Disclosures. Interpreting Liver Tests: What Do They Mean? Liver Function Tests. Objectives. Common Tests. Case 1

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1 Disclosures Interpreting Liver Tests: What Do They Mean? I have no financial disclosures to make. Roman Perri, MD Vanderbilt University Medical Center Nashville, TN Objectives Discuss tests commonly used to assess liver disease and liver function Clarify common clinical questions Discuss the use of each test in the setting of specific clinical cases Liver Function Tests A broad array of laboratory tests are available to test specific liver functions What are commonly referred to as LFTs do not actually test a specific liver function Utilizing available tests, patterns of liver injury and assessment of liver function is possible Common Tests AST, ALT Bilirubin Total/fractionated Alkaline Phosphatase Albumin Prothrombin Time/INR Others ggt, 5-NT, urinary bilirubin/urobilinogen, functional studies Case 1 55 yo woman with history of osteoporosis, chronic diarrhea, and basal cell skin cancers Abdominal discomfort/bloating prompted abdominal ultrasound and laboratory evaluation Abdominal ultrasound normal.

2 Case 1 Laboratory Evaluation AST 111 U/L (4-40) ALT 169 U/L (4-40) Alk Phos 79 U/L (40-110) T Bili 0.3 mg/dl ( ) Albumin 4.4 g/dl ( ) PT 14.6 seconds (12-15) AST (SGOT) and ALT (SGPT) are most common markers of liver injury Enzymes play a role in gluconeogenesis AST ALT Assay for transaminases involves enzymatic activity of AST/ALT coupled with oxidation of NADH to NAD AST less specific for liver injury Glutamate Oxaloacetate Pyruvate ALT Aspartate Alanine -ketoglutarate Severity of elevation can be informative <3x ULN Chronic hepatitis NASH Drug toxicity 3-10x ULN Acute hepatitis Autoimmune hepatitis Cholangitis >10x ULN Viral hepatitis Drug toxicity Hepatic necrosis/ Ischemia AST/ALT ratio can be instructive Alcoholic liver disease NASH Progression to cirrhosis Impaired function of hepatic sinusoidal cells?» Park GJ, et al. J Gastroenterol Hepatol 2000

3 Acetaminophen NSAIDs Statins Niacin Sulfonamides Macrolides Azole antifungals Isoniazid Amiodarone Methotrexate HIV medications Anesthetic agents Androgens Anticonvulsants Sprue Thyroid disease Cardiac disease Infiltrative diseases Addison s disease Anorexia nervosa Etc. Other causes How to assess (a guideline) Case 2 AST/ALT elevated >3 x ULN? YES Investigate Viral Autoimmune Metabolic NO Imaging Liver biopsy Symptoms? Duration >6 mo YES NO Recheck every 3-6 mo 49 yo woman with progressive weakness and dyspnea. Also with abdominal discomfort and anorexia. No GI bleeding but with poor appetite, has lost 20 pounds over last several months. Case 2 Laboratory Evaluation AST 155 U/L (4-40) ALT 78 U/L (4-40) Alk Phos 1923 U/L (40-110) T Bili 4.4 mg/dl ( ) Albumin 2.6 g/dl ( ) PT 14.2 sec (12-15)

4 Markers of cholestasis Alkaline phosphatase Catalyze the hydrolysis of phosphate esters at alkaline ph Physiologic significance remains unclear despite ubiquitous nature 80% present in liver and bone Placenta, intestine, kidney are also sources Alkaline phosphatase Synthesized by bile duct epithelium Increased synthesis in setting of bile duct obstruction Intrahepatic Extrahepatic Diffuse/infiltrative Massive elevations (>1000 U/L) suggest granulomatous or infiltrative disease Alkaline phosphatase Assessment of elevated levels Confirm liver origin If significantly elevated (>2x) or prolonged elevation, abdominal imaging to evaluate for biliary ductal dilatation Diagnostic imaging of bile ducts vs. AMA/liver biopsy assessment may be required Alkaline phosphatase Recognize pitfalls Fasting patient blood types B/O Children Elderly Pregnant women Hypothyroidism Wilson s disease Bilirubin Derived from hemoglobin Undergoes conjugation in hepatocytes An important indicator of hepatic dysfunction Poor bile flow leads to jaundice Acute hepatitis Cirrhosis Sepsis/critical illness Bile duct damage PBC/PSC Unconjugated (>70%) Bilirubin Hemolysis Physiologic (newborns) Inherited Gilbert s syndrome Crigler-Najjar syndrome Conjugated (>50%) Intrinsic liver disease Obstruction Sepsis Inherited Dubin-Johnson Rotor s syndrome

5 Bilirubin Significance of elevation Acute hepatitis commonly elevated and tends to decrease with resolution of inflammation -bilirubin Cirrhosis correlates with survival (MELD) PBC correlates with survival (Mayo) Case 3 Otherwise healthy 34 yo man with 2 weeks of malaise and nausea without emesis. Has noticed dark urine and scleral icterus. Presented to occupational health clinic and abnormal liver tests were noted. He was admitted to the hospital Endorses trip to Las Vegas recently with consumption of raw seafood. Case 3 Laboratory Evaluation AST 1379 U/L (4-40) ALT 2151 U/L (4-40) Alk Phos 103 U/L (40-110) T Bili 4.2 mg/dl ( ) Albumin 4.0 g/dl ( ) PT 15.6 seconds (12-15) Markers of Liver Function While AST/ALT elevations can certainly catch one s attention, they do not serve, per se, as markers of liver function Specific tests assay the liver s ability to perform its vital functions Liver Synthetic Function Albumin Long T1/2 renders it unreliable in acute liver disease Acute phase reactant Depends on nutritional status, osmotic pressure, protein loss Does correlate with survival from liver disease Liver Synthetic Function Prothrombin time Liver is the site of synthesis of many coagulation factors Rate of conversion of prothrombin to thrombin with addition of thromboplastin/ca ++ affected by deficiencies of clotting factors INR standardizes PT for patients on warfarin therapy PT/INR useful as a prognostic test

6 Prothrombin Time Clinical utility MELD score CTP score King s College Criteria Limitations Warfarin therapy Lab variability Other Liver Tests -glutamyl transpeptidase Present in entire biliary tree A very sensitive indicator of biliary tract pathology, though lacks specificity Most useful role is now confirmation of liver origin of alkaline phosphatase (find out cost of this versus alk phos isoenzymes) Other Liver Tests 5 -NT Widespread distribution throughout the body Only released by hepatobiliary tissue due to detergent action of bile salts Association with canalicular basement membranes provides utility as a confirmatory test of liver origin of alkaline phosphatase Other Liver Tests Urinary bilirubin Always conjugated Signifies presence of liver disease Absence of bilirubinuria in the jaundiced patient can be helpful Bilirubin Derived from breakdown of hemoglobin Blood bilirubin Hepatocyte conjugation Kidney conjugated bilirubin Portal vein Sm. bowel urobilinogen excreted in urine excreted in stool Urobilinogen Intestinal bacteria metabolize conjugated bilirubin to urobilinogen A fraction of this is excreted in the urine Levels should be low if extrahepatic obstruction prevents bilirubin from reaching the intestines In practice, is rarely helpful

7 Conclusions Liver tests can direct attention to a wide variety of liver diseases Different tests measure inflammation/cholestasis/liver function The pattern and duration of liver test elevation is often helpful in elucidating the etiology of the specific laboratory abnormality