Abnormal Liver Tests Harry Colt, MD 9/4/07 Goal At the conclusion of this session, participants will be able to initiate appropriate evaluation and management of abnormal liver tests. Objectives Participants will be able to: 1. recognize common patterns of abnormal liver tests 2. list the common causes of hepatocellular injury 3. list the common causes of cholestatic disease 4. initiate further workup of abnormal liver tests. Why is this important? one of the common problems in everyday clinical practice sorting out the cause, can initially seem puzzling knowledge of the pathophysiology of the enzymes and patterns of abnormalities are helpful Case # 1 62 yo man with hypertension, obesity and hyperlipidemia has a CMP which is normal except for AST194, ALT132. What do you want to know and/or do? Evaluation of Abnormal liver test includes history physical analysis of enzyme pattern 1. hepatocellular or cholestatic 2. magnitude of abnormality 3. rate of change further testing History HPI anorexia, nausea, vomiting, fatigue jaundice, pruritus, clay colored stools, dark urine History (cont’d) PMH alcohol use medication list OTC meds, illicit meds, herbal remedies blood transfusions sexual history occupational history raw oysters, clams, etc. Family history (Gilberts, Wilson’s, hemochromatosis, alpha one antitrypsin deficiency Physical jaundice, hepatomegaly, ascites, RUQ tenderness, palmar erythema, spider nevi, asterixis, encephalopathy Pattern of Liver Enzyme Elevation Hepatocellular or cholestatic? Magnitude of change? Rate of change? Hepatocellular (aminotransferases) not liver “function” tests sensitive indicators of liver cell injury released when liver cell membrane damaged AST found in liver, cardiac muscle, skeletal muscles, kidneys, brain, pancreas ALT found in liver, skeletal muscle Degree of Elevation Important! Causes of Hepatocellular Pattern alcohol induced liver injury medications (prescriptions, OTC, drugs, herbs chronic Hepatitis B chronic Hepatitis C autoimmune hepatic steatosis (fatty liver) hemochromatosis Wilson’s disease alpha-one antitrypsin deficiency celiac disease Non-Liver Causes of Hepatocellular Pattern inherited disorders of muscle metabolism Acquired muscle disease strenuous exercise Case # 1 62 yo man with hypertension, obesity and hyperlipidemia has a CMP which is normal except for AST194, ALT132. What tests do you want to order? Initial Tests (Hepatocellular) Hep C antibody Hep B Sag (Hep B SAb, Hep B Cab) Fe, TIBC SPEP *increased polyclonal immunoglobulins suggest autoimmune hepatitis *low alpha one globulin suggests alpha one antitrypsin deficiency ----------------------------------------------------------- Ceruloplasmin (<40 yo) Additional Tests (Hepatocellular) PCR for Hep C RNA alpha one antitrypsin phenotyping antiendomysial and antigliadin Ab ultrasound liver biopsy Alcoholic Liver Disease AST> ALT (at least 2:1) if AST twice ALT, 90% have alcoholic liver disease if AST 3x ALT, 96% have alcoholic liver disease only rarely in alcoholic liver disease is AST >8x normal or ALT >5x normal Hepatitis C 4 million Americans Hep C antibody positive 3 million chronically infected (Hep C virus RNA present) risk factors: blood transfusions, IV drug use, tattoos/body piercing, high risk sexual activity, work duties initial test: Hep C Ab (92-97% sensitivity) if positive, confirm with PCR for Hep C virus RNA if positive for RNA, consider liver biopsy if Hep C and fibrosis, usually treat Hep B tests: Hep B Sag, Hep B SAb, Hep B Cab Hep B Sag positive, Hep B Cab positive Hep B Hep B SAb positive, Hep B Cab positive immune to Hep B if Hep B Sag positive, do Hep B e antigen and Hep B virus DNA if Hep B virus DNA and Hep e antigen present, consider liver biopsy and treatment Autoimmune Hepatitis primarily young to middle aged women ♀:♂ = 4:1 80% of those with autoimmune hepatitis have hypergammaglobulinemia on SPEP liver biopsy is necessary for diagnosis important: amenable to treatment Hepatic Steatosis and Nonalcoholic Steatohepatitis usually only mild elevation of aminotransferases AST:ALT usually less than 1:1 ultrasound or CT can identify this diagnosis of nonalcoholic steatohepatitis requires liver biopsy steatosis has benign course nonalcoholic steatohepatitis can progress to cirrhosis weight loss is key to treatment Hemochromatosis common genetic disorder, autosomal recessive; homozygote frequency 1:300 excessive GI absorption of iron, and subsequent iron deposition in heart, lung, skin screening test: Fe, TIBC if Fe/TIBC >45%, consider hemochromatosis if abnormal, liver biopsy important to diagnose for both individual and family Wilson’s Disease Rare genetic disorder (1:30,000-1:300,000) of biliary copper excretion Usually onset before age 25, but consider up to age 40 Suspect if psych/neuro problems Screen with ceruloplasmin, reduced in 85% Also diagnosed by Kayser-Fleischer rings 24 hour urine for copper excretion – excretion of >100g suggests Wilson’s Confirm by liver biopsy Alpha-one Antitrypsin Deficiency 1:1600-1:2800, suspect if pulmonary disease Screen by diminished alpha globulin on SPEP or direct measurement of alpha-one antitrypsin Confirm by phenotype determination Non-Hepatic Causes If other causes ruled out, consider celiac sprue Test for antigliadin or antiendomysial antibodies Acquired and congenital muscle disorders and strenuous exercise can cause elevated hepatocellular enzymes if muscle disorder suspected, check CPK and aldolase which should be elevated If ALT & AST elevated, but all other blood tests normal? If AST, ALT <2x normal, observe If AST, ALT >2x normal, biopsy Case: 62 yo man with hypertension, obesity, hyperlipidemia has CMP notable for AST 194, ALT 132. What would you do? Answer: History (alcohol, meds, risk factors for hepatitis, family history, etc.) Physical Analyze pattern: Hepatocellular Repeat enzymes (off ETOH) if remain elevated, further workup Further eval includes: Hep C antibody Hep B SAg Fe, TIBC SPEP Further eval includes: stop med(s) ultrasound etc. Case #2 42 yo woman with hypertension has CMP which is notable for alkaline phosphatase of 320. What do you do next? History (abd pain, jaundice, pruritis, etc. Physical Evaluate pattern of enzymes 1. hepatocellular or cholestatic 2. magnitude of abnormality 3. rate of change Further testing Causes of Elevated Alk Phos Alk phos can come from liver, bone, placenta, intestine (rare) Alk phos higher in children, pregnant women First goal is to: identify the source (liver vs bone) Methods: 1. Alk phos fractionation 2. GGT Causes of Elevated Alk Phos If liver source established, suspect cholestasis or infiltrative liver disease Causes include: partial obstrction of bile ducts, primary biliary cirrhosis, sclerosing cholangitis, certain drugs (eg, steroids), sarcoidosis, granulomatous disease, metastatic cancer How to distinguish these entities? Next step ultrasound antimitochondrial antibodies (suggestive of primary biliary cirrhosis) If antimitochondial antibodies positive, consider liver biopsy for primary biliary cirrhosis If biliary dilatation or choledocholithiasis, consider ERCP If US and antimitochondrial antibodies negative, and Alk phos significantly elevated (>50%), consider liver biopsy If US and antimochondrial antibodies negative, and Alk phos <50% elevated, observe Other Liver Tests GGT Very sensitive for hepatobiliary disease, but low specificity Fallen out of favor except as confirmatory test BILIRUBIN Unconjugated huperbilirubinemia caused by increased bilirubin production or decreased hepatic uptake Most common causes of unconjugated hyperbilirubinemia: Gilbert’s (5%), hemolysis Tests of Liver Function 1.Albumin – synthesized by liver Nonspecific. Decreased in advanced stage liver disease, malnutrition, nephrotic syndrome Albumin has 20 day half life, so if due to liver, it indicates at least several weeks of liver disease Tests for Liver Function (cont’d) 2. INR Prolonged by end stage liver disease, warfarin, vitamin K deficiency INR dependant on clotting factors which have half life of one day More sensitive indicator of liver synthetic function Questions? Cases Case #3 A 36 yo man seeks medical attention because of anorexia, nausea, and vomiting of 5 days duration. Has low grade fever, and pain in RUQ of abdomen. What else do you want to know? History: Pertinent history includes longstanding alcohol abuse, consumption of raw oysters during a recent vacation, and taking 2 g acetaminophen for back pain daily Case #3: Liver tests show: bilrubin 4.8 ALT 950 (18x normal) AST 700 (12x normal) Alk Phos 480 (2-3x normal) What is the most likely cause? What would you do next? Questions? Case #4: A 72 yo man with alcoholic cardiomyopathy is admitted for heart failure. Medications include captopril and furosemide which were started 2 weeks earlier. On admission, bilirubin is 3.0, Alk phos 600, AST 9,200, ALT 6,000. What else do you want to know? What is the most likely cause for his elevated LFTs? His captopril and furosemide are discontinued, and 3 days later his liver tests show: bilirubin 3.8, Alk Phos 320, AST 400. What is most likely? Case #5: A 48 yo man with arthritis and Hilar adenopathy comes in for a low grade fever. Liver tests are bilirubin 0.8, Alk Phos 2,200, AST 88, ALT 72. What would you do next? What is the most likely cause? Case #6: 72 yo woman with diabetes,HTN, CHF, hyperlipidemia, obesity, and remote h/o alcohol abuse. Meds include: metformin, lovastatin, enalapril, propranolol, and ASA. LFTs on CMP show AST 340, ALT 100, Alk phos 150, TB 0.8 What is your differential? What is most likely? Resources 1.Giannini E, et al. Liver Enzyme Alteration: A Guide for Clinicians. CMAJ 2005;172(3):367-79. 2. Pratt D, Kaplan M. Evaluation of Abnormal Liver-Enzyme Results in Asymptomatic Patients. NEJM 2000;342(17):1266-71.