1. Pathophysiology of Jaundice by Dr.Rahul M.D Final Year Department Of Physiology SMS Medical College ,Jaipur 2. Introduction. Jaundice (french: Jaune-Yellow) or icterus Is a yellowish discolouration of tissue resulting from the deposition of bilirubin . Tissue deposition of bilirubin occurs only in the presence of serum hyperbilirubinemia is a sign of either liver disease or a hemolytic disease. ( Reference : Harrisons textbook of medicine/16th ed/vol.1 /238-240) 3. Carotenemia and use of the drug Quinacrine are few other causes of yellow coloration of tissue . Carotenemia can be distinguished from jaundice by sparing of sclera. In 4-37% patients treated with Quinacrine , yellowish discolouration of skin is seen . Unlike carotenemia ;quinacrine can cause discolouration of sclera. 4. Slight increase in serum bilirubin are best detected by examining the Sclera as sclera is rich in elastin and the bilirubin has high affinity for the elastin . The normal plasma concentration of bilirubin is less than 21 mol/L (1.2 mg/dL). The presence of scleral icterus indicates a serum bilirubin of atleast 3.0 mg/dl. (Reference: Harrisons textbook of medicine/16thed/vol.1 /238-240) 5. Under steady state normal metabolic conditions about 3.9 mg/kg or 250 to 350 mg of bilirubin is produced each day from breakdown of Haem from RBC in spleen and liver. 1gm of hemoglobin yields 36.2 mg of bilirubin . Reference :API textbook of Medicine/7th ed/page-580. 6. The breakdown of haeme produces bilirubin (an insoluble waste product) Bilirubin must be made water soluble to be excreted. This transformation can be studied in 5 broad steps;- 1. Heme degradation & Formation of bilirubin 2. Plasma transport 3. Liver uptake & Conjugation 4. excretion of bilirubin 5. Formation and excretion of urobilinogen 7. Reference : Bilirubin metabolism: Applied physiology : X. Wang et al: Current Paediatrics (2006) 16, 7074 Heme degradation & Formation of bilirubin 8. Reference: Harrisons Internal Medicine/17thed/fig:297-1: Hepatocellular bilirubin transport : Albumin-bound bilirubin in sinusoidal blood passes through endothelial cell fenestrae to reach the hepatocyte surface, entering the cell by both facilitated and simple diffusional processes. Within the cell it is bound to glutathione-S-transferases and conjugated by bilirubin-UDP-glucuronosyltransferase (UGT1A1) to mono- and diglucuronides, which are actively transported across the canalicular membrane into the bile ABBREVIATIONS : ALB: albumin UCB :unconjugated bilirubin UGT1A1: bilirubin-UDP glucuronosyltransferase BMG: bilirubin monoglucuronide GST: glutathione-S-transferase MRP2: multidrug resistance associated protein 2 BDG : bilirubin diglucuronide BT :proposed bilirubin transporter 9. BILIRUBIN IN THE GUT 10. A recap on catabolism of hemoglobin 11. Van Den Berg test It is helpful in determining the type of bilirubin present in serum. normal serum gives a negative van den berg test. When diazo reagent is added to serum containing conjugated bilirubin (water soluble) a purple coloration is obtained within 30 seconds .This is called Direct positive van den berg reaction. It is performed using the diazo reagent (mixture of sulphanilic acid , hydrochloric acid and sodium nitrite). 12. When diazo reagent is added to serum containing mainly unconjugated biluruibin (water insoluble ), no colour is obtained but with addition of solvent like alcohol , purple colouration is obtained .This is Indirect positive van den berg reaction . 13. If the serum contains both unconjugated and conjugated bilirubin in high concentration the purple color is produced immediately (direct positive) which is further intensified by the addition of alcohol (indirect positive). This type of reaction is known as biphasic. Reference for van den berg test : Biochemistry : U.Satyanarayan :Elseveir: 4rth ed:chap 20/Pg 455 14. 1. Hemolytic (Prehepatic) : Intracorpuscular Defects: - Hereditary spherocytosis - Hemoglobinopathies : sickle cell anemia, -thalassemia Extra-corpuscular defects : - Infections: Malaria - Drugs : quinine ,sulphonamides - Burns - Poisons : snake venom - Mismatched blood transfusion ETIOLOGICAL CLASSIFICATION OF JAUNDICE 15. 2. Hepatocellular (Hepatic ) : a. Infections: viral hepatitis , malaria , typhoid ,septecemia b. Toxic : - Anaesthetic agents : Halothane , Chloroform - Antitubercular drugs: Rifampicin ,Isoniazid ,P.A.S - Metals : Arsenic ,Mercury ,Gold c. Cirrhosis: 1. Portal 2. billiary . 3. Obstructive jaundice (post hepatic) stones , stricture , parasites , ca head of pancreas , congenital biliary atresia 16. 4. Congenital Hyperbilirubinemia : A. Unconjugated : 1. Disturbance of bilirubin transport : Gilbert syndrome 2. Disturbance of bilirubin conjugation: Crigler Najjar Syndrome. B. Conjugated : Distrubance in excretion of Bilirubin : Dubin Johnson syndrome , Rotors Syndrome Reference: Practical Medicine : P.J .Mehta /16th ed/18-19 17. Van den berg test Indirect positive reaction Biphasic reaction Direct positive reaction Mechanism of Production Excessive breakdown of RBCs producing unconjugated bilirubin in the amounts more than the healthy liver can conjugate and excrete. Inability of liver to efficiently conjugate and transport bilirubin into the bile due to liver cell damage . Obstruction of the bile ducts so conjugated bilirubin cant flow through the biliary tract freely resulting in increased serum conjugated bilirubin. Type of serum bilirubin accumulated unconjugated hyperbilirubenemia. Both unconjugated & conjugated bilirubin is increased in serum conjugated hyperbilirubenemia. Hemolytic Jaundice (Prehepatic) Hepatic Jaundice Obstructive Jaundice (Post hepatic) 18. Urine urobilinogen Increases (liver excrete lot of conjugated bilirubin in the intestine with the bile so more urobilinogen is formed part of it is reabsorbed and goes to general circulation thus urine urobilinogen is increased.) Decreases (Damaged liver cells produce & excrete less of conjugated bilirubin so less urobilinogen is formed.) Markedly decreased/absent (due to obstruction, conjugated bilirubin is not released into the intestine thus no urobilinogen is formed. Hemolytic Jaundice (Prehepatic) Hepatic Jaundice Obstructive Jaundice (Post hepatic) Urine Bilirubin Absent (Unconjugated bilirubin is water insoluble transported in plasma in bound form with albumin .Since albumin is not filtered in urine ,unconjugated is too not filtered into urine so this is called Acholuric Jaundice.) Present (conjugated bilirubin is water soluble and present in plasma in dissolved form and gets filtered in urine , such jaundice is called choluric jaundice) Present (Since conjugated bilirubin is filtered in urine) 19. Hemolytic Jaundice (Pre hepatic) Hepatic Jaundice Obstructive Jaundice (Post hepatic) Faecal Fat level normal (as bile is present in gut for normal digestion of fat ) Increased (bile deficiency in the intestine so emulsification and absorption of fat is inadequate thus producing bulky ,pale greasy and foul smelling faeces called steatorrhoea ) Increased Faecal Stercobilinogen markedly increased reduced Absent Peripheral blood film Anemia ,reticulocytosis Normal Normal 20. Hemolytic Jaundice (Pre hepatic) Hepatic Jaundice Obstructive Jaundice (Post hepatic) Serum alkaline phosphatase normal Because excreted in bile increased Because less excretion in bile markedly increased Because not excreted in bile Plasma albumin, globulin and A/G Ratio normal albumin is decreased due to less synthesis by damaged . Globulin increases A/G Ratio decreases Normal Liver function tests normal As liver is healthy Impaired As liver is damaged normal or mildly impaired 21. Clinical characterstics Hemolytic Jaundice (Pre hepatic) Hepatic Jaundice Obstructive Jaundice (Post hepatic) Pruritis Absent Transient Marked Tender Liver Absent May be present Absent Spleen Present may be present Absent Gall bladder Not Palpable Not Palpable May be Palpable Urine colour Normal Deep yellow Deep yellow stool colour Dark brown coloured stool Pale faeces Clay coloured stool Reference :PJ Mehta : Practical Medicine :16th ed : Page 20 & Indu Khurana :Textbook of Physiology :Table 3.2-3 Page.161. 22. FIG.20.1 (A) Normal Bilirubin Metabolism (B) alterations in bilirubin metabolism along with enzymes in 3 types of jaundice. Note: RED-changes in hemolytic jaundice . Green changes in hepatic jaundice . Blue changes in obstructive jaundice Reference : Biochemistry :U.Satyanarayan:fig.20.1/chap20/457 23. Crigler-Najjar Syndrome (Type I) Is a rare genetic disorder and is caused by complete absence of UDP-glucuronyltransferase (UGT1A1) It is inherited as an autosomal recessive trait. Severe hyperbilirubenemia develops within the first 72 hours of life. Serum bilirubin levels are >30 mg/dl resulting into kernicterus . 24. Management is by repeated exchange transfusion and phototherapy to keep the serum bilirubin