemistry Tests. Gastroenterology 2002;123: Q & A Contact Information Steven A. House, MD shouse@tjsamson.org or steven.house@louisville.edu Office: