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Malik alqub MD. Phd.

Malik alqub MD. Phd. LIVER FUNCTION TEST. Liver. Largest solid organ, right upper quadrant (RUQ). Large reserve capacity Capable of regeneration Function: Metabolism: fat, CHO, protein, drugs, hormones Filtration: bacteria, endotoxins, viruses,

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Malik alqub MD. Phd.

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  1. Malik alqub MD. Phd. LIVER FUNCTION TEST

  2. Liver • Largest solid organ, right upper quadrant (RUQ). • Large reserve capacity • Capable of regeneration • Function: Metabolism: fat, CHO, protein, drugs, hormones • Filtration: bacteria, endotoxins, viruses, antigens, byproducts of coagulation • Storage: fluids, vitamins, minerals

  3. The normal liver

  4. The normal liver

  5. The normal liver Central vein Hepatic artery Portal vein

  6. Liver dysfunction diagnosis • The diagnosis of liver disease depends on a combination of patient history, physical examination, laboratory testing, biopsy and sometimes imaging studies such as ultrasound scans.

  7. Liver Function Tests • A misnomer • elevated aminotransferases/alkaline phosphatase are only markers of liver injury, not liver dysfunction • Albumin/Bili/PT can be affected by extrahepatic factors • nutritional state • hemolysis • antibiotic use • Poor sensitivity and specificity for liver disease

  8. “True liver tests” • Galactose clearance • Caffeine Clearance • LidocaineMetabolite Formation • IndocyanineGreen

  9. History • Systemic symptoms • Family Hx • Hemochromatosis, Wilson’s Disease, alpha1 antitrypsin deficiency • Gilbert’s syndrome, Dubin-Johnson Syndrome, Rotor’s syndrome • Sexual History • Tattoos • Travel history

  10. History • Occupational exposures • Chemicals (vinyl choloride, dimethylformamide, 2-Nitropropane, Trichloroethylene) • Other co-morbid illnesses • Autoimmune diseases, IBD, Diabetes Mellitus • Medications • Prescription • Herbals, Vitamins

  11. Medications causing elevation of aminotransferases • Acetaminophen • Amoxicillin-clavulanic acid • HMGCoAreductaseinhbtrs • NSAIDS • Phenytoin • Valproate

  12. General categories of tests • variety of tasks, • no single test • not very sensitive (cirrhosis) • or specific (non-hepatic factors)

  13. Three categories • Markers of Liver Injury/Necrosis • Markers of Cholestatic Liver Disease • Markers of Liver Function

  14. Three categories • Markers of Liver Injury/Necrosis • Markers of Cholestatic Liver Disease • Markers of Liver Function

  15. Common serum liver chemistry tests

  16. Normal values

  17. ALT (SGPT) and AST (SGOT) levels • AST and ALT are markers of hepatocellular injury • Participate in gluconeogenesis, transfer of amino groups from aspartate or alanine to ketoglutaric acid to form oxaloacetete or pyruvate. • AST present in cytosol and mitochondria in liver, cardiac muscle, skeletal muscle, kidney, brain, pancreas, lungs, WBC and RBC. • ALT a cytosolic enzyme, highest concentration in the liver • ALT considered a “liver specific” enzyme

  18. Isolated elevated AST • If ALT normal, then reflective of cardiac or muscle disease. • Marco-AST • Rare • AST complexed with an immunoglobulin and is not cleared from the blood • Does not indicate serious liver disease • Drugs • Acetominophen, NSAIDs, ACE-I, Niacin, Erythromycin, Fluconazole

  19. Useful paradigm to categorize increased levels of AST, ALT • Mild AST, ALT elevation (less than 5 times ULN) - ALT predominant or AST predominant • AST, ALT greater than 15 times normal AGA Technical review, Gastroenterology 2002

  20. Three categories • Markers of Liver Injury/Necrosis • Markers of Cholestatic Liver Disease • Markers of Liver Function

  21. Alkaline phosphatase • Present in nearly all tissues - isoenzymes • Localised in the microvilli of the bile canalicus in the liver • Also present in bone, intestine, placenta, kidney and wbc • Elevation may be physiological or pathological • Normal adult serum AP is from liver and bone • Intestine contributes about 15%

  22. Alkaline Phosphatase • Catalyze the hydrolysis of a large number of organic phosphate esters, optimally at an alkaline pH. • Liver - synthesized in the bile duct epithelial cells • Bone - osteoblastic activity • Kidneys • Intestine • Placenta- levels may double late in pregnancy

  23. Elevation of s. alkaline phosphatase • Isolated • Associated with hyperbilirubinemia (cholestatic disorders) • May be sole abnormality in many cholestatic or infiltrative diseases • To be interpreted in the clinical setting of history and physical examination if sole abnormality

  24. GGT • Catalyzes the transfer of the γ-glutamyl group from γ-glutamyl peptides (glutathione) to other peptides and L-amino acids. • Elevated in liver, biliary, or pancreatic disease. • Very sensitive for detecting hepatobiliary disease, but poor specificity • Used primarily to confirm hepatic origin of elevated ALP

  25. Three categories • Markers of Liver Injury/Necrosis • Markers of Cholestatic Liver Disease • Markers of Liver Function • Bilirubin • Albumin • PT

  26. Three categories • Markers of Liver Injury/Necrosis • Markers of Cholestatic Liver Disease • Markers of Liver Function • Bilirubin • Albumin • PT

  27. Bilirubin • Product of hemoglobin breakdown • 2 Forms • Unconjugated (indirect)- insoluble • ↑ in hemolysis, Gilbert syndrome, meds • Conjugated (direct)- soluble • ↑ in obstruction, cholestasis, cirrhosis, hepatitis, primary biliary cirrhosis, etc. • No elevation until loss of > 50% capacity

  28. Unconjugated Hyperbilirubinemia • >80% of total bilirubin is indirect • Liver function is otherwise normal • Increased bilirubin production • hemolysis - T.B. seldom > 5 mg/dL • ineffective erythropoeisis • blood transfusion • resorption of hematomas

  29. Unconjugated Hyperbilirubinemia • Decreased hepatocellular uptake • drugs (e.g., rifampin) • Gilbert's syndrome? • Decreased conjugation • Gilbert's syndrome • Crigler-Najjar syndrome • Physiologic jaundice of the newborn

  30. Conjugated Hyperbilirubinemia • Hepatocellular dysfunction • Biliary obstruction • + Urobilinogen • unconjugatedbilirubin is tightly bound to albumin and not excreted renally • marker of hepatobiliary disease

  31. Three categories • Markers of Liver Injury/Necrosis • Markers of Cholestatic Liver Disease • Markers of Liver Function • Bilirubin • Albumin • PT

  32. Albumin • Synthesized exclusively by the liver • 20 day half life - levels usually preserved acutely • Synthesis regulated by nutritional states, osmotic pressure, systemic inflammation, and hormones • Hypoalbuminemia most common in patients with chronic liver disorders (ie cirrhosis) due to decreased synthesis • Not specific for liver disease

  33. Three categories • Markers of Liver Injury/Necrosis • Markers of Cholestatic Liver Disease • Markers of Liver Function • Bilirubin • Albumin • PT

  34. Prothrombin Time • Factor 1 - fibrinogen • Factor II- prothrombin • Factor V - proaccelerin; labile factor • Factor VII - stable factor • Factor IX - Christmas factor • Factor X - Stuart Prower factor • Factor XII and XIII - prekallikrein and high molecular weight kinogen

  35. Prothrombin Time • Parenchymal liver disease • Poor utilization of vitamin K • Hypovitaminosis K • Prolonged obstructive Jaundice • Steatorrhea • Dietary Deficiency • Antibiotics (alter gut flora) • Differentiate by giving IV Vitamin K • normalization or 30% improvement within 24 hrs surmises good parenchymal function

  36. Platelets • Thrombocytopenia seen in liver is thought to be due to congestive splenomegaly • Mechanism is platelet sequestration • Correlation shown between spleen size and thrombocytopenia • Platelet count rarely less than 50K • Bleeding associated with it uncommon • Congestive splenomegaly does not induce a significant hemostaticdefect

  37. Malik alqub MD. Phd. Jaundice

  38. Bilirubin Metabolism • Pre-hepatic • Hepatic • Post-hepatic

  39. Bilirubin Metabolism: Pre-Hepatic • Bilirubin is formed in macrophages of the reticuloendothelial system. The initial substrate is predominantly hemaglobin. • Heme group biliverdin bilirubin • Bilirubin is insoluble in water and so must be carried by albumin within plasma. • Bilirubin circulates in the blood before uptake by the liver. • Pre-hepatic jaundice = if bilirubin is not taken up by the liver or if it is produced in excess, unconjugated bilirubin is deposited in extra-hepatic tissues.

  40. Bilirubin Metabolism: Hepatic • Bilirubin is taken up into hepatocytes and bound to intracellular proteins. • Bilirubin + UDP glucuronic acid = bilirubin diglucuronide > bilirubin monoglucuronide > UDP • The glucuronide conjugated form of bilirubin is water soluble and is excreted into bile. Excretion occurs into the bile canaliculus by carrier-mediated transport. • Hepatic jaundice = disorders of bilirubin uptake or conjugation

  41. Bilirubin Metabolism: Post-Hepatic • Glucuronide-conjugated bilirubin in bile may be degraded to urobilinogen or partially reabsorbed into plasma. • Urobilinogen pathway: • may be reabsorbed by the gut and returned to the liver • converted to urobilin • reabsorbed into plasma for excretion by kidneys • Conjugated bilirubin pathway: • May be acted upon by bacterial enzymes within the gut to form the bile pigment stercobilinogen. Stercobilinogen may be reabsorbed into plasma for recycling to the liver or for excretion by the kidney, or, it may be oxidized to stercobilin. • Obstructive jaundice = failure of bilirubin to reach the gut, resulting in a reduction in pigment within the stool

  42. DDX: Unconjugated Hyperbilirubinemia • Increased Bilirubin Production • Extravascularhemolysis • Extravasation of blood into tissues • Intravascular hemolysis • Errors in production of red blood cells • Impaired Hepatic Bilirubin Uptake • CHF • Portosystemic shunts • Drug inhibition: rifampin, probenecid • Impaired Bilirubin Conjugation • Gilbert’s disease • Crigler-Najarr syndrome • Neonatal jaundice (this is physiologic) • Hyperthyroidism • Estrogens • Liver diseases (chronic hepatitis, cirrhosis, Wilson’s)

  43. DDX: Conjugated Hyperbilirubinemia • Intrahepatic Cholestasis (impaired excretion) • Hepatitis (viral, alcoholic, and non-alcoholic) • Primary biliary cirrhosis or end-stage liver dz • Sepsis and hypoperfusion states • Pregnancy • Infiltrative disease: TB, amyloid, sarcoid, lymphoma • Drugs/toxins i.e. chlorpromazine, arsenic • Post-op patient or post-organ transplantation • Hepatic crisis in sickle cell disease

  44. Evaluation: History • Fever/chills, RUQ pain (cholangitis) • Hepatitis risk factors • Exposure to toxic substances • Inherited disorders including liver diseases and hemolytic conditions • H/O blood transfusion • TPN use • H/O abdominal surgery • HIV status • Travel history • Use of drugs or herbal medications • Use of alcohol

  45. Evaluation: PE • Signs of end stage liver disease (cirrhosis): ascites, splenomegaly, spider angiomata, and gynecomastia • Look for jaundice: under tongue, conjunctiva, skin • Hyperpigmentation (hemochromatosis) • Kayser-Fleischer ring (Wilson’s disease) • Xanthomas (primary biliary cirrhosis) • Courvoisier’s sign = painless, palpable/distended gallbladder on exam (think of CA)

  46. Evaluation: Labs • Normal LFTs r/o hepatic injury or biliary tract disease • Consider inherited disorders or hemolysis • Greater increase in Alk Phos than AST/ALT implies “cholestasis” (intrahepatic vs. obstruction) • ↑Alk Phos also seen in sarcoid, TB, bone • In this case, GGT is specific for biliary origin • Predominant increase in AST/ALT implies intrinsic hepatocellular disease • AST/ALT ratio > 2 in alcoholic hepatitis • ↓albumin or ↑PT advanced liver disease

  47. THE NORMAL LIVER OFFERS ALMOST NO RESISTANCE TO FLOW Normal Liver Hepatic vein Sinusoid Liver Coronary vein Portal vein Splenic vein

  48. ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE Cirrhotic Liver Portal systemic collaterals Distorted sinusoidal architecture leads to increased resistance Portal vein Splenomegaly

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