Liver physiology

physiology of liver as an inddispensible organ stating its many vital functions.

1. LIVER Seat & Mirror Of The Soul Dr. Misbah-ul-Qamar

2. Summarized Functions Of Liver Filtration and storage of blood Metabolism of carbohydrates, proteins, fats, hormones, and foreign chemicals (3) Formation of bile (4) Storage of vitamins and iron (5) Formation of coagulation factors. Dr. Misbah-ul-Qamar

3. Physiologic anatomy of liver Largest organ in the body (1.5 kg= 3.3 pounds) It contributes 2% of total body weight in average adult human Functional unit = liver lobule The human liver contains 50,000 to100,000 lobules. Dr. Misbah-ul-Qamar

4. STRUCTURE OF LIVER LOBULE It is a cylindrical structure with Length= several millimeters Diameter= 0.8-2 millimeters It is constructed around a central vein Dr. Misbah-ul-Qamar

5. Main components of a lobule Central vein Cellular plates Portal venules Hepatic sinusoids Hepatic arterioles Dr. Misbah-ul-Qamar

6. Structure Of The Liver Lobule Central Vein: In the centre of lobule ( central vein  hepatic veins  vena cava ) 2. Lobule is composed of Cellular Plates: Radiate from the central vein like spokes in a wheel. each plate is Usually two cells thick Between adjacent cells lie bile canaliculi that empty into bile ducts There are fibrous septa which separate adjacent liver lobules. In the septa lie bile ducts, portal venules , hepatic arterioles & lymphatic vessels 3. Portal Venules : Receive their blood from portal vein (venous outflow of GIT) From venules , blood flow into hepatic sinusoids Dr. Misbah-ul-Qamar

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8. Lobule structure (cont’d) 5. Hepatic Sinusoids Lie between the hepatic plates Blood flows from portal venules and arterioles to sinusoids then into the central vein That’s how hepatic cells are exposed continuously to portal venous blood Hepatic arterioles: Supply arterial blood to the septal tissues between the adjacent lobules Many of arterioles drain directly into sinusoids Dr. Misbah-ul-Qamar

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10. Venous sinusoids are lined by: (1) Endothelial cells (2) Kupffer cells (liver macrophages) Significance of Kupffer cells They are capable of phagocytizing bacteria & other foreign matter in hepatic sinus blood Dr. Misbah-ul-Qamar

11. Spaces of Disse Also called peri -sinusoidal spaces Narrow tissue spaces between endothelial cells and the hepatic cells Endothelial lining has extremely large pores These spaces connect with lymph vessels in septum Significance Excess fluid in spaces is removed through lymphatics Large substances (portions of plasma proteins) can move freely into spaces through large pores of endothelium Dr. Misbah-ul-Qamar

12. Blood Flow Design Of Liver Dr. Misbah-ul-Qamar

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14. Unique features of circulation through liver Dr. Misbah-ul-Qamar

15. Hepatic Vascular and Lymph Systems Blood flows through liver from portal vein and hepatic artery High blood flow Sinusoids receive 1350ml/min (27% of CO) From portal vein=1050ml/min From hepatic artery= 300ml/min The liver has high blood flow and low vascular resistance Low vascular resistance Pressure in portal vein= 9mmHg Pressure in hepatic vein=0mmHg This small pressure difference shows very low resistance to blood flow through sinusoids Dr. Misbah-ul-Qamar

16. Cirrhosis of the liver greatly increases resistance to blood flow Cirrhosis : Destruction of parenchyma of liver and its replacement with fibrous tissue Fibrous tissue contracts around the blood vessels, and impedes blood flow thus increasing resistance Cause : Alcoholism Ingestion of poisons like carbon tetrachloride Viral diseases like hepatitis Dr. Misbah-ul-Qamar

17. The Liver Has Very High Lymph Flow Half of the lymph formed in the body arises in the liver. Hepatic sinusoids are very permeable  passage of fluid and proteins into the spaces of disse Protein concentration of lymph from liver= 6g/dl(slightly less than that of plasma) Extreme permeability of the liver sinusoid epithelium allows large quantities of lymph to form. Dr. Misbah-ul-Qamar

18. In case of High hepatic vascular pressure When pressure in hepatic vein rises (3-7mmHg above normal: Excessive amount of fluid begin to transude into lymph Fluid also leak into abdominal cavity through outer surface of liver capsule Similarly blockage of portal flow causes portal hypertension Dr. Misbah-ul-Qamar

19. Portal hypertension Prolonged elevation of portal venous pressure above normal Increased capillary pressure in intestinal wall- loss of fluid from capillaries into wall and lumen of the intestines Dr. Misbah-ul-Qamar

20. Causes of portal hypertension: Formation of clot (portal vein thrombosis) Cirrhosis of liver Veno-occulusive disease Cystic liver disease Sarcoidosis drugs Dr. Misbah-ul-Qamar

21. Ascites: Collection of free fluid in the peritoneal cavity Transudation of fluid into lymph and leakage from surface of liver into abdominal cavity due to high pressure in hepatic veins Dr. Misbah-ul-Qamar

22. Liver regeneration & transplant Dr. Misbah-ul-Qamar

23. Regulation of liver mass- Regeneration Liver possesses a remarkable ability to restore itself after significant hepatic tissue loss from either partial hepatectomy or acute liver injury as long as injury is uncomplicated by infection or inflammation. During this process, hepatocytes replicate until original size and volume has been restored Hepatocyte growth factor, produced by mesenchymal cells, cause liver cell division Blood levels increase 20 fold after partial hepatectomy Dr. Misbah-ul-Qamar

24. Other growth factors are also involved like; Epidermal growth factor Tumor necrosis factor Interleukin-6 Dr. Misbah-ul-Qamar

25. Termination of regeneration: Transforming growth factor - a cytokine released by hepatocytes-potent inhibitor of liver cell proliferation.   Dr. Misbah-ul-Qamar

26. Role of Hepatic stellate cells in liver regeneration These are liver specific resident mesenchymal stem cells. they secrete growth factors promoting the regeneration of hepatic epithelial cells. Dr. Misbah-ul-Qamar

27. Transplant Only a small portion of donor’s liver is transplanted which attains normal mass through regeneration Dr. Misbah-ul-Qamar

28. Functions of liver Love your liver! Dr. Misbah-ul-Qamar

29. Major 4 functions of liver Reservoir function Blood cleansing function Metabolic functions Bile formation & excretion Dr. Misbah-ul-Qamar

30. RESERVOIR FUNCTION Dr. Misbah-ul-Qamar

31. The Liver Functions as a Blood Reservoir Liver is a large expandable, venous organ capable of acting as a blood reservoir  blood is stored in its blood vessels. Supplies extra blood in times of diminished blood volume. Normal blood volume in liver = 450 milliliters( including that in both hepatic veins & hepatic sinuses) Maximum blood volume which can be stored in liver = 0.5 to 1liter Dr. Misbah-ul-Qamar

32. In which conditions blood storage occurs in liver? Congestive cardiac failure When high pressure in rt. Atrium causes back pressure in liver In times of excess blood/plasma volume Dr. Misbah-ul-Qamar

33. BLOOD CLEANSING FUNCTION Through hepatic macrophage system Dr. Misbah-ul-Qamar

34. Why portal blood needs cleansing Blood flowing through intestinal capillaries picks up many bacteria from intestines As indicated by the growth of colon bacilli in: Blood sample from portal vein before it enters liver: occurs almost always when cultured Blood sample from systemic circulation: extremely rare Dr. Misbah-ul-Qamar

35. Hepatic Macrophage System consisting of Kupffer cells What are Kupffer cells: Large phagocytic macrophages that line the hepatic venous sinuses Main Function : Cleanse blood of bacteria & endotoxins from portal circulation as it passes through the sinuses Cellular debris, viruses, proteins & particulate matter in blood are also phagocytosed Other functions performed by Kupffer cells: processing of antigens, release of various proteins, enzymes, cytokines and other chemical mediators Dr. Misbah-ul-Qamar

36. C leansing effectiveness of liver Kupffer cells perform their action at a high speed  only a momentary contact of 0.01 second with a bacterium transports it inward through the wall of kupffer cell bacterium is permanently lodged inside macrophage until digested Less than 1% of the bacteria entering the portal blood succeeds in passing through the liver Dr. Misbah-ul-Qamar

37. Endocrine function Secretion of hormones Erythropoietin – 10% is secreted from liver Thrombopoietin - stimulates platelet production Insulin like growth factor-I - stimulates growth Hepcidin - inhibits iron uptake from the intestines Dr. Misbah-ul-Qamar

38. Activating vitamin D in conjunction with kidneys Dr. Misbah-ul-Qamar

39. Formation of blood cells: During intrauterine life . This function is lost at birth but liver retain the potentiality of forming red blood cells Dr. Misbah-ul-Qamar

40. Removal of worn out red blood cells by reticuloendothelial cells in conjunction with spleen and bone marrow Dr. Misbah-ul-Qamar

41. Metabolic functions of liver Liver is a large, chemically reactant pool of cells that have a high rate of metabolism Involved in metabolism of Carbohydrate Protein Fats Dr. Misbah-ul-Qamar

42. Protein Metabolism 1. Deamination of amino acids 2. Formation of urea for removal of ammonia. 3. Formation of all plasma proteins except gama globulins 4. Inter-conversions of the various amino acids and synthesis of other compounds from amino acids Most important function of liver Body cannot dispense with liver for protein metabolism for more than a few days without death ensuing Dr. Misbah-ul-Qamar

43. De- amination I t is required before protein is used for energy or converted into carb or fat E.g ,: deamination of alanine plays an important role in hepatic gluconeogenesis Enzymatic processes convert amino acids to their respective keto acids. Some deamination can occur in other tissues of body (kidney) but mainly in liver Branched chain amino acids are primarily metabolized by skeletal muscle Large amount of ammonia is also formed in deamination Dr. Misbah-ul-Qamar

44. Formation of urea Ammonia formed from deamination is highly toxic to tissues (↑ ammonia due to liver disease = hepatic coma ) Decreased blood flow through liver (shunting of portal vein into vena cava)  excessive ammonia (extremely toxic condition) 2 molecules of ammonia+ CO 2 = Urea Urea thus formed readily diffuses out of liver & can be excreted by kidneys Dr. Misbah-ul-Qamar

45. Formation of plasma proteins 90% of plasma proteins formed by liver: Albumin Alpha1-antitrypsin Proteases/ elastases All coagulation factors (exception: factor VIII & Von Willebrand factor) Max. rate of plasma protein production by liver: 15-50g/day Even if half plasma proteins lost somehow, liver can replenish in 1-2 weeks Plasma protein depletion causes liver enlargement by rapid mitosis of hepatic cells  rapid output of PPs. Chronic liver disease (e.g., cirrhosis edema & ascites due to very low albumin) Dr. Misbah-ul-Qamar

46. Inter-conversion between AAs This transamination allows formation of non-essential AAs & compensate for any dietary deficiency Mechanism: transamination from available amino acid to keto acid A keto acid is formed by liver (with required chemical composition)  an amino radical is transferred to take place of keto oxygen Dr. Misbah-ul-Qamar

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48. Role of liver in Carbohydrate metabolism Glycogen storage Inter-conversion of carbs Gluconeogenesis Fomation of chemical compounds Dr. Misbah-ul-Qamar

49. Glycogen storage 1. Storage of large amounts of glycogen: most of glucose absorbed from meal is stored as glycogen in liver When glycogen storage is exceeded, glucose is stored as fat in liver or adipose tissue Only liver & muscle can store significant amount of glycogen Dr. Misbah-ul-Qamar

50. Glucose buffer action Glycogen storage function allows liver to perform its glucose buffer action remove excess glucose from blood & thus maintain normal blood glucose concentration Returns it when blood levels fall Importance of liver’s buffer action: of In a person with poor liver function: glucose level after carb rich meal may rise 2-3 times Dr. Misbah-ul-Qamar

51. Inter-conversion of carbs 2. Conversion of galactose and fructose to glucose F inal products of carbohydrate metabolism are glucose, fructose & galactose  all cells utilize glucose to produce energy in form of ATP via glycolysis or citric acid cycle Dr. Misbah-ul-Qamar

52. Gluconeogenesis amino acids & glycerol (from triglycerides) are converted into glucose again to maintain blood glucose concentration when glucose level falls below normal Glucocorticoids, catecholamines , glucagon & thyroid hormone greatly enhance gluconeogenesis by liver – whereas insulin inhibits it Dr. Misbah-ul-Qamar

53. Carb metabolism (cont’d) 4. Formation of many chemical compounds from intermediate products of carbohydrate metabolism – liver & kidney are unique in their capacity to form lactate, pyruvate, amino acids & glycerol. Note: liver can also utilize the phospho-gluconate pathway which not only provides energy but also produces an important cofactor in synthesis of fatty acids. Dr. Misbah-ul-Qamar

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55. Fat Metabolism Although most cells of the body metabolize fat, certain aspects of fat metabolism occur mainly in liver 1. Oxidation of fatty acids to supply energy for body functions 2. Synthesis of large quantities of cholesterol, phospholipids, and most lipoproteins 3. Synthesis of fat from proteins and carbohydrates Dr. Misbah-ul-Qamar

56. How energy is extracted from fats Neutral fat is first split into glycerol & fatty acids Then fatty acids are split by beta oxidation into two-carbon acetyl radicals that form acetyl coenzyme A acetyl- CoA can enter the citric acid cycle & be oxidized to liberate energy Note : Beta-oxidation can take place in all cells of body but it occurs especially rapidly in hepatic cells Dr. Misbah-ul-Qamar

57. Liver’s role in energy provision to other tissues Liver itself cannot use all all the acetyl-CoA that is formed  it is transported throughout body in a highly soluble form( acetoacetic acid) Acetoacetic acid condensation of 2 molecules of acetyl CoA In tissues it is reconverted to acetyl CoA & is oxidized for energy Dr. Misbah-ul-Qamar

58. Anabolic role of liver in fat metabolism 80% of cholesterol synthesized in liver is converted into bile salts Remainder of cholesterol & phospholipids are transported in lipoproteins to tissue cells where they form: Cell membranes Intracellular structures Multiple chemical substances for cellular function Dr. Misbah-ul-Qamar

59. Anabolic role of liver in fat metabolism When carb stores are saturated, liver converts excess ingested carb into fat Almost all the fat synthesis in body from carb & proteins occur in liver Fatty acids thus formed can be used immediately or are transported in lipoprotein to adipose tissue Dr. Misbah-ul-Qamar

60. RBCs & renal medulla can utilize only glucose Neurons normally utilize only glucose but after a few days of starvation, they can switch to breakdown products of fatty acids made by liver Dr. Misbah-ul-Qamar

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62. Other Metabolic Functions of the Liver 1.The liver is a storage site for vitamins. 2.The liver stores iron as ferritin . 3.The liver forms a large proportion of the blood substances used in coagulation. eg : fibrinogen, prothrombin , Factor VII, Vit K dependant : prothrombin ,Factors VII, IX, and X 4.The liver removes or excretes drugs, hormones, and other substances. Dr. Misbah-ul-Qamar

63. Storage of vitamins Vitamins stored in greatest quantity in liver is vitamin A Large quantities of vitamin D and B 12 also stored in liver Dr. Misbah-ul-Qamar

64. Storage of iron as ferritin Greatest proportion of body’s extra iron is stored in hepatic cells Apoferritin protein in hepatocytes can combine reversibly with iron Liver is also important blood iron buffer as ferritin releases the iron when body fluids’ iron levels are low Dr. Misbah-ul-Qamar

65. Formation of blood substances used in coagulation Makes most of the pro-coagulants with exception of factor III, IV, VIII Fibrinogen, prothrombin , accelerator globulin, factor VII For the formation of these substances, liver requires vitamin K In its absence coagulation may be prevented by decreased concentration of these substances Liver also makes protein regulators of coagulation & fibrinolytic pathways . Such regulators include: protein C, Plasminogen activator inhibitor, antithrombin III. Dr. Misbah-ul-Qamar

66. Coagulopathy in liver disease Most common coagulation disturbances occurring in liver disease include thrombocytopenia & impaired humoral coagulation. The INR is used to measure blood clotting time. A high INR usually means that liver is not working optimally. Dr. Misbah-ul-Qamar

67. Removal and excretion of drugs, hormones and minerals Liver provides an active chemical medium to detoxify drugs into bile such as Sulfonamides Penicillin Ampicillin Erythromycin Thyroxine & steroid hormones (estrogen, cortisol, aldosterone) are either altered or excreted by liver Normal thyroid function is dependent on hepatic formation of more active T 3 from T 4 Also a major site of degradation for insulin, glucagon & ADH Excretion of body calcium also depend on liver through bile. Dr. Misbah-ul-Qamar

68. other important proteins produced by liver Transport proteins: transferrin, haptoglobin , ceruloplasmin Complement proteins: C-reactive protein, serum amyloid-A, alpha1-acid glycoprotein Dr. Misbah-ul-Qamar

69. Excretion of bilirubin It is a greenish yellow pigment which is an end product of Hb degradation Measurement of bilirubin provides valuable tool for diagnosing blood & liver diseases Dr. Misbah-ul-Qamar

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71. 600-1000ml/day BILE Dr. Misbah-ul-Qamar

72. Composition Of Bile Water Inorganic salts : Na + , K + , Ca ++ , Cl - , HCO 3 Bile salts : Sodium tauro-cholate , Sodium glyco-cholate Pigments: Bilirubin and Biliverdin Lipids: Cholesterol, Lecithin and traces of fatty acid Dr. Misbah-ul-Qamar

73. 4 major functions of bile Fatty acid metabolism Excretion of waste products Kill off bad microbes Blood sugar metabolism (through role of BAs as signalling molecules in glucose metabolism) Dr. Misbah-ul-Qamar

74. Basic functions of bile Plays main role in fat digestion & absorption because of bile salts It serves as a mean for excretion of waste products (bilirubin & excess cholesterol) from blood Dr. Misbah-ul-Qamar

75. Other functions Alkalinity of bile help in neutralizing acidity of chyme Excretion of bile pigments, heavy metals, toxins, cholesterol, and lecithin. Dr. Misbah-ul-Qamar

76. Functions of bile due to bile salts Bile salts emulsify fat globules-help in digestion Absorption of fats Bile salts stimulate secretion of bile from liver- choleretic action Cholagogue action -increase release of bile from gall bladder by stimulating the secretion of cholecystokinin Bile salts act as laxatives by causing CCK release (enhancing motility) Dr. Misbah-ul-Qamar

77. Overview of biliary transport Dr. Misbah-ul-Qamar

78. Secretion of bile Secreted by hepatocytes Contains large quantities of bile acids, bile pigments, cholesterol, lecithin and fatty acids Bile from the hepatocytes is secreted into biliary canaliculi Dr. Misbah-ul-Qamar

79. Formation And Conduction Of Bile Formed by hepatic cells Bile canaliculi Terminal bile duct Hepatic duct Common bile duct(CBD) Duodenum Gall Bladder through cystic duct Dr. Misbah-ul-Qamar

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82. Physiologic anatomy of biliary secretion Bile is secreted in 2 stages Secretion of initial bile parenchymal secretion Addition of 2 nd secretion (ductal secretion) Dr. Misbah-ul-Qamar

83. Stages of bile secretion Initial bile is secreted from hepatocytes into bile canaliculi which flows toward bile ducts, finally reaching into duodenum or gallbladder In its course through bile ducts, 2 nd portion of liver secretion is added to initial. Dr. Misbah-ul-Qamar

84. Stages of bile secretion Initial bile: It contains large amounts of bile acids, cholesterol & other organic constituents Additional secretion: This additional secretion is watery solution of sodium & bicarbonate, stimulated by secretin It can increase total quantity of bile as much as 100% Dr. Misbah-ul-Qamar

85. Role of secretin in controlling bile secretion Secretin may increase bile secretion, sometimes doubling it after a meal This increase consists of rich watery solution of sodium bicarbonate by epithelial cells of bile ductules This bicarbonate helps in neutralizing the HCl from stomach Dr. Misbah-ul-Qamar

86. Storage of bile Bile is secreted continually by liver cells It is stored in gallbladder until needed in duodenum Gallbladder can hold 30-60ml, bile is concentrated 5-fold ( upto 20-fold ) GB is not a passive reservoir of bile, it absorbs, secretes & alters constituents of bile. Dr. Misbah-ul-Qamar

87. How the bile is concentrated in GB? Dr. Misbah-ul-Qamar

88. Concentration of bile in gallbladder water , sodium, chloride & other electrolytes (HCO 3 ) are absorbed from gallbladder mucosa Absorption is caused by active transport of sodium through epithelium This transport is followed by secondary absorption of chloride, water & others bile is concentrated which contains bile salts, cholesterol, lecithin & bilirubin Dr. Misbah-ul-Qamar

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90. Liver secretion of cholesterol Bile salts are formed in hepatic cells from cholesterol in blood plasma In the process of secreting bile salts 1-2 grams of cholesterol are removed from blood plasma It is secreted into the bile each day Amount of cholesterol in bile is determined by quantity of fat that the person eats Dr. Misbah-ul-Qamar

91. Gallstones Dr. Misbah-ul-Qamar

92. Formation of gallstones Cholesterol is insoluble in pure water Bile salts & lecithin in bile combine with cholesterol & form a colloidal solution in gallbladder Under abnormal conditions when there is excessive absorption of water (active sodium transport & passive water absorption from chronically inflammed GB mucosa) & bile salts from gallbladder epithelium, cholesterol is left behind which begins to precipitate First small crystals of cholesterol are formed which progress to gallstones Dr. Misbah-ul-Qamar

93. Gallstones These could have calcium nature also which normally is prevented by acidifying GB bile through secretion of hydrogen ion from GB mucosa. Dr. Misbah-ul-Qamar

94. Functions Of Gallbladder Dr. Misbah-ul-Qamar

95. Functions of Gallbladder Storage of bile Mucosal a bsorption Concentration of bile constituents Maintenance of pressure in biliary system Secretion of mucin Alteration of bile pH Dr. Misbah-ul-Qamar

96. Functions of Gallbladder Storage of bile : because bile is continuously formed & released by hepatocytes but not continuously utilized. Released from GB intermittently when required Mucosal absorption : Absorbs H 2 O, Na + , Cl - and other electrolytes from bile Bile concentration : Concentrates bile salts, cholesterol, lecithin and bilirubin in bile Dr. Misbah-ul-Qamar

97. Functions of gallbladder (cont’d) Maintenance of pressure in biliary system : due to the concentrating capacity, gallbladder maintains pressure (7cmH 2 O) in biliary system. T his pressure is essential for release of bile into intestine Dr. Misbah-ul-Qamar

98. Functions of gallbladder (cont’d) Secretion of mucin : mucin is added to bile when bile is released into intestine. Mucin acts as lubricant for movement of chyme in intestine Dr. Misbah-ul-Qamar

99. Functions of gallbladder (cont’d) Alteration of bile pH : pH of bile is decreased from 8-8.6 to 7-7.6. it becomes less alkaline when it is stored in gallbladder Dr. Misbah-ul-Qamar

100. Gall Bladder Emptying Dr. Misbah-ul-Qamar

101. Emptying of gallbladder requires Contraction of GB Relaxation of sphincter of Oddi Dr. Misbah-ul-Qamar

102. Emptying of Gallbladder Contraction of GB Causes: Cholecystokinin Vagal stimulation (weak effect) 2. Relaxation of sphincter of Oddi Causes: Cholecystokinin Neurogenic ( vagus ) Receptive relaxation during peristalsis Dr. Misbah-ul-Qamar

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105. Bile salts Dr. Misbah-ul-Qamar

106. Bile salts Liver cells synthesize about 6gm of bile salts daily Precursor of bile salts : cholesterol Sources of cholesterol Diet Synthesized in liver cells during course of fat metabolism Dr. Misbah-ul-Qamar

107. Formation of bile salts Cholesterol  formation of bile acids ( end products of cholesterol catabolism) conjugation of bile acidsformation of bile salts Dr. Misbah-ul-Qamar

108. Formation of bile salts Cholesterol is first converted into Bile acids: Cholic acid in about equal quantities Chenodeoxycholic acid These acids combine with glycine & taurine to form conjugated bile acids Salts of these acids are then secreted in bile Sodium glycholate Sodium taurocholate Dr. Misbah-ul-Qamar

109. FUNCTIONS Of Bile Salts Emulsification of fats: 2. Micelles formation: Dr. Misbah-ul-Qamar

110. Emulsification of fats Bile salts and agitation by GIT breaks fat globules to smaller size This emulsification is also called detergent function of bile salts Detergent action decreases the surface tension of particles It allows agitation in intestinal tract to break fat globules into minute sizes Dr. Misbah-ul-Qamar

111. Micelles formation Micelles are small physical complexes of lipid molecules that arrange themselves in a spherical form in aquous solutions. Micelles have amphipathic nature (contain both hydrophilic & hydrophobic regions) Bile salts form micelles of fatty acids, monoglycerides , cholesterols & other lipids Dr. Misbah-ul-Qamar

112. Micelle formation (cont’d) It is even more important function of bile salts than emulsification The micelles are semi-soluble in chyme due to electrical charges of bile salts This is how bile salts carry micelles to intestinal mucosa for absorption Without bile salts, 40% of ingested fats are lost in feces Dr. Misbah-ul-Qamar

113. Applied physiology : use of orlistat The drug binds to lipases in gut & blocks their action Reduced micelle formation due to orlistat induced blockage of triglycerides digestion Dr. Misbah-ul-Qamar

114. R ecycling of bile salts Role of enterohepatic circulation Dr. Misbah-ul-Qamar

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116. ENTEROHEPATIC CIRCULATION 94% of bile salts are absorbed from gut into portal blood Passed to liver, absorbed by hepatocytes through sinusoids Again excreted into bile Again reabsorbed Dr. Misbah-ul-Qamar

117. Reabsorption Of Bile Salts From Gut On average bile salts make an entire circuit 17 times before being excreted in feces Sites for reabsorption: The bile salts which are reabsorbed from gut One half are absorbed by diffusion through mucosa in early portion of small intestine Remainder is absorbed by active transport process through mucosa of distal ileum Dr. Misbah-ul-Qamar

118. Importance of enterohepatic circulation Q uantity of bile secreted each day is highly dependent on availability of bile salts Greater the quantity of bile salts in enterohepatic circulation  greater the rate of bile secretion Dr. Misbah-ul-Qamar

119. Amount of bile salts Usually total amount of bile salts in circulation is 2.5 grams 1.1g/dl bile salts secretion from liver. Dr. Misbah-ul-Qamar

120. BILIRUBIN Dr. Misbah-ul-Qamar

121. Many waste substances are excreted in the bile and eliminated in the feces. One of these is the greenish yellow pigment Bilirubin . BILIRUBIN: Major end product of hemoglobin degradation Helps in diagnosing hemolytic blood diseases and various types of liver diseases Dr. Misbah-ul-Qamar

122. Origin & fate of bilirubin RBCs rupture after 120 days Released hemoglobin is phagocytized by tissue macrophages Split into globin and heme Heme ring is opened to give (1) Free iron (2) Protoporphyrin IX (Stored as ferritin) (Converted to bilirubin) Dr. Misbah-ul-Qamar

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124. Initially biliverdin , is formed but immediately reduced to bilirubin Released from the macrophages into the plasma. Binds to Albumin in plasma Absorbed through hepatic cells Conjugated with glucuronic acid to form bilirubin glucuronide , Excreted from the hepatocytes into intestine through bile canaliculi and then into the intestines. Converted to urobilinogen by action of bacteria Urobilin in urine Stercobilin in feces Dr. Misbah-ul-Qamar

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127. Don’t wait for jaundice to appear! Beware of bilirubinuria . Dr. Misbah-ul-Qamar

128. Bilirubin & its relation to jaundice Dr. Misbah-ul-Qamar

129. It is jaundice, nigga! Yellowish tint to the body tissues Dr. Misbah-ul-Qamar

130. Jaundice—Excess Bilirubin in the ECF Large quantities of bilirubin in the extracellular fluids, Free Bilirubin Or Conjugated Bilirubin . Normal plasma concentration = 0.5 mg/dl Detectable clinically when plasma bilirubin exceeds 1.5mg/dl Can rise to = 40 mg/dl Dr. Misbah-ul-Qamar

131. What Could Be The Causes Of Jaundice Excessive hemolysis Obstruction to bile outflow from liver Dr. Misbah-ul-Qamar

132. Causes of jaundice ( 1) Hemolytic Jaundice Increased destruction of red blood cells, with rapid release of bilirubin into the blood. Excess bilirubin is beyond the conjugating ability of liver so the excess bilirubin is in UNCONJUGATED form (2) Obstructive Jaundice Obstruction of the bile ducts due to stones or damage to the liver cells due to cancer The bilurubin is normally conjugated but can not be excreted into the intestine due to obstruction. The bilirubin formed is CONJUGATED Dr. Misbah-ul-Qamar

133. Mechanisms producing jaundice: Increased production of bilirubin Impaired excretion of bilirubin Dr. Misbah-ul-Qamar

134. Types of jaundice: Hemolytic jaundice  prehepatic Hepatocellular jaundice  hepatic Cholestatic jaundice  post hepatic Dr. Misbah-ul-Qamar

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136. Hemolytic jaundice Also known as prehepatic jaundice Increased destruction of red blood cells or their precursors in bone marrow Anemia, malaria, neonatal jaundice, transfusion reactions and autoimmune diseases Previously known as achluric jaundice ( no bile pigments in urine & excessive unconjugated bilirubin in circulating blood ) Dr. Misbah-ul-Qamar

137. Hemolytic jaundice (cont’d) Clinical features: Pallor of skin Splenomegaly Normal or dark colored stools Urine is dark colored-increased urobilin Dr. Misbah-ul-Qamar

138. Hemolytic jaundice (cont’d) Investigations: Plasma bilirubin level high (< 6mg/dl) Hyperbilirubinaemia is of unconjugated type Urobilinogen is increased in urine No bilirubinurea Liver function tests are otherwise normal Dr. Misbah-ul-Qamar

139. Hepatocellular jaundice Results from inability of liver to transport bilirubin into bile as a consequence of parenchymal liver disease Congenital diseases like gilbert’s syndrome, crigler - najjar , dubin - johnson syndrome and rotor syndrome Acquired: Acute or chronic liver parenchymal disease Dr. Misbah-ul-Qamar

140. Hepatocellular jaundice Both conjugated and unconjugated bilirubin is increased in plasma Other clinical features and investigations vary with the underlying disease Dr. Misbah-ul-Qamar

141. Cholestatic jaundice Occurs as a result of obstruction of bile flow Stones in bile ducts, carcinoma of head of pancreas, ampullary carcinoma, cholangiocarcinoma , biliary strictures, drugs, alcohol, sclerosing cholangitis Dr. Misbah-ul-Qamar

142. Cholestatic jaundice Jaundice dark urine pale stools ( clay colored stools due to deficiency of bile salts ) Steatorrhea and weight loss Hyperbilirubinaemia of conjugated type Liver function tests are abnormal Dr. Misbah-ul-Qamar

143. Dr. Misbah-ul-Qamar Purple intensified on alcohol addition

144. Van den Bergh reaction It is a specific test for identification of increased serum bilirubin levels. Normal serum gives a negative Van Den Bergh reaction. Dr. Misbah-ul-Qamar

145. Van den Bergh reaction (cont’d) Principle: diazotitised sulfanilic acid reacts with bilirubin to form a purple coloured azobilirubin . Reagent used: Diazo reagent (mixture of sulphanilic acid, hydrochloric acid & sodium nitrite) Test- 2 types Direct (measures conjugated bilirubin)  produce purple color immediately Indirect (measures total bilirubin )  gives purple color only on addition of alcohol Dr. Misbah-ul-Qamar

146. Let’s get wasted? What does binge drinking do to your liver (ALD )? Causes acute or chronic inflammation of liver Dr. Misbah-ul-Qamar

147. Liver cirrhosis It is a late stage of scarring (fibrosis) of the liver caused by many forms of liver diseases & conditions, such as hepatitis & chronic alcoholism. 1 st sign of cirrhosis: Jaundice Survival rate of cirrhosis: at 5 years, it vary from 0-80% Dr. Misbah-ul-Qamar

148. LFTs Dr. Misbah-ul-Qamar

149. At a glance Bilirubin AST (10-40units/L) & ALT (7-56units/L), AST/ALT ratio is increased in disease. Total proteins (60-80g/L) & A/G ratio (normal: slightly higher than one) Dr. Misbah-ul-Qamar

150. Summary of LFTs Dr. Misbah-ul-Qamar

151. LFTs: Bilirubin 1 .Determination of total, unconjugated and conjugated bilirubin in serum Total serum bilirubin: 0.3-1.0mg/ dL Conjugated bilirubin: 0.1-0.3mg/ dL Unconjugated bilirubin: 0.2-0.7mg/ dL Dr. Misbah-ul-Qamar

152. 2.Urine bilirubin : presence of bilirubin in urine always indicates a disease Seen in hepatic and post hepatic jaundice Dr. Misbah-ul-Qamar

153. Estimation of urobilinogen Urobilin in urine Urobilinogen in feces Urobilinogen is colorless, urobilin has yellow pigment. Dr. Misbah-ul-Qamar

154. 3.Fecal urobilinogen : 100-250mg of urobilinogen is excreted in feces Increased in hemolytic jaundice Decreased in hepatic and post hepatic jaundice Dr. Misbah-ul-Qamar

155. 4.Urinary urobilin : Normally 0.5-4mg/day is excreted in urine Increased excretion in hemolytic conditions Decreased excretion in biliary obstruction Dr. Misbah-ul-Qamar

156. Serum transaminases: AST-SGOT ALT-SGPT Increased in hepatitis Dr. Misbah-ul-Qamar

157. Serum alkaline phosphatase: Level is increased in extrahepatic and intrahepatic biliary obstruction It is an early sign of cholestatic liver damage caused by drugs High values also occur in osteoblastic diseases of bones e.g. rickets Dr. Misbah-ul-Qamar

158. Plasma proteins level Serum albumin level decreases in liver disease Decreased albumin/globulin ratio Tests of coagulation Prothrombin time is prolonged Dr. Misbah-ul-Qamar

159. Cholesterol (free and esterified) levels of serum help in assessing liver function Increased in complete obstruction of bile duct Dr. Misbah-ul-Qamar

160. Indicator of glycogenic function of liver Intravenous galactose tolerance test : It determines the rate of utilization of galactose by liver. In liver damage, galactose is metabolized at a slower rate. 0.5 gram of galactose is given by intravenous injection. Normally it disappears in 75minutes. Dr. Misbah-ul-Qamar

161. Epinephrine tolerance test Response of liver glycogen to adrenaline for assessment of metabolic function of liver Epinephrine markedly stimulates glycogen breakdown to glucose in liver  increase in blood glucose levels Dr. Misbah-ul-Qamar

162. Tumor Plasma alpha fetoprotein : increased in primary hepatoma Dr. Misbah-ul-Qamar

163. Other investigations Viral markers( HbSAg , anti HCV) Ultrsonography , CT scan and MRI, Liver biopsy Dr. Misbah-ul-Qamar

164. Clinical manifestations of severe liver disease Asthenia (loss of strength) Jaundice Fetor hepaticus Hamorrhages Portal hypertension Ascites Hepatic encephalopathy Dr. Misbah-ul-Qamar

165. Symptoms of end-stage liver disease Easy bleeding or bruising Persistent or recurring yellowing of skin & eyes Intense itching Loss of appetite & nausea Swelling due to fluid buildup in abdomen & legs Dr. Misbah-ul-Qamar

166. Wilson’s disease/ hepatolenticular degeneration Rare genetic disorder Excess copper is stored in various body tissues, particularly the liver, brain & corneas of eyes Symptoms don ’ t appear until copper builds up in heavy amount  Jaundice , personality changes (anxiety, psychosis, speech & coordination problems) Kayser -Fleischer ring Dr. Misbah-ul-Qamar

167. ALF Dr. Misbah-ul-Qamar

168. Acute liver failure (ALF) It ia a rare syndrome defined by rapid decline in hepatic function . Dr. Misbah-ul-Qamar

169. ALF Cause: ALF might be caused by toxicity of drugs, viral infection, vascular problem (shock) etc. Features: Characterized by jaundice, coagulopathy (INR>1.5), & hepatic encephalopathy in patients with no evidence of prior liver disease. Dr. Misbah-ul-Qamar

170. Liver Repair Dr. Misbah-ul-Qamar

171. Liver repair Liver has a unique & extraordinary capacity for repair through regeneration, even in adult organisms, though not overnight nor for eternity. It can restore upto 70% of lost mass & function after just a few weeks. Dr. Misbah-ul-Qamar

172. Mechanism for Liver repair (cont’d) In a healthy adult liver, cells are dormant & rarely undergo cell division. However if liver is damaged, the liver cells re-enter the cell cycle to divide & produce more of themselves. Damaged liver cells undergo reprogramming to repair & restore themselves through a signal to return to an early stage of postnatal organ development. Dr. Misbah-ul-Qamar