Jaundice & Abnormal Liver Span.pdf

JAUNDICE & ABNORMAL LIVER SPAN Dina C. Gonzales, MD, MHPEd, FPCP, FPSG, FPSDE (11-25-2013) Internal Medicine We’re

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“Don’t memorize. What you do is to picture or understand the problem.” ~Dean Dra. Gonzales

JAUNDICE BILIRUBIN PRODUCTION AND METABOLISM  250-300 mg of bilirubin/day is produced  70-80%  Breakdown of senescent of RBC (main source)  20-30%  Prematurely destroyed erythroid cells  Turnover of hemoproteins (e.g. mygolobin, cytochromes)  REMEMBER: Normal RBC lifespan = 120 days

 “Icterus” or “ictericia”  Yellowish discoloration of tissue resulting from deposition of bilirubin  2 main pathophysiologic mechanisms of jaundice:  Cholestasis  Hepatocellular disease SERUM HYPERBILIRUBINEMIA  Elevated serum bilirubin  Causes:  Liver disease  Hemolytic disorder  Icteric Sclera (Jaundice)  At least 3.0 mg/dL  High elastin content in sclerae  (+) affinity for bilirubin  As serum bilirubin levels rise:  Skin will become icteric or even green DIFFERENTIAL DIAGNOSIS OF YELLOWISH SKIN 1. Carotenoderma  Yellow color imparted to skin by presence of carotene with ingestion of excessive amounts of vegetables and fruit (carrots, squash) with carotene  Yellow palms, soles, forehead, nasolabial folds 2. Quinacrine treatment  Quinacrine is an anti-malarial drug, though used rarely nowadays  Can cause scleral icterus 3. Excessive exposure to phenols  Seen in factory workers BILIRUBINURIA  Darkening of urine 2º renal excretion of conjugated bilirubin  Another sensitive indicator of increased serum bilirubin

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1. FORMATION OF BILIRUBIN  Occurs in reticuloendothelial cells in liver and spleen  Reactions: 1. OXIDATIVE cleavage of -bridge of porphyrin group of hemoglobin to open the heme ring  Catalyzed by enzyme heme oxygenase 2. REDUCTION of central methylene bridge of bilirubin  Catalyzed by cytosolic enzyme bilirubin reductase  Bilirubin formed in reticuloendothelial cells  Insoluble in water  Reversible non-covalent binding to albumin (conjugation)  Renders bilirubin soluble and can be transported in blood 2. HEPATIC UPTAKE AND INTRACELLULAR BINDING

*Albumin is the main carrier protein in the blood, and is produced by the liver

 Within the hepatocyte, bilirubin is kept in solution by binding as a non-substrate ligand to several glutathione s-transferases

3. CONJUGATION  In the endoplasmic reticulum  Bilirubin is solubilized by conjugation to glucuronic acid forming BILIRUBIN MONOGLUCURONIDE and DIGLUCURONIDE  Conjugation of glucuronic acid to bilirubin is catalyzed by bilirubin uridine-diphosphate (UDP) glucuronosyltransferase (UGT) DEFINITION OF TERMS Complete absence of Bilirubin Crigler-Najjar Type I UDP glucoronosyltransferase Mutation in Bilirubin UDP Crigler-Najjar Type II glucoronosyltransferase Reduced activity of Bilirubin Gilbert’s syndrome UDP glucoronosyltransferase

4. EXCRETION  Bilirubin glucoronides are excreted across the canalicular membrane into the bile canaliculi by ATP dependent transport process mediated by canalicular membrane protein called multidrug resistance associated protein-2 (MRP2)

80-90% 10-20% Small fraction (