Elevated Liver Enzymes Workup, When to Worry, When to Refer

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1 Elevated Liver Enzymes Workup, When to Worry, When to Refer Ontario College of Family Physicians Annual Scientific Assembly Barry Lumb

2 No disclosures

3 Liver Biochemistry Bilirubin Hepatocellular - AST, ALT Cholestasis - Alkaline phosphatase, GGT Synthetic Albumin, INR Protein electrophoresis Autoimmune, genetic, metabolic studies Viral serology

4 Imaging Ultrasound CT MRI ERCP

5 Bilirubin Balance between production and hepatic elimination Catabolic product of heme metabolism Glucuronyltransferase Huge hepatic reserve even in severe liver disease Conjugated (direct) vs Unconjugated (indirect) rarely useful

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7 Gilberts syndrome 5% of Caucasian population Impaired UDP glucuronosyl transferase Total bilirubin < 80 Conjugated ~ 10% of total Rise in Bili stress, dehydration Normal liver enzymes, increased Bili with fasting or stress Risk of acetaminophen toxicity

8 Delta Bilirubin Portion of conjugated bilirubin covalently bonded to albumin Prolonged elevation of bilirubin leads to accumulation of delta bilirubin Very slow to clear (albumin ½ life near 3 weeks)

9 Hepatocellular enzymes AST, ALT Sensitive indicators of hepatocellular damage AST many sources ALT liver only ALT serum half life > AST Hepatocellular damage ALT elevation predominant AST:ALT ratio <1

10 Hepatocellular enzymes AST, ALT? Extent of investigation of ALT < 2 x normal Rule out Hepatitis B & C NAFLD Drugs Differentiate AST, ALT <5X normal or > 15x normal

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13 Severe AST/ALT Elevation Acute viral hepatitis - all kinds Medications/toxins Ischemia Wilson s (young patient) Transient with acute obstruction (significant abdominal pain)

14 Alcohol and liver enzymes Prolonged intake Depletion of hepatic AST and ALT but ALT predominant AST/ALT ratio > 2 (>70%) Total AST <

15 Alkaline phosphatase Many sources fractionation rarely helpful Stimulation of production and leakage into the serum in damaged hepatocytes Predominant elevation suggests a cholestatic process Moderate elevation is non-specific

16 GGT Sensitive but non-specific indicator of biliary disease Clarification of source of raised AP Induced by ethanol, phenytoin and other drugs Strong association with BMI, NAFLD, alcohol, cholesterol, triglycerides, analgesic usage

17 Cholestasis Intrahepatic Drugs and toxins Hepatitis B & C Infiltration sarcoid, TB, tumour NAFLD PBC, PSC HIV, CMV, micrsosporidia Extrahepatic Earlier and higher rise in Bili Intraluminal Stones, parasites Mucosal Extrinsic Pancreas, gallbladder, nodal

18 Alcohol (again) Elevated AST (<400) AST/ALT ratio >2 Minimal elevation of AP Elevated GGT (sometimes striking) Don t forget about acetaminophen risk in chronic alcohol use!

19 INR Liver produces - I, II, V, VII, IX, X, XII, XIII Vitamin K II, VII, IX, X Fat soluble so high risk of deficiency in some cholestatic conditions especially extrahepatic Prolonged INR implies major compromise of liver function

20 Albumin Synthesis, degradation and volume of distribution Prolonged half life 20 days In stable outpatient situation may be a reasonable index of impaired liver function

21 Gammaglobulins Any chronic liver disease can be associated with a polyclonal rise in gammaglobulins Beta-gamma bridging IgA alcohol, NAFLD IgG autoimmune, viral IgM primary biliary cirrhosis

22 Autoantibodies SMA (smooth muscle antibody) ANA Autoimmune hepatitis AMA (anti-mitochondrial antibodies) Primary biliary cirrhosis anti-lkm (anti-liver, kidney, microsomal antibody) Type II autoimmune hepatitis and overlap syndromes

23 Hemochromatosis Remember that ferritin is an acute phase reactant Fasting iron saturation of >45% warrants further investigation >50% female and >60% male PPV 86% Genotype if strong clinical suspicion Possible liver biopsy with quantitative iron

24 Routine screening investigations Hepatitis serology Celiac screen Lipids, hemoglobin A1C ANA AMA anti-mitochondrial antibody Ferritin, Fe, TIBC, Saturation Alpha-1-antitrypsin Ceruloplasmin

25 Ultrasound Initial basic imaging almost always Poor for pancreas Generally good for liver parenchyma Very good for bile duct Beware of false negatives! Doppler options Beware false negatives again!

26 CT Always contrast! Otherwise maybe MRI Excellent for pancreas, vascular integrity, nodal assessment Not so good for bile duct size Beware of the thickened bowel wall!

27 MRI General use in abdominal scanning doubtful Very good for further differentiation of liver masses (hemangiomas) MRCP very useful for non-invasive assessment of bile duct and pancreas

28 ERCP Significant risk of pancreatitis! Vast majority of ERCP should be interventional not diagnostic (CT and MRCP) Cholangitis is rare in malignant causes of obstruction