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Functions of the liver Hormonal metabolism

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1 Functions of the liver Hormonal metabolism
Carbohydrate metabolism Gluconeogenesis Glycogen synthesis and breakdown Fat metabolism Fatty acid synthesis Cholesterol synthesis and excretion lipoprotein synthesis Ketogensis bile acid synthesis 25-hydroxylation of vitamin D Protein metabolism synthesis of plasma proteins Some coagulation factor Urea synthesis Hormonal metabolism Meabolism and excretion of steroid hormones metabolism of polypeptide hormones Drugs and foreign compounds metabolism and excretion Storage Glycogen, Vitamin A , B12 , iron Metabolism and excretion of bilirubin Dr/ Ragaa Salama

2 Functions of the Liver & Liver Function Tests
Classified into : 1-Metabolic 2-hematological function 3-Excretory function measure bilirubin 4-storage 5-serum enzymes derived from liver AST, ALT, ALP. GGT, 5’ nucleotidase. 6- Synthetic function Serum protein , albumen, prothrombin time 7-detoxification and phagocytosis. Dr/ Ragaa Salama

3 Liver Function Tests biochemical investigation to detect the abnormalities and the extent of liver damage Alanine aminotransferase(ALT) or SGPT Aspatate aminotransferase (AST) or SGOT Total protein albumin / globulin ratio ( A / G ratio) Alkaline phosphatase Bilirubin 5'Nuclotidase Gamma Glutamyl transferase ( GGT). Alpha fetoprotein (AFP). Lactate dehdrogenase (LDH). Ammonia Prothormbin time Dr/ Ragaa Salama

4 Liver Function Tests Liver chemistry test
Clinical implication of abnormality ALT Hepatocellular damage AST Bilirubin Cholestasis, impair conjugation, or biliary obstruction ALP Cholestasis, infiltrative disease, or biliary obstruction PT Synthetic function Albumin GGT Cholestasis or biliary obstruction Bile acids 5`-nucleotidase LDH Hepatocellular damage, not specific no single test provide accurate global assessment of hepatic function Dr/ Ragaa Salama

5 Principle: transamination reaction
Dr/ Ragaa Salama

6 Alanine aminotransferase(ALT ) Aspatate aminotransferase (AST)
Enzymes reflect hepatocellular damage. Transfer of amino groups from aspartate or alanine to α- Ketoglutarate leading to formation of oxaloacetate and pyruvate. ALT is found mainly in liver cells, more specific to liver It is sensitive index of acute hepatocellular injury Causes of increased level: 1- hepatitis cirrhosis obstructive jaundice AST is found mainly in cardiac, hepatic, muscle and kidney. AST  following myocardial infarction ,a peak h after infarction Dr/ Ragaa Salama

7 Estimation of Alanine aminotransferase (ALT ) (SGPT)
Principle: the rate of decrease in the absorbance is proportional to ALT activity ALT α- Ketoglutarate + alanine glutamate + pyurvate LDH Pyurvate + NADH+H lactate + NAD+ + H2o Procedure: Test Reconstituted reagent 3ml Pre-warmed at 37 ºC then added : Sample 0.2 ml (200 µl) Mix and incubate at 37ºC for 1 min. Read the absorbance A1 at 340nm against d H2O . Re-incubate at 37ºC and after exactly 3 min read the absorbance (A2 ) . Calculation: ( A1 ــــ A2 ) x 857 U/L Normal value of ALT = 5-40 U/L Dr/ Ragaa Salama

8 Estimation of Aspartate aminotransferase (AST ) (SOPT)
Principle: the rate of decrease in the absorbance is proportional to AST activity AST α- Ketoglutarate + aspartate glutamate + oxaloacetate MDH oxaloacetate + NADH.H L-Malate + NAD+ + H2o Procedure: Test Reconstituted reagent 3ml Pre-warmed at 37 ºC then added : Sample 0.2 ml (200 µl) Mix and incubate at 37ºC for 1 min. Read the absorbance A1 at 340nm against d H2O . Re-incubate at 37ºC and after exactly 5 min read the absorbance (A2 ) . Calculation: ( A1 ــــ A2 ) x 514 U/L Normal value of AST = IU/L Dr/ Ragaa Salama

9 Bilirubin Produced by catabolism of old RBCs and other hemoproteins ( cytochrom oxidase, P-450). Normal level ( total) is ≤ 1 mg/dl (17.1 µmol /L) direct ≤ 0.2 mg/dl Hyperbilirubinemia :bilirubin in the blood 1.0 mg/dL. Genral Causes of Hyperbilirubinemia : 1-    production of bilirubin more than liver capacity, 2-liver cell damage failure of liver to excrete it in bile 4- obstruction of bile pathways. At bilirubin blood level of mg/dL, bilirubin diffuses to tissues (e.g., skin, mucous membranes and sclera of the eyes) and stains them yellow, a condition called jaundice or icterus. Kernicterus: high level of unconjugated bilirubin can pass immature blood brain barrier causing a necrotic syndrome that occurs from bilirubin neurotoxicity usually in low birth weight infant. Dr/ Ragaa Salama

10 Bilirubin Metabolism stercobilnogen in stool Dr/ Ragaa Salama

11 Normal serum gives a negative Van den Bergh reaction . Principle
This is specific reaction to identify the increase in serum bilirubin level . Normal serum gives a negative Van den Bergh reaction . Principle Van den Bergh reaction is a mixture of sulfanilic acid and sodium nitrate sulfanilic acid + sodium nitrate → Diazotized sulfanilic acid Diazotized sulfanilic acid + bilirubin → Azobilirubin ( purple color). Dr/ Ragaa Salama

12 Procedure : pipette in a clean dry test tubes:
Blank Test sulfanilic acid 3ml sodium nitrate - 0.05 ml d H2O Mix and wait for 1min Serum sample 0.2ml (200 µl) After 1 min read the absorbance of test and blank at 540nm against d H2O ( direct biliurbin) then add Methanol Mix by inversion and wait for 5 min read the absorbance of test and blank at 540nm against d H2O ( total biliurbin) Standard: Pour Bilirubin Equivalent Standard (2.5 mg/dl then 5 mg/dl )into a clean vial, read and record its absorbance against d H2O at 450 nm Calculation: direct biliurbin= A (test)- A(blank) x 2.5 mg/dl A (standard) Total bilirubin= A (test)- A(blank) x 5 mg/dl Indirect bilirubin=total - direct Dr/ Ragaa Salama

13 Comparison between 3 types of jaundice
Hemolytic J aundice Obstructive J aundice Hepatic Bilirubin Unconjugated  Conjugated  Both  VonDenBerg Indirect + Direct + Biphasic Serum enzymes ALT,AST,ALP normal ALP   ALT,AST  ALT,AST   ALP  In urine Not excreted excreted urobilinogen Excreted  Normal or ↓ Dr/ Ragaa Salama

14 Types of Hyperbilirubinemias (Jaundice)
I- Uncojugated hyperbilirubinemia: causes: Hemolytic diseases: Hemolytic anemia , Rh incompatability, G6PD. the unconjugated hyperbilirubinemia is mild because of the ability of adult liver to get rid of bilirubin. Neonatal (Physiological) jaundice: ↑hemolysis due to immature hepatic system. Treated by phenobarbital and blue light phototherapy → bilirubin excretede in bile without conjugation. Crigler-Najjar syndrome type I and II: It is an autosomal recessive absence or deficiency of UDP-glucuronyltransferase in the liver. Treated by phenobarbital and blue light phototherapy may be fatal by age 15 months. Gilbert syndrome: harmless mild hyperbilirubinemia due ↓ UDP-glucuronyltransferase. Toxic hyperbilirubinemia: liver cell damage by CCl4, cirrhosis, viral hepatitis and chloroform. Brest feed hyperbilirubinemia: β –glucurnidase in breast milk which deconjugate bilirubin Lucy-drescall syndrom: familial ,mild,last 2-3 weeks due to inhibitor of congjugation Dr/ Ragaa Salama

15 Alkaline phosphatase II - Conjugated hyperbilirubinemia: causes :
Obstructive (cholestatic) jaundice: It is due to the obstruction of hepatic or common bile ducts that regurgitate conjugated bilirubin into the blood with choluria. Chronic idiopathic jaundice (Dubin-Johnson and Rotor syndromes): They are benign inherited defect in transport system of conjugated bilirubin. Alkaline phosphatase ALP is present at or in cell membrane . The response of the liver to any form of biliary tree obstruction is to induce the synthesis of ALP. The main site of new enzyme synthesis is the hepatocytes adjacent to the biliary canaliculi. Some of the newly formed enzyme enters the circulation to raise the enzme level in serum Dr/ Ragaa Salama

16 Alkaline phosphatase principle
Hydrolysis of p-nitrophenyl phosphate → alkaline pH→ yellow p-nitrophenoxide ions. test Working reagent 1 volume of ALP substrate + 9 vol of ALP buffer →1ml Pre-worm at 37ºC add sample 20 µl serum Mix and incubate at 37ºC for 1 min. Read the absorbance A1 at 405 nm against d H2O . Re-incubate at 37ºC and after exactly 3min read the absorbance (A2 ) → ∆ A calculation ∆ A/min = A2 -― A1 / 2 , ∆ A/min X 2720 = U/L Dr/ Ragaa Salama

17 Alkaline phosphatase ALP is present at or in cell membrane, Its function by 3 ways 1- Hydrolysis Phosphotrnsferase pyrophosphtase Sources : Liver , bone ( osteoblast), intestinal epithelial cells proximal convoluted tubules of the Kidney and placenta . Clinical significance: Physiological causes: growing children , healing of bone fracture, 3rd trimester of pregnancy from placenta, lactation. Pathological causes : 1- hepatobiliary dis ( extrahepatic ,intra hepatic obstruction), Infectious hepatitis 2- bone dis. associated with increase osteoblastic activity like Paget’s disease (10-25 fold) as osteoblast rebuild bone that resorbed by uncontrolled activity of osteoclast, osteogenic bone cancer Moderate rise in osteomalacia but normal in osteoprosis, rickets (2-4 fold),Fanconi Syndrom,1ry&2ry hyperparathyrodism Dr/ Ragaa Salama

18 Albumin Synthesized mainly by the liver Osmotic effect
Transport substances Half life is 3 weeks It decreased in liver diseases Non-hepatic causes of hypoalbuminemia( Differential diagnosis) : Decreased synthesis : malnutrition, malabsorbtion, malignant diseases. Increased catabolism : injury, postoperative Acute inflammation Chronic inflammation Increased loss ( nephrotic syndrome, protein –losing enteropathy, burns, exudative skin disease Dr/ Ragaa Salama

19 Liver is the primary site for synthesis of plasma proteins
In acute hepatic dysfunction , little changes In chronic, ↓ albumen, globulin, A/G ratio is inverted in chirrosis. ↓ albumen, in sever liver disease, in active hepatitis suggests a poor prognosis. In portal hypertension, albumen leaks of liver surface→ peritoneal cavity → osmotic pressure of peritoneal cavity → ascities.  α 1 globulin, α 1 antitrypsin, α 2 & β globulin in cirrhosis, chronic cholestasis due to  production and ↓ clearance. IgG  autoimmune hepatitis& cirrhosis. Dr/ Ragaa Salama

20 Estimation of serum albumin
Principle Albumin+ Bromocresol green Albumin bromocresol green complex Blank Standard test Albumen color reagent 2.5 ml - 0.2ml (200 µl) sample Mix and allow to stand at room temp. For 5 min Set wavelength at nm and zero instrument with the blank . Read absorbance of all tubes within min. Calculation: A (test) x 5 g/dl ( concentration of standard) A (standard) Dr/ Ragaa Salama

21 Estimation of serum total protein
Principle Protein + Biurt reagent( Cu+2) Alkaline pH Cu+2-protein complex ( blue color). Blank standard test Biuret reagent 1 ml 1 m l - (20µl ) sample 0.02 ml (20µl) Mix and let stand at room temp. for 10min. Read the absorbance of standard and test at 540 nm against blank Calculation: A (test) x 5 g/dl ( concentration of standard) A (standard) Dr/ Ragaa Salama

22 5'Nuclotidase Indication: Isolated increase in alkaline phosphatase.
Alkaline phosphatase and 5'Nuclotidase usually increase and decrease in parallel in hepatobiliary disease. Alkaline phosphatase and 5’ nuleotidase: found near the bile canalicular membrane of hepatocytes REFLECT CHOLESTASIS Dr/ Ragaa Salama

23  in all types of liver diseases α- fetoprotein
Gamma Glutamyl transferase ( GGT).  in all types of liver diseases α- fetoprotein hepatocelular carcinoma , Acute & chronic hepatitis. It is present in early fetal life and reappear in malignant liver, used as tumor marker Dr/ Ragaa Salama

24 Coagulation factors: With the exception of Factor VIII, the blood clotting factors are made exclusively in hepatocytes. Because of their rapid turnover, measurement of the clotting factors is the single best acute measure of hepatic synthetic function and helpful in both the diagnosis and assessing the prognosis of acute parenchymal liver disease Dr/ Ragaa Salama

25 Serum prothrombin time: collectively measures factors II, V, VII, and X
Marked prolongation of prothrombin time, > 5s above control is a poor prognostic sign in acute viral hepatitis and other acute and chronic liver diseases. Dr/ Ragaa Salama

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