Jaundice

Jaundice and clinical conditions associated with jaundice.jaundice, clinical conditions associated with jaundice, hemolytic jaundice, prehepatic jaundice, hepatic jaundice, posthepatic jaundice, obstructive jaundice, wilson's disease, hepatitis virus B, hepatitis virus C, HBV, HCV, Cholelithiasis, cholesterol stone, pigment stone, brown stone, black stone, bilirubin, transaminase, AST, ALT, ALP, pancreatic carcinoma, carcinoma of pancreatic head

1. JAUNDICE MARYAM JAMILAH BINTI ABDUL HAMID 082013100002 IMS BANGALORE

2. LEARNING OUTCOME Definition Clinical examination Classification Etiology Pathogenesis

3. DEFINITION A yellowish discoloration of tissue resulting from the deposition of bilirubin Also known as icterus Clinical jaundice when serum bilirubin level >2 mg/dl

4. CLINICAL EXAMINATION Sclera Conjunctiva Underneath the tongue Skin

5. What is bilirubin? Tetrapyrrole pigment, 250-300 mg/day produced Source: End product of heme degradation Senescent erythrocyte (70-80%) Prematurely destroyed erythroid cells in bone marrow Turnover of hemoproteins ; myoglobin & cytochromes formed in tissues throughout the body

6. What is bilirubin? (cont.) Normal values & types:- Total serum bilirubin : <1 mg/dl Conjugated/direct bilirubin ; 0.1- 0.3 mg/dl Unconjugated /indirect bilirubin ; 0.2-0.7 mg/dl Formation:- In reticuloendothelial cells ; spleen & liver Microsomal enzyme; heme oxygenase Cleaves α bridge of the porphyrin group & opens the heme ring End-product: biliverdin , carbon monoxide, iron Cytosolic enzyme; biliverdin reductase Reduces central methylene bridge of biliverdin End-product: bilirubin

7. Unconjugated bilirubin bound to albumin is taken up by hepatocytes via a process that at least partly involves carrier-mediated membrane transport In hepatocytes , unconjugated bilirubin is bound in the cytosol to a number of proteins including proteins in the glutathione-S- transferase superfamily . Protein decrease efflux of bilirubin back into serum and present bilirubin for conjugation

8. In endoplasmic reticulum , bilirubin is solubilized by conjugation to glucuronic acid , a process that disrupts the internal H-bonds & yields bilirubin monoglucoronide & diglucoronide ; Uridine diphosphate-glucuronosyl transferase (UDPGT)

9. Diffuse from endoplasmic reticulum to canalicular membrane  bile  duodenum  proximal small intestine  distal ileum & colon  hydrolyzed to unconjugated bilirubin by β glucuronidases  reduced by normal gut bacteria & form colourless tetrapyrroles ( urobilinogens )

10. A) 80-90%of urobilinogens excreted in feces either unchanged or into urobilins B) 10-20% urobilinogens enters enterohepatic circulation and re-excreted by liver *however, <3 mg/dl escapes hepatic uptakes and filter across the renal glomerulus & excreted in urine

11. Bilirubin should be balanced ! Balance between input from production of bilirubin and hepatic/ biliary removal of the pigment in normal person Causes of hyperbilirubinemia Overproduction of bilirubin Impaired uptake, conjugation, or excretion of bilirubin Regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts

12. Increase unconjugated bilirubin Overproduction Impairment of uptake Defect conjugation of bilirubin Increase conjugated bilirubin Decrease excretion into the bile ductile Backward leakage of the pigment

13. PREHEPATIC JAUNDICE UNCONJUGATED HYPERBILIRUBINEMIA HEMOLYTIC DISEASE Inherited Spherocytosis , elliptocytosis , G6PD, Pyruvate kinase Sickle cell anemia Acquired Microangiopathic hemolytic anemia Spur cell anemia Paroxysmal nocturnal hemoglobinuria Immune hemolysis Parasitic infection; malaria, babesiosis INEFFECTIVE ERYTHROPOIESIS Cobalamin , folate,iron deficiencies Thalassemia DRUGS Rifampicin , probenecid , ribavirin INHERITED CONDITIONS Crigler-Najjar type I & II Gilbert’s syndrome

14. CONJUGATED HYPERBILIRUBINEMIA INHERITED CONDITIONS Dubin -Johnson syndrome Rotor’s syndrome PREHEPATIC JAUNDICE

15. DUBIN-JOHNSON SYNDROME Autosomal recessive trait Defect excretion of conjugated bilirubin so increase conjugated bilirubin Defect ATP-dependent organic anion transport in bile canaliculi ; mutation of MRP-2 protein Black liver jaundice CRIGLER-NAJJAR Defect in conjugation Type 1 (congenital non-hemolytic jaundice) Deficiency of UDP glucuronyl transferase Jaundice appears within 24 hr after birth, kernicterus Fatal ; die within 2 years old Type 2 Milder form GILBERT’S SYNDROME Autosomal dominant Defect uptake of bilirubin by liver 3 mg/dl serum bilirubin, mild jaundice

16. Black liver jaundice seen in Dubin -Johnson syndrome Phototheraphy

17. HEPATIC JAUNDICE VIRAL HEPATITIS Hepatitis virus; HAV, HBV , HCV , HDV, HEV Epstein-Barr virus Cytomegalovirus Herpes simplex virus ALCOHOL WILSON’S DISEASE AUTOIMMUNE HEPATITIS DRUG TOXICITY Predict/dose dependent; paracetamol Unpredictable/ idiosyncratic; isoniazid , chloramphenicol ENVIRONMENTAL TOXINS Vinyl chloride Jamaica bush tea Wild mushroom

18. Hepatitis B, Hepatitis C, Hepatitis D

19. Alcohol Liver Disease Excessive intake of alcohol; everyday Stages:- MINIMAL CHANGE, OR FATTY LIVER not linked to deterioration in liver function liver function tests (LFT); abnormal Fatty liver is reversible with abstinence from alcohol ALCOHOLIC HEPATITIS mild to life threatening LFTs will almost always be abnormal may develop jaundice abstinence from alcohol can reverse the effects continue to drink heavily lead to cirrhosis

20. CIRRHOSIS irreversible stage of ALD scarring of the liver and development of liver nodules severely affects liver function and reduces life expectancy LFT abnormal Jaundice , bruising or bleeding Can lead to decompensated ALD

21. Wilson’s disease Rare autosomal recessive inherited disorder of copper metabolism Excessive deposition of copper in the liver, brain, and other tissues Often fatal if not recognized and treated when symptomatic Kayser -Fleischer Ring Rhodanine stain (specific for copper)

22. OBSTRUCTIVE JAUNDICE INTRAHEPATIC Viral hepatitis Fibrosing cholestatic hepatitis (HBV,HBC) HAV, EBV CMV Alcoholic hepatitis Drug toxicity Pure cholestasis ; anabolic & contraceptive steroids Cholestatic hepatitis; erythromycin estolate,chlorpromazine Chr. Cholestasis ; chlorpromazine, prochlorperazine Primary biliary cirrhosis Primary sclerosing cholangitis Vanishing bile duct syndrome Inherites Cholestasis of pregnancy Total parental nutrition Nonhepatobiliary sepsis Benign postoperative cholestasis Paraneoplastic syndrome Venoocclusive disease Graft- vs -host disease Infiltrative disease; TB, lymphoma, amyloid Infections; malaria, leptospirosis

23. EXTRAHEPATIC MALIGNANT Cholangiocarcinoma Pancreatic cancer (head) Gallbladder cancer Ampullary cancer Malignant involvement of the porta hepatis lymph nodes BENIGN Cholelithiasis Choledocholithiasis Postoperative biliary structure Primary sclerosing cholangitis Chr. Pancreatitis AIDS cholangio pathy Mirizzi’s syndrome Parasitic disease; ascariasis

24. Cholelithiasis 10% to 20% in Western countries & Northern Hemisphere, 20% to 40% in Latin American countries, 3% to 4% in Asian countries Cholesterol and Pigment stones  insoluble calcium bilirubinate salts Unconjugated bilirubin in the biliary tree Factors: Demography: Asian more than Western, rural more than urban Chronic hemolysis (e.g., sickle cell anemia , hereditary spherocytosis ) Biliary infection Gastrointestinal disorders : ileal disease (e.g., Crohn disease), ileal resection or bypass, cystic fibrosis with pancreatic insufficiency

25. BLACK PIGMENT STONE BROWN PIGMENT STONE In sterile gallbladder bile In infected intrahepatic or extrahepatic ducts Small, fragile to touch and numerous Soft, greasy, soaplike consistency Radiopaque Radiolucent

26. Choledocholithiasis Stones within the biliary tree Obstructions to the flow of bile In Western nations, almost all stones are derived from the gallbladder In Asia, incidence of primary ductal and intrahepatic (usually pigmented stone formation) is more higher Factors: Bile stasis, bactibilia , chemical imbalances, pH imbalances, increased bilirubin excretion and the formation of sludge

27. Pancreatic carcinoma Location: head of pancrease Causing obstruction of the common bile duct and pancreatic duct Obstruction jaundice

28. REFERENCES Robbins Pathology 9 th edition Harrison’s Internal Medicine 18 th Edition http://www.netdoctor.co.uk/diseases/facts/alcliver.htm http://imgarcade.com/1/pigment-gallstones/

29. THANK YOU