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Approach to Abnormal Liver Tests

Approach to Abnormal Liver Tests. Anne Larson, MD Hepatology University of Washington. Case 1 – 65 y/o woman. comes to you to establish care complaints fatigue pruritis dry eyes past history hysterectomy for fibroids 10 years ago no alcohol, tobacco or drug use.

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Approach to Abnormal Liver Tests

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  1. Approach to Abnormal Liver Tests Anne Larson, MD Hepatology University of Washington

  2. Case 1 – 65 y/o woman • comes to you to establish care • complaints • fatigue • pruritis • dry eyes • past history • hysterectomy for fibroids 10 years ago • no alcohol, tobacco or drug use

  3. Case 1 – 65 y/o woman • exam • spider angiomata • mild splenomegaly • otherwise normal

  4. Case 1 – 65 y/o woman • screening labs reveal • platelets 90,000 - alk phos 4x uln • bilirubin normal - albumin 3.3 (nl >3.5) • AST/ALT normal - PT normal • what do you want to do next? • be thinking about this

  5. Case 2 – 43 y/o female • complaining of • 4 days of prolonged, severe RUQ pain • fever, severe nausea, some vomiting • worse after eating • Past History • 20 yr ago began periodic attacks • evening RUQ pain, fluctuating intensity, no fevers • lasting 1-4 hours with residual RUQ tenderness

  6. Case 2 – 43 y/o female • Past History (cont) • during last 8 years, continued episodes • pain more intense and prolonged, accompanied by penetrating pain to back below scapula • marked tenderness in RUQ persisting days • told in the past she had gallstones

  7. Case 3 • Exam • temp 38.5°C pulse 100 uncomfortable/sweating • marked tenderness in RUQ with splinting • (+) Murphy's sign • icterus • bilirubin 6 mg/dl - alk phos 3x nl (~400 U/L) • ALT 100 mg/dl - normal albumin, PT • WBC 28,000 - GGT 150 U/L (nl <45) • how would you proceed?

  8. Approach to Abnormal Liver Tests • If patient is asymptomatic • The First Step: • repeat the tests to confirm the results • make sure to stop all alcohol use

  9. The Diagnosis • No single test is sufficient • No single battery of tests is sufficient

  10. The Diagnosis • Most liver disease can be diagnosed by: • taking a meticulous history • recognizing the pattern of enzyme elevations • rationally selecting a few “second-line” tests and imaging studies

  11. Types of Liver Tests • grouped by the liver function they assess • measures of hepatobiliary cell injury • measures of transport efficiency of organic compounds • measures of hepatic synthetic function

  12. Tests Reflecting Cell Injury • Aminotransferases (ALT & AST) • Alkaline Phosphatases • Transpeptidases • 5’-Nucleotidase

  13. Tests Reflecting Cell Injury • Aminotransferases • Catalyze -amino group transfers • aspartate or alanine  ketoglutarate • indicators of liver cell (hepatocyte) injury • sensitive but not specific • most useful marker of cell inflammation or necrosis • represent a “leak” from damaged cells

  14. Tests Reflecting Cell Injury • Aminotransferases - cont • aspartate aminotransferase (AST) • in cytosol and mitochondria • liver > heart > skeletal muscle > kidneys > brain > pancreas > lungs > WBCs > RBCs • alanine aminotransferase (ALT) • in cytosol • predominantly liver • more sensitive and specific than AST

  15. Tests Reflecting Cell Injury • Aminotransferases – cont. • elevated in nearly all liver diseases (ALT > AST) • marked  is usually hepatocellular disease • levels may/may not reflect extent of damage • do not correlate with eventual outcome • usually <500 in obstructive jaundice • usually parallel each other • AST > ALT with EtOH, fulminant, and pregnancy

  16. Tests Reflecting Cell Injury • Alkaline Phosphatase • catalyzes organic phosphate esters • the enzyme is bound to hepatic canalicular membrane • elevation may be due to induction of enzyme synthesis rather than inability of liver to secrete it into the bile • increases seen with cell injury or obstruction • slight to moderate (1-2x) – usually hepatocellular • large increases (3-10x) – obstruction or cholestasis

  17. Tests Reflecting Cell Injury • Alkaline Phosphatase – cont. • isolated elevations • infiltrative disease – tumor, abscess, granuloma, amyloid • Non-liver causes of elevations: • bone disease » diabetes • chronic renal failure » intestinal disease • renal cancer » genetic (pseudoelevation) • pregnancy » osteitis deformans • sepsis (esp. GNRs) » multiple bone fractures • Hodgkin's disease » intraabdominal infections • hypothyroidism » pernicious anemia • congenital hypophosphatasia » zinc deficiency

  18. Tests Reflecting Cell Injury • -glutamyl transpeptidase (GGT) • catalyzes transfer of -glutamyl groups • high concentrations in bile ductule epithelial cells • useful to exclude “bone” source for Alk Phos • correlates with alk phos levels in liver disease • sensitive but not specific •  in renal failure, MI, pancreatitis, diabetes

  19. Tests Reflecting Cell Injury • GGT – cont. • Causes of elevations: • liver disease » pancreatic disease • alcohol » renal disease • cardiac disease » obesity • radiotherapy » diabetes • drugs – GGT is “inducible” • phenobarbitalanticoagulants • dilantinoral contraceptives • acetaminophentricyclic antidepressants

  20. Tests Reflecting Cell Injury • 5’-Nucleotidase (5NT) • hydrolyzes 5’ phosphates from nucleotides • associated with canalicular and sinusoidal membranes • physiologic function unknown • only hepatobiliary tissue can release 5’-NT • specific for hepatic disease • highest in cholestatic conditions

  21. Tests Measuring Transport Efficiency • Hepatic clearance reflects: • delivery to hepatocyte (blood flow) • uptake by hepatocyte

  22. Tests Measuring Transport Efficiency Hemoglobin (1) Other Tissue Cytochromes, etc. Heme B-Alb (2) Alb

  23. Tests Measuring Transport Efficiency • Hepatic clearance reflects: • delivery to hepatocyte (blood flow) • uptake by hepatocyte • transport within hepatocyte • molecular alterations within hepatocyte

  24. Tests Measuring Transport Efficiency Hemoglobin (1) Other Tissue Cytochromes, etc. Heme B-Alb (2) Alb B (3)  Conjugated (4)  

  25. Tests Measuring Transport Efficiency • Hepatic clearance reflects: • delivery to hepatocyte (blood flow) • uptake by hepatocyte • transport within hepatocyte • molecular alterations within hepatocyte • secretion by hepatocyte into bile • passage down bile ducts into duodenum

  26. Tests Measuring Transport Efficiency Hemoglobin (1) Other Tissue Cytochromes, etc. Heme B-Alb (2) Alb B (3)  Conjugated (4)   Secreted (5) Urine 1% (6) Feces 99%

  27. Tests Measuring Transport Efficiency Hemoglobin (1) Other Tissue Cytochromes, etc. Heme B-Alb (2) Alb B (3)  Conjugated (4)   Secreted (5) Urine 1% (6) Feces 99%

  28. Tests Measuring Transport Efficiency • Remember, hepatic clearance reflects: • delivery to hepatocyte  hemolysis • uptake by hepatocyte  shunts, drugs (i.e., sulfa) • transport within hepatocyte  drugs, genetics • molecular alterations within hepatocyte  genetics • secretion into bile  cell damage, genetics • passage down bile ducts  obstruction

  29. Transport Efficiency • Bilirubin • derived mainly from hemoglobin (95%) • continuous production (300 mg daily) • normal liver reserve can rev up 2-3 times • normal values of “total” bilirubin = 0.1-1.0 mg/dL • conjugated plus unconjugated • direct plus indirect • jaundice evident with levels >3.0 mg/dL

  30. Tests Measuring Transport Efficiency • Types of Bilirubin Direct BilirubinIndirect Bilirubin conjugated unconjugated water soluble lipid soluble polar non-polar seen in urine not in urine

  31. Tests Measuring Synthetic Function • Prothrombin Time (PT) • Albumin • Number Connection Tests / mental status • The liver is the only source of albumin and the prothrombin group of clotting factors

  32. Tests Measuring Synthetic Function • Prothrombin Time (PT) • sick liver can’t make clotting factors • factors 2, 5, 7, 9, 10 (made only in the liver) • prolonged PT reflects failure of liver synthesis • Other causes of prolongation: • congenital deficiencies • consumptive coagulopathies (i.e., DIC) • drugs (i.e., warfarin) • vitamin K deficiency (i.e., dietary,  bile output)

  33. Tests Measuring Synthetic Function • Albumin • most important plasma protein made by the liver • accounts for 65% of protein in serum • half-life ~17-21 days • useful indicator of liver function • Other causes of decrease: • sepsis or multiple organ failure • acute liver failure • dietary

  34. Tests Measuring Synthetic Function • Number Connection Test • liver is site of detoxification • failure leads to toxins in blood • toxins unknown • encephalopathy is sign of liver synthetic failure

  35. The Approach • Important questions to address: • acute vs. chronic (6 months, ?cirrhosis) • hepatocellular vs. cholestatic • asymptomatic vs. symptomatic • ?impaired function • recent insults to the liver? • EtOH, medications, pregnancy, hepatitis, herbs, gallstones, hypotension, toxins

  36. The Approach • Hepatocellular Injury • mainly  AST & ALT +/-  AP, GGT, bilirubin •  2 enzyme elevations  high likelihood of liver dz • guides: • Mild (<3 x normal) • fatty liver, EtOH, chronic hepatitis • Moderate (2-10 x normal) • EtOH, chronic hepatitis, cirrhosis, neoplasm, gallstones • Severe (>10x normal; usually >1,000) • ischemic, viral, toxic (e.g., acetaminophen, herbs)

  37. The Approach • Cholestatic Liver Disease • mainly alkaline phosphatase & GGT +/- bilirubin • determine source of AP • determine fraction of bilirubin elevated • if all indirect, generally not liver • ultrasound and/or CT scan • to rule out obstructive disease, tumors, gallstones

  38. The Approach • Chronic Liver Disease •  6 months of abnormal liver tests • symptoms • asymptomatic – majority of cases • fatigue • arthralgias • pruritis • jaundice

  39. The Approach • Chronic Liver Disease – cont. • Common Causes – 95% of cases: • Hepatitis C - (+) HCV-Ab and HCV-PCR • Hepatitis B – (+) HBsAg and HBV-DNA • Alcoholic liver disease • Hemochromatosis – fasting Fe/TIBC >50%;  ferritin • Autoimmune hepatitis – (+) ANA, (+) ASMA,  IgG

  40. The Approach • Chronic Liver Disease – cont. • Less Common Causes • Primary Biliary Cirrhosis (PBC) - (+) AMA;  IgM • Primary Sclerosing Cholangitis (PSC) – abnormal ERCP • Wilson’s Disease ( ceruloplasmin) • 1-Antitrypsin Deficiency ( 1AT level) • Drugs (i.e., MTX, INH, amiodarone, methyldopa)

  41. The Approach • Chronic Liver Disease – cont. • signs of cirrhosis • spider angiomata • gynecomastia • portal hypertension (caput medusa) • palmar erythema (seen in 10-15% of normal population) • advanced end stage liver disease – refer pronto! • ascites »  albumin • varices »  prothrombin time • encephalopathy

  42. Case • screening labs reveal • platelets 90,000 - alk phos 4x nl • bilirubin normal - albumin 3.4 (nl >3.5) • AST/ALT normal - PT normal • what are the possible diagnoses? • what do you want to do next?

  43. Case 1 • Further lab testing: • HAV (-) HBV (-) HCV (-) • ANA (-) • ASMA (-) • AMA (+) 1:1280 • iron studies normal • ultrasound – splenomegaly, small liver, no bil dil • What Next?

  44. Case • Answer: • primary biliary cirrhosis • just beginning to decompensate  send for OLT

  45. Summary • No ideal study or battery to evaluate liver • abnormal liver tests are often the first sign of liver disease • normal or minimally elevated tests don’t exclude serious disease or cirrhosis • liver biopsy remains the gold standard to detecting and determining cause of disease

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