Ramzi Shawahna

1. RamziShawahna LIVER FUNCTION TEST

2. Liver Liver: • Is the largest solid organ • Has large reserve capacity • Is capable of regeneration Function: • Metabolism: fat, protein, drugs, hormones • Filtration: bacteria, endotoxins, viruses, antigens, byproducts of coagulation • Storage: fluids, vitamins, minerals

4. 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.

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

6. History • Systemic symptoms • Family Hx • Hemochromatosis, Wilson’s Disease, alpha1 antitrypsin deficiency • Gilbert’s syndrome, Dubin-Johnson Syndrome, Rotor’s syndrome • Alcoholism • Drug abuse

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

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

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

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

11. Common serum liver chemistry tests

12. Normal values

13. 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

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

17. 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 WBCs • Elevation may be physiological or pathological • Normal adult serum AP is from liver and bone • Intestine contributes about 15%

18. 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

19. Elevation of serum 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

20. 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

21. 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

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

27. 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

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

29. 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

30. 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

31. 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

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

33. 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.

34. 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

35. 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

36. UnconjugatedHyperbilirubinemia • 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)

37. Conjugated Hyperbilirubinemia • IntrahepaticCholestasis (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