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02.01.12(b): Liver Tests - Use and Interpretation


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02.01.12(b): Liver Tests - Use and Interpretation

  1. 1. Author(s): Rebecca W. Van Dyke, M.D., 2012License: Unless otherwise noted, this material is made available under the termsof the Creative Commons Attribution – Share Alike 3.0 License: have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use,share, and adapt it. The citation key on the following slide provides information about how you may share and adapt thismaterial.Copyright holders of content included in this material should contact with any questions,corrections, or clarification regarding the use of content.For more information about how to cite these materials visit medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or areplacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to yourphysician if you have questions about your medical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
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  3. 3. M2 GI Sequence Liver Tests: Use and Interpretation Rebecca W. Van Dyke, MDWinter 2012
  4. 4. Learning Objectives• A. General: Understand the laboratory tests that are used in the clinical approach to liver disease and the pattern of abnormalities that occur in specific forms of liver injury. – 1. When do we suspect a patient has liver disease? What tests can be used to accept or deny the presence of liver disease? – 2. Can we define the type of liver disease the patient has by analyzing the results of the liver tests? – 3. How much functional liver tissue is present in a patient?•• B. Specific: – 1. Be able to interpret panels of biochemical liver tests in terms of general type of liver disease, chronicity and severity. – 2. Be able to construct a differential diagnosis for different patterns of liver test results. – 3. Be able to identify potential problems in interpreting liver tests.
  5. 5. Industry Relationship DisclosuresIndustry Supported Research and Outside Relationships• None
  6. 6. How Do We Tell Someone Has Liver Disease?Clues that may lead to a suspicion of liver disease: Anorexia Fatigue Nonspecific Nausea Vomiting Mental confusion Jaundice (“yellow eyes”) More specific Dark urine (“coca-cola” urine) (late findings) Abdominal swelling; ascites Peripheral edema; leg swellingUnfortunately none of these are specific markers of liver diseaseand for many patients these are very late findings.
  7. 7. Purpose of Liver Tests1. Screen for clues to the presence of liver injury/disease liver cell injury bile flow/cholestasis2. Quantitate degree of liver function/dysfunction quantitative liver tests3. Diagnose general type of liver disease pattern of liver test abnormalities4. Diagnosis of specific liver disease disease-specific tests such as serology for viral hepatitis
  8. 8. Tests of Liver Cell Injury/Death Transaminases Alanine amino transferase (ALT) Aspartate amino transfersase (AST)
  9. 9. Transaminases are enzymes that catalyze the transfer of α-amino groups from amino acids to α-keto acids.These enzymes are important in gluconeogenesis. ALT (alanine aminotransferase) alanine pyruvic acid + + ketoglutarate glutamate AST (aspartate aminotransferase) aspartate oxaloacetic acid + + ketoglutarate glutamate
  10. 10. Transaminases: AST(SGOT) ALT(SGPT) Many tissues Liver only Cytosol/mitochondria CytosolNormal blood levels: 20-70 IU/liter (depending on method)Some AST/ALT release occurs normallyRequire pyridoxal 5’-phosphate as an essential cofactor
  11. 11. Multi-channel Automated Analysis of Enzymes in Blood lampPatient λserum ALT Colored + product substrateSubstrate λ Absorbance converted to enzyme activity Photodetector
  12. 12. Release of AST/ALT from Liver Cells during Acute Hepatocellular Injury AST ALT
  13. 13. TransaminasesWhy do we used these enzymes to indicate liver damage? 1. Convenient to measure 2. Present in liver cells in large amounts 3. Direct release of enzymes into blood through fenestrated endothelium allows rapid “quantitative” assessment of ongoing hepatocyte necrosis 4. Blood level roughly proportional to the number of hepatocytes that died recently (hours-days)
  14. 14. Patterns: AST and ALT in Various Liver Diseases 30 00 20 00 AT S 500 AT LSerumEnzymeLevel(IU/ml) 200 10 0 Acute viral Acute viral Mild chronic Cirrhosis hepatitis A hepatitis A hepatitis C (little ongoing (clinically severe) (clinically mild) (asymptomatic) injury)
  15. 15. Ischemic infarction: how high would AST/ALT go?
  16. 16. TransaminasesSpecial considerations:1. AST is also present in other tissues (muscle, brain, kidney, intestine). ALT is more specific for liver.2. Even very mild liver abnormalities can cause slightly elevated AST/ALT - for example, mild fatty liver.
  17. 17. Fatty Liver:Most Common Cause of Mildly Increased AST/ALT (~1.5-3x upper limit of normal)
  18. 18. TransaminasesProblems with using transaminases to assess liver injury:3. Only assess injury over the past 1-2 days as enzymes are cleared efficiently from blood by RES5. May not accurately assess hepatocyte death from apoptosis7. Magnitude of elevation does not necessarily correlate with extent of liver function or dysfunction at the present time or in the future.AST and ALT = rate of destruction of hepatocytesLiver function = number of functional hepatocytes left
  19. 19. Not all liver abnormalities cause liver cell death: simple liver cyst with normal liver tests
  20. 20. Transaminases and Alcoholic Liver Disease: A TwistPyridoxal 5’-phosphate (P5P) deficiency:q AST and ALT require P5P (vit. B-6) as an enzymatic cofactorq Alcoholics are often deficient in P5P as their major calorie source is alcoholq P5P deficiency results in lower synthesis of AST/ALT (less in hepatocytes) and very low enzymatic activity (ALT worse than AST)q Less AST/ALT released into blood and it isn’t measured by lab assays
  21. 21. Transaminases and Alcoholic Liver Disease Further: Mitochondrial AST and alcohol q Alcohol shifts mAST from mitochondria to plasma membrane where it readily enters blood – thus AST easier to remove from hepatocytes.Therefore: AST>>ALT is released into bloodfrom damaged hepatocytes ANDboth AST/ALT enzymatic activities in bloodare lower than expected from the extent of liverdamage/dysfunction.
  22. 22. AST/ALT and Pyridoxal 5’ Phosphate AST is Affected Less than ALT so AST>ALT P5’PNumerous active enzymes with P5’P Few inactive enzymes without P5’P Poorly measured by lab assays
  23. 23. Release of AST/ALT from Liver Cells After Alcohol Exposure A T S ALT Alcohol increases mitochondrial AST on liver cell plasma membrane where it readily enters blood. Thus AST>>ALT in blood.
  24. 24. Patterns: AST versus ALT 1000 Ratio 2.4 Ratio 0.65 Ratio 0.8 650 ASTSerumEnzyme ALTLevel(IU/ml) 200 100 Alcoholic Acute viral Mild chronic hepatitis hepatitis A hepatitis C
  25. 25. Tests of Cholestasis/Reduced Bile FlowEnzymes released as a Accumulation in liver/blood consequence of decreased of substances normally bile flow excreted in bile Alkaline phosphatase Bilirubin or 5’-nucleotidase Bile salts Leucine aminopeptidase γ-glutamyl transpeptidase
  26. 26. Alkaline Phosphatase:Location at Canalicular (Apical) Membrane
  27. 27. Alkaline phosphataseOrigin of enzyme and mechanism of increase in cholestatic liver disease: 1. Apical membrane of hepatocyte and bile duct cells 2. Very sensitive to any changes in bile flow, obstruction of large or small bile ducts. 3. Amplified by bile acid retention 4. Easily released into blood as it is a GPI-anchored protein solubilized from membrane by detergents (bile acids)Easily measured spectrophotometricallyPurpose: ? Detoxifies lipopolysaccharide (LPS) from bacteria
  28. 28. Bile Acids(Bile Salts) such asTaurocholatestimulate productionof alkalinephosphatasemolecules.
  29. 29. Normal (A) and(B) BlebbedHepatocytesBile acid-induced injury
  30. 30. Release of GPI-Anchored Proteins From Liver During Cholestasis GPI-Anchored Proteins Alkaline Phosphatase 5’ Nucleotidase GGTP Hepatocyte Bile canaliculusBlood
  31. 31. Alkaline Phosphatase in Various Liver Diseases 10 50 10 00 Degree of elevation of AP is highly variable depending on duration and extent of cholestasis and other unknown factors. 50 0SerumEnzymeLevel(IU/ml) 20 0 10 0 Long-standing Acute bile Mild early Hepato- bile duct duct partial cellular obstruction obstruction bile duct disease obstruction
  32. 32. Alkaline PhosphataseInterpretation of elevated levels: 1. Cholestasis (especially in extrahepatic obstruction 2. Infiltrative diseases (granulomas) 3. Neoplastic disease infiltrating liverSensitive test as will go up if only some small ducts areobstructed and/or if there is only partial obstruction ofmajor ducts.Disadvantages: Not completely specific because of isoenzymes in other organs (bone, intestine, placenta) Ex: bone disease, intestinal obstruction, pregnancy.
  33. 33. Serum Bilirubin (Bile Acids)Rationale: Liver is virtually the only mechanism for excretion Cholestasis from any cause results in “back-up” of these compounds in bloodInterpretation: Cholestasis: extrahepatic or intrahepaticDisadvantages: Does not distinguish hepatocellular disease, in which hepatocytes don’t make bile, from bile duct obstruction
  34. 34. BilirubinAn organic anionThe byproduct of heme breakdownIn mammals bilirubin must be conjugated to glucuronic acid and excreted in bileBlood levels go up if any steps in production or hepatocyte excretion are altered. However obstruction at the level of bile ducts must be complete or virtually complete for bilirubin levels in blood to change
  35. 35. Hepatic Bilirubin Transport SER UDP-glucuronide RBC + breakdown Unconj BR in RES Conj BR Unconj BR BileUnconj CanaliculusBilirubin Conj BR MRP-2: Multispecific organic anion transporter Conj Conjugated bilirubin BR Glutathione S-conjugates other organic anions ATP Blood Hepatocyte
  36. 36. Hepatic Bilirubin Transport and Mechanisms of Hyperbilirubinemia Gilberts syndrome (mild) Crigler-Najjar syndrome (severe) SERHemolysis Unconj BR BileUnconj CanaliculusBilirubin Conj BR Multispecific organic anion transporter Conj Conjugated bilirubin BR Glutathione S-conjugates other organic anions ATP Blood Hepatocyte Dubin-Johnson syndrome Rotors syndrome ?estrogen/cyclosporin
  37. 37. Mechanism of Hyperbilirubinemia in Liver Disease SER UDP-glucuronide + Unconj BR Conj BR Unconj BRUnconjBilirubin Conj BR Conj BR Albumin Overall Rate-Limiting Step
  38. 38. Interpretation of Elevated Serum BilirubinConjugated hyperbilirubinemia: BR reached liver and was conjugated but not excreted in bile 1. Cholestasis/biliary obstruction (must be essentially complete) 2. Hepatocellular damage (collateral damage to all liver functions) bile formation impaired >> conjugation impaired 3. Rare disorders of canalicular secretion of conjugated bilirubinUnconjugated hyperbilirubinemia: BR didnt reach liver efficiently or wasnt conjugated 1. Massive overproduction - acute hemolysis 2. Impaired conjugation common: Gilberts syndrome (mild) rare: Crigler-Najjar syndrome (severe)
  39. 39. Further: Bilirubin Undergoes Non-Enzymatic Reaction with Albumin Formation of Bilirubin-Albumin Conjugates Bili-albumin conjugate or "delta bilirubin" Blood Alb Hepatocyte B -G R lu Alb ER BR BR Alb BR B -G R lu B -G R lu Bile B -G R lu
  40. 40. Why is Bili-Albumin of Clinical Interest?• Not of interest during liver disease as this form of bilirubin is measured as conjugated bilirubin.• However, after resolution of cholestasis/liver disease, bili-albumin is cleared like albumin – Albumin half-life: several weeks – Conj. bilirubin half-life: hours to days –• Thus resolution of jaundice is often SLOW compared to improvement of other liver functions.
  41. 41. Purpose of Liver Tests1. Screen for clues to the presence of liver injury/disease liver cell injury bile flow/cholestasis2. Quantitate degree of liver function/dysfunction quantitative liver tests3. Diagnose general type of liver disease pattern of liver test abnormalities4. Diagnosis of specific liver disease disease-specific tests such as serology for viral hepatitis
  42. 42. TESTS OF LIVER FUNCTION Blood LevelProduction Albumin Clotting factors Blood Level Elimination Bilirubin Bile Acids Metabolism C-Aminopyrine 14 Metabolites CO2 14
  43. 43. Albumin• Rationale – Liver is the sole source• Interpretation of Decreased Level – Decreased liver production – Increased renal/GI loss (nephrotic syndrome; protein losing enteropathy in inflammatory bowel disease – Protein malnutrition• Disadvantages – Prolonged half-life – No unique interpretation
  44. 44. Prothrombin Time• Rationale – Liver is sole source of vitamin K-dependent clotting factors, including those critical for PT – Factor VII has very short half-life (hours)• Interpretation of Increased PT – Hepatocyte protein synthesis impaired – Vitamin K deficiency/Coumadin therapy – Disseminated intravascular coagulopathy• Advantages – Rapidly reflects changes in liver function
  45. 45. Interpretation of Abnormal Albumin/Prothrombin TimeLiver markedly diseased - reserve function goneAlbumin: monitors slow changes in liver function (months to years) reflects long-term liver dysfunctionProtime: monitors rapid changes in liver function (hours to days/weeks) reflects either short or long-term liver dysfunction
  46. 46. Other Clues to Globally Impaired Liver FunctionBilirubin: goes up with any disease that globally impairs liver function (OR blocks bile flow)Glucose: hypoglycemia (late finding; indicates very poor liver function)BUN: low BUN is a late and poorly specific finding in liver dysfunction due to poor urea synthesis
  47. 47. Purpose of Liver Tests1. Screen for clues to the presence of liver injury/disease liver cell injury bile flow/cholestasis2. Quantitate degree of liver function/dysfunction quantitative liver tests3. Diagnose general type of liver disease pattern of liver test abnormalities4. Diagnosis of specific liver disease disease-specific tests such as serology for viral hepatitis
  48. 48. Interpretation of Liver TestsA. Consider nonhepatic causes of abnormal liver testsB. Examine the pattern of liver test abnormalities to categorize liver disease: 1. cholestatic versus hepatocellular 2. acute versus chronic 3. decompensated versus mild functional function impairment
  49. 49. Patterns of Abnormal Liver Tests Hepatocellular CholestasisMajor: AST/ALT Alkaline PhosphataseMinor: Bilirubin Bilirubin PT/albumin AST/ALT PT (Vit K deficiency)
  50. 50. Patterns: Acute Liver Disease 20 Hepatocellular disease Cholestatic diseaseFoldIncrease 10 2 1 AST or ALT Alkaline Bilirubin PT Phosphatase
  51. 51. Clues to Acute vs Chronic Liver DiseaseAbnormalities of PT versus albuminKnown duration of abnormal liver testsHistory of exposure to potential causative agentsClinical signs of consequences of long-standing liver diseaseTempo of subsequent changes in AST/ALT, bilirubin, PT chronic tends to change slowly acute tends to change quickly
  52. 52. 20 Patterns: Chronic Liver Disease with Impaired Liver FunctionFoldIncrease 10 2 1 Albumin AST or ALT Alkaline Bilirubin PT Phosphatase -2
  53. 53. Clues to Severity of Liver Dysfunction Prothrombin time Albumin (Bilirubin, glucose) (Clinical signs of consequences of severe liver dysfunction such as hepatic encephalopathy)
  54. 54. Clues to severityof liver damageand, potentially, toseverity of liverdysfunction maycome from thetemporal sequenceof changes inreadily available livertests.For example, rapidfall in AST/ALTin severe hepatitismay not be a goodsign.
  55. 55. Purpose of Liver Tests1. Screen for clues to the presence of liver injury/disease liver cell injury bile flow/cholestasis2. Quantitate degree of liver function/dysfunction quantitative liver tests3. Diagnose general type of liver disease pattern of liver test abnormalities4. Diagnosis of specific liver disease disease-specific tests such as serology for viral hepatitis These are discussed in future lectures
  56. 56. Summary• Use biochemical tests to assess – Presence of liver disease – General type of liver disease – Sense of severity of liver dysfunction – Sense of acute versus chronic disease• Use liver tests with other data to work through differential diagnosis – See algorithms in syllabus and textbook
  57. 57. Approach to the Patient with Jaundice (Bilirubin) History, PE Lab tests: AP, AST/ALT, Alb. PT Normal liver tests Abnormal findings suggesting liver disease Suspect intrahepatic Suspect extrahepatic Fractionate bilirubin cholestasis or cholestasis hepatocellular disease Noninvasive imaging of the Unconjugated biliary tree: ultrasound or CT hyperbilirubinemia Specific diagnostic tests (may go to direct duct hepatitis screen visualization in some cases) AMA, ANA, SMA Ceruloplasmin Hemolysis Fe/TIBC, ferritin Gilbert’s syndrome Normal Normal ducts, Dilated Stop drugs Crigler-Najjar syndrome ducts still suspect ducts Consider liver biopsy extrahepatic Consider CT to r/o structural cholestasis disease Medical management/Conjugated observation Relief of biliaryhyperbilirubinemia Direct duct obstruction: visualization surgical (ERCP or PTC) endoscopic percutaneous Dubin-Johnson syndrome Rotor syndrome No obstruction visualized Obstruction visualized
  58. 58. Approa ch to Pa tie nt with Incre a se d Alka line Phospha tase Alkaline phosphatase (AP) Exclude pregnancy, physiologic causes Obtain additional biochemical markers of cholestasis (GGTP, 5-NT, or AP isoenzymes, serum bilirubin) Nonhepatic cause of AP Hepatic cause of AP Consider: bone disease (eg, Pagets disease, Large (> 3-fold) Modest (< 3-fold) hyperparathyroidism, bone elevation of AP elevation of AP metastasis) ectopic AP secretion Consider: hepatocellular injury Abdominal ultrasound or CT scan (eg, viral and alcoholic hepatitis) Dilated ducts Non-dilated ducts Consider: choledocholithiasis, Normal or diffusely Focal hepatic defects abnormal liver cancer of the pancreas, cholangiocarcinoma, biliary stricture, pancreatitis Consider: primary or Liver biopsy and metastatic cancer of the consider: primary liver, pyogenic/amebic biliary cirrhosis, abscess granulomasModified from: Kelley Textbook of Internal Medicine, 3rd edition, 1997, pp 663.
  59. 59. A variety of cases are provided in yoursyllabus to allow practice in analyzingliver tests.