LIVER FINAL on function of liver disease

Liver

1. PHYSIOLOGY OF HEPATOBILIARY SYSTEM PRESENTED BY – DR. PRAVESH KUMARI MODERATOR – DR. RAVI PRAKASH

2. LIVER Liver is the largest and most complex internal organ of body. The weight of liver is about 1.5kg. It is located below the diaphragm in the right upper quadrant of the abdominal cavity. All blood flows from intestine and pancreas and reaches liver via portal venous system. Liver is supplied by T6-T11 sympathetic nerve fibres, right and left vagal nerve parasympathetic fibres and right phrenic nerve fibres. The majority of sensory afferent fibres travel with sympathetic fibres.

3. HEPATIC ANATOMY

4. INTERNAL ANATOMY

5. HEPATIC LOBULE

6. HEPATIC BLOOD FLOW Vascular supply of the liver 25% - 30% of cardiac output. Hepatic artery Portal vein Blood flow: 25% 75% O2 supply: 50% 50% Pressure : 35mmHg 5-13 mmHg Sinusoids = 2-3 mmHg

7. Hepatic arterial flow is dependent on metabolic demand (autoregulation) whereas flow through the portal vein is dependent on blood flow to the gastrointestinal tract and the spleen.

8. HEPATIC LYMPHATIC DRAINAGE Filtration of plasma through sinusoids into perisinusoidal space of Disse. Drainage via periportal space of mall into lymphatic vessels of portal canal. 80% via portal hepatis into thoracic duct. 20% via hepatic veins into IVC.

9. FUNCTIONS OF LIVER Metabolic Carbohydrates: Glucose homeostasis via gluconeogenesis and glycogenolysis. Lipids: Degraded to Acetylcoenzyme , a key molecule in synthesis of ATP, Cholesterol and Phospholipids. -Protein metabolism: Deamination Formation of ammonia Interconversion b\w nonessential AA Formation of plasma proteins (except immunoglobulins) albumin, AAT, proteases\elastases , coagulation factors (except factor VIII & von Willebrand factor) pseudocholinesterase, protein inhibitors, transport proteins.

10. Bilirubin conjugation and secretion. Bile formation. Hematologic function. Hematopoiesis 9 th to 24 th week gestation Clears Fibrin degradation products and Lactate. - Important in shock and massive blood loss and transfusion.

11. Hormonal function Insulin degraded 50% in the first pass T4 to T3 conversion Aldosterone, estrogen , androgen, ADH all are inactivated by the liver Liver disease thus, results in endocrine abnormalities Immunologic function - Kupffer cells phagocytose antigens

12. Drug Biotransformation Make drugs more polar for efficient elimination Phase I Reaction Cytochrome P450 system Oxidation/reduction Mixed- function Oxidases Phase II Reaction Conjugation most commonly catalyzed by UDP- glucuronyl transferase Storage Function - Storage of Vit. D, E, A, B12, and K.

13. LIVER FUNCTION TEST USED TO……. Detect the presence of liver disease Distinguish among different types of liver disorders Gauge the extent of known liver damage Follow the response to treatment

14. CATEGORIZATION: Test based on detoxification and excretory function Test for enzymes that reflect damage to hepatocytes Test for enzymes that reflect cholestasis Test that measures synthetic function

15. Test based on detoxification and excretory function: Van den Bergh assay: determination of total, conjugated (direct) and unconjugated bilirubin (indirect) Normal value of total <1-1.5mg/dl Normal value of direct: up to 15% of the total (upper limit = 0.3mg/dl)

16. Test based on detoxification and excretory function: Isolated elevation of UCB- bilirubin elevated but < 15% direct – Work Up for hemolysis – if absent – Gilbert disease Conjugated hyperbilirubinemia- liver or biliary tract disease In most liver diseases both fractions are increased

17. Test based on detoxification and excretory function: Urine Bilirubin: Any bilirubin found in urine is conjugated bilirubin Bilirubinuria implies the presence of liver disease Blood ammonia : Was used for detecting encephalopathy or for monitoring hepatic synthetic function (poor cor r elation)

18. Test for enzymes that reflect damage to hepatocytes: Aminnotransferases (ALT and AST) AST: liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leucocytes, and RBC –(Normal serum level) ALT: Liver –(normal serum level) Liver cell damage – increased permeability – increase serum levels But poor correlation b/w liver cell damage and level of AST and ALT Up to 300 U/L – non specific/ any type of liver disorder

19. Test for enzymes that reflect damage to hepatocytes: Aminotransferases (ALT and AST): Levels > 1000 U/L extensive hepatocellular injury ( viral hepatitis, Ischemic liver disease, Drug or toxin induced) In most acute hepatocellular damage ALT>AST AST:ALT > 2:1 (suggestive) & > 3:1 ( highly suggestive) of (Alcoholic Liver Disease) ALD Aminotransferases are usually not greatly elevated in obstructive jaundice

20. Test for enzymes that reflect cholestasis: ALP, 5’NT, GGT GGT – more diffuse localization – less specific than ALP and 5’NT Use of GGT to identify patient with occult alcohol use ALP: non pathological causes of increased levels

21. Test for enzymes that reflect cholestasis: ALP: < 3 fold increase: not specific for cholestasis (seen in almost any type of liver disease) > 4 fold increase: cholestatic liver disorder, infilterative liver disease (Cancer), bone conditions with rapid turnover of bone ( Pagets disease) ALP is NOT useful to distinguish b/w intra and extra hepatic obstruction

22. Test that measure biosynthetic function of the Liver: Serum albumin : Synthesized exclusively by hepatocytes T1/2 : 15-20 days NOT a good indicator of acute/mild hepatic dysfunction Minimum change in Viral hepatitis/drugs induced hepatitis/ Obs. Jaundice In hepatitis , Alb umin levels less than 3gm/dl- chronic liver disease Other causes of decrease: Protein malnutrition/ Protein losing enteropathies / Nephrotic syndrome/ Chronic infections

23. Test that measure biosynthetic function of the Liver Coagulation Factors: Except for factor VIII, blood clotting factors are exclusively synthesized in hepatocytes T1/2 of factors VII- 6 hrs / Fibrinogen – 5 days (shorter than albumin) Rapid turnover- thus measurement of clotting factors is the single best acute measure of hepatic synthetic function (in the diagnosis and assessment of liver function in acute parenchymal liver disease)

24. Test that measure biosynthetic function of the Liver Coagulation Factors: Prothrombin Time (PT) – collectively measures II/V/VII/X Biosynthesis of factors II/VII/IX/X depends on Vit. K PT may be elevated in hepatitis, cirrhosis and disorders that result in Vit. K deficiency ( eg obstructive jaundice) Markedly prolonged PT (>5 secs above control), not corrected by Vit. K is a poor prognostic sign in acute viral hepatitis and other acute and chronic liver diseases

25. BILE FORMATION Bile plays an important role in absorption of fat and excretion of bilirubin, cholesterol and many drugs. Hepatocytes continuously secrete bile salts, cholesterol, phospholipids, conjugated bilirubin, other substances into bile canaliculi. Bile ducts from hepatic lobules join and eventually form the right and left hepat ic duct, which together with the cystic duct from the gall bladder forms common bile duct.

26. COMPOSITION OF BILE 97% water <1% bile salts Pigments Inorganic salts Lipids Cholesterol Fatty acids Lecithin Alkaline phosphatase

27. BILIARY SYSTEM

28. BILIRUBIN FORMATION AND EXCRETION

29. Main source : Heme metabolism Daily production- 250-350mg/dl 80% is derived from phagocytosis of old RBCs by macrophages After release from RE cells bilirubin tightly bound to albumin Hepatocytes extract this unconjugated bilirubin from albumin and produce conjugates with glucuronic acid Conjugated bilirubin secreted in bile and excreted via gut

30. The conjugated bilirubin is hydrolyzed and converted to urobilinogen by the intestinal pathogens. The urobilinogen is then oxidized to orange color stercobilin and excreted in the stool. About 15~20% of the urobilinogen is reabsorbed from the intestine into portal veins and finally 90% of it is returned to the liver and is re-excreted in the bile. The remaining 10% gets into the systemic circulation and finally excreted in the urine through kidney as urobilin.

31. HYPERBILIRUBINEMIA A condition in which there is too much bilirubin in blood stream causing yellowish discoloration of skin and mucus membrane. Normal range < 1 mg/dl Indirect: 0.2-0.7mg/dl; Direct: 0.1-0.4mg/dl, Clinically obvious jaundice occurs at 2-3 mg/dl

32. Based on underlying derangement of Bilirubin metabolism Prehepatic – Hemolytic jaundice Intrahepatic – Hepatocellular Posthepatic – Ob s tructive / Cholestatic

33. PREHEPATIC- HEMOLYTIC JAUNDICE Intraerythrocyte defects Sperocytosis Sickle cell disease Thalassemia 2. Extraerythrocyte defects Autoimmune antibodies Malaria Prosthetic heart valves Drugs: Sulphasalazine , dapsone PNH

34. HEPATOCELLULAR JAUNDICE Causes: Viral Hepatitis Alcoholic hepatitis Cirrhosis 4. Drug induced hepatitis Halothane INH Rifampicin Chlorpromazine Erythromycin

35. POST HEPATIC/ CHOLESTATIC JAUNDICE Failure of normal amounts of bile to reach the duodenum Involves interference with bile flow or formation Can be anywhere between the sinusoidal membrane of hepatocyte and the ampulla of Vater Cholestatis causes the retention in blood of substances normally excreted in bile Absence of bile in duodenum Systemic manifestations of cholestatis

36. CAUSES OF OBSTRUCTIVE JAUNDICE Intrahepatic causes Drugs / alcohol abuse Sex hormones (OC, Anabolic steroids) Erythromycin & Nitrofurantoin Azathioprine, Cyclosporine A Chlorpromazine Carbamazepine 2. Viral hepatitis 3. Pregnancy 4. TPN induced 5. Prim ary Biliary Cirrhosis 6. Primary Sclerosing cholangitis 7. Postoperative

37. EXTRAHEPATIC CAUSES BENIGN Gallstone/Choledocholithiasis- most common Chronic pancreatitis Strictures- iatrogenic, trauma Parasitic infections- ascariasis Biliary atresia Choledochal cysts MALIGNANT Ca. of pancreas/ampulla/bile duct/gallbladder

38. CHILD-TURCOTTE-PUGH SCORE

39. CHILD-TURCOTTE-PUGH SCORE The score is then used to classify the patient into one of three groups:- class A (score of 5-6) class B ( score of 7-9) class C ( score of >10) A higher CTP class is associated with a greater risk of mortality. In early retrospective series of cirrhotic patients undergoing abdominal surgery, the mortality risks associated with CTP class A,B,C were 10%, 30% and 73 to 82% respectively.

40. The risk has been found to be even lower in patients undergoing laparoscopic procedures class A : 2% class B : 12% class C : 12% Suggesting that improvements in perioperative care and surgical techniques have made surgery safer for patients with cirrhosis. A disadvantage of CTP score is that the grading of encephalopathy and ascites is subjective. The score doesn’t take into account other predicators of operative risk such as the type of surgery or the etiology of the cirrhosis.

41. MODIFIED END STAGE LIVER DISEASE (MELD) SCORE It includes- patient’s INR Serum creatinine Serum Bilirubin Etiology of liver disease It is a validated measure of mortality risk in patients with ESLD and is the basis of the liver allocation system for transplantation. MELD score was a predictor for mortality at 30 days, 90 days, 1 year and 5 years.

42. The 30 days mortality ranged from 5.8% in patients with a MELD under 8 to over 50% in patients with a MELD score greater than 20. The incorporation of serum sodium into the MELD score (MELD-Na) as well as a combination of serum sodium and patient age (integrated MELD or; i MELD) have been shown to improve the accuracy of predictions of survival over MELD. The use of MELD-Na and iMELD may allow more accurate prediction of mortality following non hepatic surgery.

43. SYNDROMES GILBERT SYNDROME The most common example of hereditary hyperbilirubinemia. It is inherited as an autosomal dominant trait with variable penetrance. The 1degree defect is a mutation in the glucuronosyl transferase enzyme. Plasma bilirubin concentrations rarely exceed 5mg/dl but can increase two-fold to three fold with fasting, illness or stress.

44. CRIGLER-NAJJAR SYNDROME It is a rare hereditary form of severe unconjugated hyperbilirubinemia that is inherited as an autosomal recessive trait and results from a mutation in the glucuronosyl -transferase enzyme, which is typically reduced to less than 10% of normal. Severe jaundice appears in the first days of life and can lead to brain damage in infants. Treatment includes daily exchange transfusions in the neonatal period and daily phototherapy (12 hrs/day) as well as oral calcium treatment to bind bile in the gut. Long-term phenobarbital therapy may decrease jaundice by stimulating activity of glucuronosyltransferase. Definitive treatment is liver transplantation before significant brain damage develops.

45. DUBIN-JOHNSON SYNDROME It is a rare, benign genetic liver disorder. It is inherited as an autosomal recessive pattern. It is caused by a variant in the gene for the transporter protein that is responsible for moving the bilirubin, a normal breakdown product of RBCs, into the bile which then leaves the body through stool. It is associated with blood clotting abnormality, a prolonged PT, caused by a decrease in factor VII. Onset usually occurs during puberty or adulthood but it has rarely been described in the newborn period. Use of alcohol, birth control pills, infection amd pregnancy can lead to an increase in jaundice.

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