Bilirubin PDF

Bilirubin Jason Ryan, MD, MPH Bile Produced in liver Stored in gall bladder Secreted into duodenum after meal Wikipedia/Public Domain Mostly water Phospholipids, electrolytes Bile salts – necessary for lipid absorption Bilirubin – mode of excretion from body Bilirubin...

Bilirubin Jason Ryan, MD, MPH Bile Produced in liver Stored in gall bladder Secreted into duodenum after meal Wikipedia/Public Domain Mostly water Phospholipids, electrolytes Bile salts – necessary for lipid absorption Bilirubin – mode of excretion from body Bilirubin Bilirubin Heme (brown/yellow color) Heme Metabolism Heme released from old RBCs Some from myoglobin, cytochromes Macrophages engulf residual heme Converted to biliverdin then bilirubin NADPH NADPH Bilirubin Heme Biliverdin ( brown/yellow) Heme Biliverdin Oxygenase (green) Reductase Bilirubin Poor solubility in water Carried by albumin to liver Bilirubin Bilirubin Conjugation in Liver Unconjugated Bilirubin UDP glucuronyltransferase Glucuronic Acid Conjugated Bilirubin (Bilirubin diglucuronide) Bilirubin Conjugation Bilirubin-UDP-glucuronyltransferase (UGT) Adds glucuronic acid molecules to bilirubin Produce more water soluble compounds Bilirubin monoglucuronide Bilirubin diglucuronide ↑ water solubility facilitates excretion with bile Bilirubin Metabolism Intestines Two conversions by bacteria #1: Converted back to unconjugated in intestines Distal small intestine and colon Bacteria beta-glucuronidase enzymes #2: Unconjugated bilirubin → urobilinogen Via bacterial enzymes Open Stax College Urobilinogen Bilirubin Urobilinogen Urobilinogen Fate #1: Excretion in feces (80-90%) Converted to stercobilin (makes stool dark) Fate #2: Reabsorbed by intestines (10-20%) Most taken up by liver Small amount excreted in urine Converted to urobilin (makes urine yellow) Stercobilin Urobilin  Bilirubin Unconjugated Bilirubin Urobilinogen Urobilin Open Stax College β-glucuronidase Conjugated Unconjugated Urobilinogen Stercobilin Bilirubin Bilirubin Bacteria Bacteria Bilirubin Clinical Measurements Van den Bergh reaction Coupling of bilirubin with a diazonium salt Forms a colored complex Serum Conjugated bilirubin Soluble in water Can directly undergo the reaction in solution Serum Unconjugated bilirubin Not soluble in water Must be mixed with alcohol first Then can add to Van den Bergh medium “Indirect” bilirubin Bilirubin Clinical Measurements Urine Bilirubin (conjugated only): Normal absent Urobilinogen: Normally a small amount Jaundice Yellowing of skin, conjunctiva, mucous membranes Scleral icterus (eyes) often earliest sign Also visualized early under the tongue Normal: total bilirubin 3.0mg/dl Jaundice James Heilman, MD Dark Urine Seen with elevated conjugated bilirubin Only conjugated bilirubin is water soluble Also seen in: Rhabdomyolysis (myoglobin) Hematuria any cause Dehydration (common in actual practice) James Heilman, MD Bilirubin Metabolism Clinical Assessment #1: Serum bilirubin Total Direct Indirect #2: Urine urobilinogen (normally small amount) #3: Urine bilirubin (conjugated - normally absent) Hyperbilirubinemia Four general causes of ↑ bilirubin Hemolysis Biliary obstruction (cholestasis) Liver disease Special causes Hyperbilirubinemia Hemolysis Hemolysis or large hematomas → ↑ heme metabolism Elevated serum unconjugated bilirubin Too much bilirubin to liver (overwhelms capacity) No urine bilirubin detected Unconjugated bilirubin cannot cross glomerulus Increased urobilinogen More bilirubin → more urobilinogen Ed Uthman/Flikr Hyperbilirubinemia Biliary Obstruction Cholestasis = lack of bile flow Extrahepatic: Gallstone, pancreatic mass Intrahepatic: Alcoholic liver disease, viral hepatitis Conjugation occurs normally Excretion impaired → Elevated direct bilirubin Hyperbilirubinemia Biliary Obstruction Findings: Cholestatic LFT pattern: ↑ AlkP >> ↑ ALT/AST Clay colored stools (lack of stercobilin) Hyperbilirubinemia Biliary Obstruction Urine bilirubin detected Conjugated bilirubin water soluble Crosses glomerulus → urine Results in dark urine Absent urobilinogen No bilirubin to intestine Loss of formation of urobilinogen Hyperbilirubinemia Primary Liver Diseases Bilirubin fractionation unreliable for liver disease Often mixed increase of direct/indirect Usual finding: elevated total bilirubin Diagnosis made by: LFTs, antibody tests, imaging, biopsy Hyperbilirubinemia Primary Liver Diseases Unconjugated hyperbilirubinemia Occurs in liver disease with significant hepatocyte damage Chronic hepatitis, advanced cirrhosis Conjugated hyperbilirubinemia Occurs in “intrahepatic cholestasis” Liver disease with prominent damage to bile ducts Viral hepatitis, alcoholic hepatitis, NASH Many liver diseases have elements of hepatocyte and intrahepatic bile duct involvement Urobilinogen Primary Liver Diseases ↑↑ early in liver disease Urobilinogen from intestines reabsorbed as usual Cannot be excreted in bile Spills into urine ↓↓ late in liver disease Lack of conjugated bilirubin to intestines Less formation of urobilinogen Less urobilinogen in urine Source: Sircar, S. (2008) Principles of Medical Physiology, Thieme Medical Publishers Hyperbilirubinemia Lab Findings Disorder Bilirubin Type Urine Bilirubin Urobilinogen Hemolysis Indirect Normal (none) Increased Obstruction Direct Increased (dark) Absent Liver Disease Mixed Usually ↑ Variable Hyperbilirubinemia Special Causes Rifampin/Probenecid Gilbert’s Syndrome Crigler-Najjar Syndrome Dubin-Johnson Syndrome Rotor’s Syndrome Neonatal Jaundice Rifampin/Probenecid Rifampin (antibiotic) Probenecid (gout) Compete with bilirubin for uptake by liver Blunt hepatic uptake of unconjugated bilirubin Result: mild ↑ unconjugated bilirubin (and total) All other LFTs normal Gilbert’s Syndrome ↓ UDP-glucuronyltransferase function Commonly defective promoter UGT gene Result: Mild decrease in enzyme levels Findings: Mild ↑ total and unconjugated bilirubin (usually 20 mg/dl) Jaundice Kernicterus (cause of death) Often fatal Kernicterus Unconjugated bilirubin soluble in fats Easily crosses blood-brain barrier or enters placenta Acts as a neurotoxin Basal ganglia; brain stem nuclei Usually need bilirubin level >25mg/dl Newborns (esp. preterm) particularly vulnerable Andwhatsnext/Wikipedia Crigler-Najjar Syndrome Type II: Less severe (bilirubin AlkP Isolated No Evaluate AST/ALT Hyperbilirubinemia? Alk Phos Yes AlkP>AST/ALT Direct Indirect Dubin-Johnson Hemolysis Cholestatic Pattern Rotor’s Drugs Gallstones Gilbert’s Pancreatic Mass Crigler-Najjar Neonatal