LijzjjzjmsvvBshsjsjhdhdkdkdnhdver-functionhsjjsnsnsndudhhd-test-17-06-2023.pptx

Liver

1. Function of liver Metabolic function Liver is the central organ for metabolism of carbohydrate, protein & lipid. Through its glucostatic function, liver regulates of blood glucose concentration Integration of metabolism among tissues in well fed, fasting & starvation.

2. Synthetic function Liver is the site for synthesis of: plasma protein except gamma globulin. Clotting factors Complement factors primary bile acids Haptoglobulin Ceruloplasmin Transferin etc Function of liver

3. Secretory function Liver secrets bile into the intestine Excretory function Through biliary tract & fecal route liver excretes: - Bile pigment - Bile salts - Drugs - Steroids, cholesterol - Heavy metals Function of liver

4. Function of liver Storage function Liver store: - Glycogen - Fat soluble vitamins - Vitamin B 12 - Folic acid - Iron - Copper Detoxification function Metabolism of drugs & toxins

5. Liver function test Indications of liver function test Differential diagnosis of jaundice & diagnosis of liver disease. Assessment of the severity of liver disease. Assessment of prognosis of liver disease. Treatment monitoring & detection of complication

6. Categories of liver function test 1.Test for hepatocellular damage: It is done by measurement of serum - ALT ( Alanin aminotransferase ) - AST ( Aspartate aminotransferase ) - γ - Gt (gamma glutamyl transferase ) - These enzymes are present within hepatocytes . - Their plasma concentration ten times normal are highly specific for liver damage.

7. 2.Test for cholestasis ( biliary tract obstruction): It is done by measurement of serum. - ALP ( alkaline phosphatase ) - γ - Gt (gamma glutamyl transferase ) - 5ˊNT (5ˊ- nucleotidase ) - ALP is the most important indicator of Cholestasis . - Isolated increase in γ - Gt (other enzymes normal) indicate alcoholic hepatitis.

8. 3.Test for synthetic function It is done by measurement of Serum total protein concentration Serum albumin concentration Serum albumin to globulin ratio Prothrombin time - Albumin synthesized in liver. - Globulin ( especially gamma globulin) synthesized in plasma cells. - In hepatic dysfunction : Albumin to globulin ratio: Decreased or even reversed

9. 4. Test for excretory & conjugating function It is done by the measurement of serum bilirubin concentration. - Bilirubin is produced in reticuloendothelial cells. - Transported in blood along with albumin. - Hepatocytes take up bilirubin from blood Conjugate it within the cells & then excrete in bile 5. Test for metabolic function of liver It is done by galactose tolerance test

10. LFT commonly done in the laboratory 1. Estimation of serum bilirubin - direct (conjugated) & indirect ( unjugated ) 2. Estimation of Transaminases - Serum ALT & AST 3. Estimation of serum Alkaline phosphatase (ALP) 4. Estimation of serum GGT 5. Estimation of serum Albumin,Globulin , A/G ratio

11. BILIRUBIN METABOLISM Bilirubin is the catabolic end products of porphyrin component of heme . Heme containing substances are: Hemoglobin ( Hb ) Myoglobin Cytochromes Peroxidase & catalase It is estimated that about 80% of the heme that is subjected for degradation comes from the erythrocytes & the rest 20% comes from immature RBC, myoglobin & cytochrome .

12. 1. Production of bilirubin It occur primarily in reticuloendothelial cells of liver & spleen. Presentation of hemoglobin to reticuloendothelial cells ( RE cells). - Old, degenerated damaged RBC is engulfed by RE cells. - Then Hb is released within RE cells. Steps of bilirubin metabolism

13. Presentation of heme to reticuloendothelial cells ( RE cells ) - From Hb , globin part is separated to release the heme in RE cells. - Globin is catabolized to amino acids which join the body amino acid pool.

14. Synthesis of biliverdin from heme in RE cells. - From heme , iron is separated with release of porphyrin . - Porphyrin in oxidized by heme oxygenenase to biliverdin ( a green pigment). - Iron is subsequently reutilized.

15. Synthesis & release of bilirubin in RE cells. - Biliverdin is reduced to orange red bilirubin by biliverdin reductase . - Then it is released to blood from RE cells. - One gram of hemoglobin on degradation finally yields about 35 mg bilirubin .

16. 2.Transport of bilirubin in blood bound with albumin. Bilirubin produced & relesed from RE cells is water insoluble but soluble in lipid. It is transported in the plasma in a bound form to albumin. It is known by prehepatic / unconjugated / indirect bilirubin .

17. 3. Hepatic metaboilsm of bilirubin ( events in hepatocytes ) Hepatic uptake of bilirubin Bilirubin dissociates from the carrier albumin molecule, enters a hepatocyte via facilitated diffusion, and binds to intracellular proteins, particularly the protein ligandin .

18. Conjugation of bilirubin within hepatocytes - In smooth endoplasmic reticulum, bilirubin is conjugated with glucoronic acid by glucoronyl transferase (GT) enzyme to form bilirubin monoglucoronide & bilirubin diglucoronide . - Conjugated ( posthepatic /direct ) bilirubin produced by this process is water soluble

19. Excretion of conjugated bilirubin to bile Conjugated bilirubin is actively excreted from hepatocytes to bile & via bile goes to small intestine. Very small amount of conjugated bilirubin escapes biliary excretion & goes to portal blood. From blood conjugated bilirubin again reuptake into hepatocytes .

20. 4. Intestinal metabolism of bilirubin ( events in intestinal lumen) In the intestine, glucoronic acid is removed by bacteria ( glucoronidase ). The resulting bilirubin is converted to urobilinogen . Some of the urobilinogen is reabsorbed from the gut & enters the portal blood.

21. A portion of this urobilinogen participates in the enterohepatic urobilinogen cycle in which it is taken up by the liver, and then resecreted into the bile.

22. The remainder of the urobilinogen is transported by the blood to the kidney, where it is converted to yellow urobilin & excreted, giving urine its characteristic color.

23. Most of the urobilinogen is oxidized by intestinal bacteria to stercobilin , which gives feces the characteristic brown color.

24. Jaundice Definition: Jaundice is a clinical condition characterized by yellow colouration of the sclerae and skin caused by the deposition of bilirubin due to its elevated level in serum

25. Normal level in serum : Total bilirubin : 0.2 – 1.0 mg/dl Conjugated (direct) : 0.2 – 0.4 mg/dl Unconjugated (indirect) : 0.2 – 0.6 mg/dl Latent Jaundice : 1.0 – 2.9 mg/dl Clinical Jaundice : ≥ 3.0 mg/dl Classification of jaundice: 1. Hemolytic jaundice ( prehepatic jaundice) 2. Hepatocellur jaundice (hepatic jaundice) 3. Obstructive jaundice ( posthepatic jaundice)

26. Hemolytic jaundice Hyperbilirubinemia is due to excess production of bilirubin more than hepatic capacity to conjugate & excrete. There is more bilirubin excretion in bile with increased urobilinogen & stercobilinogen formation. The amount of urobilinogen entering the enterohepatic circulation is increased with increased urinary excretion of urobilinogen .

27. Common causes are: - Hemolysis - Ineffective erythropoiesis Cardinal features of hemolytic jaundice: - Unconjugated hyperbilirubinemia with normal liver function test - Serum bilirubin usually < 5mg/dl

28. Hepatocellular jaundice Here hyperbilirubinemia is due to hepatic failure to conjugate and/or excrete the normal load of bilirubin as a consequence of hepatic parenchymal disease. Hepatocellular jaudice is usually associated with intrahepatic biliary obstruction. - Leading to ↓ urobilinogen production, ↓ enterohepatic circulation of urobilinogen , ↓ urinary excretion of urobilinogen .

29. Common causes are: - Viral hepatitis, toxic hepatitis - Autoimmune assult on hepatocytes - Metastatic liver disease, hepatocellular carcinoma - Wilson’s disease & hemochromatosis Cardinal features of hepatocellular jaundice: Dark urine (due to bilirubinuria ) Very high serum ALT & AST Small rise of ALP

30. Obstructive jaundice Here hyperbilirubinemia is due to: regurgitation of conjugated bilirubin into the blood as a result of its failure to be excreted into the intestine because of the intrahepatic or extrahepatic biliary flow obstruction In obstructive jaundice, there is reduced entry of bilirubin in intestine leading to ↓ urobilinogen production, ↓ enterohepatic circulation of urobilinogen , ↓ urinary excretion of urobilinogen .

31. Common causes are: - carcinoma of the head of the pancreas - Cholangiocarcinoma - Cholelithiasis - Liver metastasis - Viral hepatitis - Cholangitis - Parasitic infection - Traumatic biliary stricture Cardinal features: - Dark urine - Pale stool - Very high serum ALP & γ -GT - Small/modest rise of ALT & AST

32. Biochemical findings in jaundice Parameter Normal Hemolytic Jaundice Hepatic Jaundice Obstructive Jaundice S. Bilirubin 0.2-1.0 mg/dl ↑ (rarely˃5mg%) ↑↑ (rarely˃20mg%) ↑↑↑ (maybe˃30mg%) Type of Bilirubin increased Unconjugated Both Conjugated Urinary Urobilinogen < 4 mg/dl ↑ Normal or ↑ or ↓ ↓ (Nil if complete obstruction) Urinary bilirubin Nil Nil Present Present

33. Biochemical findings in jaundice Fecal stercobilinogen 250 – 300 mg/day ↑ ↓ ↓ ( nill if complete obstruction) Bile salt Nill Nill Present Present Serum ALP 40 -125 U/L Normal ↑ ↑↑↑ Serum ALT 10 – 40 U/L Normal ↑↑↑ ↑ Serum AST 10 – 40 U/L ↑↑↑ ↑↑ ↑

34. Neonatal physiological jaundice Definition : It is the physiological jaundice that happens to occur in most of the new born babies shortly after birth. Characteristics: - Mild jaundice ( serum bilirubin rarely exceeds 5 mg%) - Predominantly unconjugated hyperbilirubinemia . -Jaundice never present at birth. It appears after birth & does not persists beyond 14 days.

35. It can be exacerbated by -Dehydration -Hypoxia -Birth trauma -Prematurity Causes: 1. Hepatic immaturity to metabolize bilirubin . 2. Increased hemolysis . 3. Increased enterohepatic circulation of unconjugated bilirubin .

36. Risk of neonatal jaundice If concentration of unconjugated bilirubin > 20 mg%, there is risk of kernicterus . The unconjugated hyperbilirubinemia of neonatal physiologic jaundice results from accelerated hemolysis & an immature hepatic system for the uptake, conjugation & secretion of bilirubin .

37. It is the clinical condition characterized by the deposition of unconjugated bilirubin in basal ganglia. Kernicterus

38. Pathophysiology : In adult individual neither conjugated nor unconjugated bilirubin from blood can deposit in brain because they can not cross the mature blood brain barrier(BBB), but they can be deposited in other tissue.

39. In infants & neonates, the immaturity of BBB allows the bilirubin to cross the barrier easily. Free (Not albumin bound) unconjugated bilirubin after crossing the BBB easily penetrates the lipid rich basal ganglia because of its lipid solubility & deposited there. This deposition is accelerated in unconjugated hyperbilirubinemia .

40. Causes of Kernicterus : High plasma concentration of unconjugated bilirubin beyond its normal albumin binding capacity (20 - 25 mg/dl). Hypoalbuminemia . Displacement of unconjugated bilirubin . Increased permeability of BBB: -In hypoxia -In septicemia -In acidosis