Jaundice V PharmD by Vineela.N

1. JAUNDICE Vineela Nekkanti V Pharm.D

2. Contents of the topic Definition Classification Signs and symptoms Diagnosis Pathophysiology Prevention Treatment

3. Definition : Jaundice, as in the French jaune , refers to the yellow discoloration of the skin. Also known as Icterus Jaundice is a liver disease characterized by elevated levels of bilirubin in the blood termed as hyperbilirubinaemia . Normal range of serum bilirubin concentration is 0.3-1.3mg/dl Jaundice occurs when bilirubin levels exceeds 2mg/dl

4. Introduction to Bilirubin : Bilirubin is a orange-yellow pigment formed in the liver by the breakdown of hemoglobin and excreted in bile. Two types of bilirubin : Conjugated and U nconjugated bilirubin Sources of Bilirubin : Catabolism of heme of hemoglobin (80-85%) Non-hemoglobin heme containing pigments such as myoglobin, catalase and cytochromes

5. Conjugated Bilirubin Unconjugated Bilirubin Water soluble Water Insoluble It reacts quickly to produce azobilirubin It reacts slowly to produce azobilirubin It produces azobilirubin only in the presence of dye It produces azobilirubin in the absence of dye Known by Direct bilirubin Known by Indirect bilirubin

6. Metabolism of Bilirubin

7. Types of Jaundice Prehepatic Jaundice Intrahepatic jaundice Post hepatic Jaundice

8. Type of Jaundice Pre-Hepatic Intra-hepatic Post-Hepatic Other Name Hemolytic jaundice Hepatocellular Jaundice Obstructive/ Regurgitation Jaundice Cause Increased hemolysis of erythrocytes Dysfunction of liver due to damage to parenchymal cells Obstruction of bile duct – prevents the passage of bile into intestine Examples Malaria, sickle cell anemia, incompatible blood transfusion Viral infection(hepatitis), poisons and toxins(chloroform, carbon tetrachloride, phosphorus), cirrhosis Gallstones, cancer of pancreas, gall bladder and bile duct

9. Type of Jaundice Pre-Hepatic Intra-hepatic Post-Hepatic Biochemical characteristics serum unconjugated bilirubin serum conjugated and unconjugated bilirubin, SGPT and SGOT Serum conjugated bilirubin and ALP Clinical manifestations Dark brown color stools Nausea and anorexia Nausea; GI pain and clay colored feces Stercobilinogen content Increased Absent Absent Urobilinogen content Increased Increased Increased

10. Etiology/Causes

11. Common Drugs Associated With Hyperbilirubinemia HEPATOCELLULAR CAUSES Acetominophen Alcohol Amiodarone Azulfidine Carbenicillin Clindamycin Colchicine Cyclophosphamide Diltiazem Ketoconazole Methyldopa Niacin Nifedipine NSAIDs Propylthiouracil Pyridium Pyrazinamide Quinidine Rifampicin Salicylates Verapamil

12. Common Drugs Associated With Hyperbilirubinemia CHOLESTATIC CAUSES Amitriptyline Androgenic steroids ( B ) Atenolol Augmentin Azathioprine Bactrim ( D ) Benzodiazeprines Captopril Carbamazole Chlordiazepoxide ( D)) Clofibrate Coumadin Cyclosporine Danazol ( B ) Dapsone Disopyramide Erythromycin Estrogens ( B ) Ethambutol Floxuridine 5-Flucytosine Fluoroquinolones Griseofulvin Haloperidol ( D ) Labetolol Nicotinic acid NSAIDs Penicillins Phenobarbital Phenothiazines ( D ) Phenytoin Tamoxifen Tegretol Thiabendazole ( D ) Thiazides Thiouracil Tolbutamide ( D ) Tricyclics ( D ) Verapamil Zidovudine

13. Increased bilirubin production Reduced bilirubin uptake by hepatic cells Disrupted intracellular conjugation Disrupted secretion of bilirubin into bile canaliculi Intra/extra-hepatic bile duct obstruction Lead to increases in free ( unconj .) bilirubin Result in rise in conj. bilirubin levels Etiopathogenesis

14. 1. INCREASED BILIRUBIN PRODUCTION ( unconj . Hyperbilirubinemia ) Hemolysis Increased destruction of RBCs eg sickle cell anemia, thalassemia Drastic increase in the amount of bilirubin produced Unconj . bilirubin levels rise due to liver’s inability to catch up to the increased rate of RBC destruction Prolonged hemolysis may lead to precipitation of bilirubin salts in the gall bladder and biliary network - result in formation of gallstones and conditions such as cholecystitis and biliary obstruction Other Degradation of Hb originating from areas of tissue infarctions and hematomas Ineffective erythropoiesis

15. 2. DECREASED HEPATIC UPTAKE ( unconj . Hyperbilirubinemia ) Several drugs have been reported to inhibit bilirubin uptake by the liver e.g . novobiocin , flavopiridol Bile MRP2 B + GST CB Plasma Hepatic cell Alb B Alb :GST B sER B + UDPGA UGT1A1

16. Neonatal jaundice occurs in 50% of newborns fetal bilirubin is eliminated by mother’s liver causes: hepatic mechanisms are not fully developed resulting in decreased ability to conjugate bilirubin rate of bilirubin production is increased due to shorter lifespan of RBCs Acquired disorders hepatitis, cirrhosis impaired liver function 3) DISRUPTED INTRACELLULAR CONJUGATION ( unconj . Hyperbilirubinemia )

17. Crigler-Najjar Syndrome, Type I (CN-I) recessive allele; mutation-induced loss of conjugating ability in the critical enzyme glucuronosyltransferase CN-II greatly reduced but detectable glucuronosyltransferase activity due to mutation (predominantly recessive); enzymatic activity can be induced by drugs Gilbert’s Syndrome glucuronosyl transferase activity reduced to 10-30% of normal; also accompanied by defective bilirubin uptake mechanism

18. 4) DISRUPTED SECRETION OF BILIRUBIN INTO BILE CANALICULI (conj. Hyperbilirubinemia ) Dubin –Johnson Syndrome mild conj. hyperbilirubinemia , but can increase with concurrent illness, pregnancy, and use of oral contraceptives; otherwise asymptomatic Inability of hepatocytes to secrete CB after it has formed Due to mutation in the MRP2 gene (autosomal recessive trait) Rotor Syndrome Autosomal recessive condition characterized by increased total bilirubin levels due to a rise in CB Caused by a defect in transport of bilirubin into bile

19. 5) Intra/extra-hepatic bile duct obstruction Intra-hepatic Obstruction of bile canaliculi , bile ductules or hepatic ducts Extra-hepatic Obstruction of cystic duct or common bile duct Cholecystitis Obstruction causes backup and reabsorption of CB which results in increased blood levels of CB

20. S igns and Symptoms Skin and sclerae - yellow Stool - light colour, clay coloured Dark urine Pain in abdomen Itching Trouble with sleeping Fatigue Swelling Ascites Mental confusion Coma Bleeding

21. Diagnosis Medical history and examination Urine test Liver function and blood tests Imaging tests Liver biopsy

22. Medical history and physical examination Patient interview for  abdominal pain, itchy skin or weight loss  malaria or hepatitis A  change of colour in your urine and stools history of prolonged alcohol  misuse Flu like symptoms Medications Occupation Physical examination : Yellowish discoloration of eye and skin Swelling of legs, ankle and feet Hepatomegaly

23. Urine test :  - to measure levels of a substance called  urobilinogen - more than normal urobilinogen levels : Pre and Intra hepatic jaundice - Less than normal urobilinogen level : Post hepatic jaundice Liver function and blood tests : Damage to liver releases liver enzymes like SGPT, SGOT and ALP and proteins, this indicates - Hepatitis - Alcoholic liver disease - cirrhosis

24. Imaging tests CT Scan MRI Scan Ultrasound Scan E ndoscopic retrograde cholangiopancreatography (ERCP ) Used  to check for abnormalities inside the liver or bile duct systems . Liver biopsy Used to diagnosis Cirrhosis and liver cancer.

25. Jaundice treatment The treatment given to someone with jaundice will depend on what type they have, how serious it is and what caused it. It may include tackling an underlying condition such as malaria and bothersome symptoms, such as itching. For genetic conditions that don't get better, like sickle cell anaemia , a blood transfusion may be given to replenish red blood cells in the body. If the bile duct system is blocked, an operation may be needed to unblock it. During these procedures measures may be taken to help prevent further problems, such as removal of the gallbladder. If the liver is found to be seriously damaged, a transplant may be an option

26. Treatment & Therapeutic Considerations PHOTOTHERAPY Through absorption of the wavelengths at the blue end of the spectrum (blue, green and white light), bilirubin is converted into water-soluble photoisomers . This transformation enhances the molecule’s excretion into bile without conjugation.

27. PHENOBARBITAL This drug is not approved by FDA for use in neither adult nor pediatric hyperbilirubinemia patients, due to possibility of significant systemic side-effects. Exact pathway is not known, but it is believed to act as an inducing agent on UDP- glucuronosyl transferase , thereby improving conjugation of bilirubin and its excretion. ALBUMIN A 25% infusion can be used in treating hyperbilirubinemia (esp. due to hemolytic disease). It is used in conjunction with exchange transfusion to bind bilirubin, enhancing its removal.

28. CLOFIBRATE ( ATROMID-S) This drug has been shown to reduce bilirubin levels via an unknown mechanism. Clofibrate is also associated with increased risk of developing cholelithiasis , cholecystitis , as well as functional liver abnormalities, which can worsen hyperbilirubinemia . PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY Allows extraction of stones and thus removal of the source of obstruction when present.

29. Prevention of Jaundice : Limit alcohol intake to not more than two drinks a day for men or one drink a day for women . Avoid exposure to  industrial chemicals . Do not use illegal drugs. Do not share needles or nasal snorting equipment . Vaccination : H epatitis A and Hepatitis B Maintain healthy body weight.