Detailed medical flowchart of bilirubin metabolism with the following sequential steps and annotations: TITLE: "Bilirubin Metabolism" STEP 1 - HEME BREAKDOWN (in reticuloendothelial system / spleen): - Senescent RBCs (70-80%) + other heme proteins (myoglobin, cytochromes) → Heme - Enzyme: Heme oxygenase (requires NADPH + O₂) → releases CO + Fe³⁺ - Heme → Biliverdin (green, linear tetrapyrrole) - Enzyme: Biliverdin reductase (requires NADPH) - Biliverdin → Bilirubin (yellow, unconjugated / indirect) - Rate: ~250-350 mg bilirubin/day STEP 2 - PLASMA TRANSPORT: - Unconjugated bilirubin is WATER INSOLUBLE - Binds tightly to ALBUMIN for transport (high-affinity site: ~25 mg/100mL plasma) - Travels in blood to the liver - Label: "Indirect (unconjugated) bilirubin" STEP 3 - HEPATIC UPTAKE: - Bilirubin dissociates from albumin at the Space of Disse - Transported across sinusoidal membrane via OATP1B1/OATP1B3 (organic anion transporters) - Binds to intracellular proteins: Glutathione-S-transferase (ligandin) — prevents efflux back to blood STEP 4 - CONJUGATION (in hepatocyte smooth ER): - Enzyme: UDP-glucuronosyltransferase (UGT1A1) - Bilirubin + UDP-glucuronate → Bilirubin monoglucuronide (BMG) - BMG + UDP-glucuronate → Bilirubin diglucuronide (BDG) ← predominant form - Now WATER SOLUBLE ("direct" / conjugated bilirubin) - Rate-limiting step: SECRETION (not conjugation) STEP 5 - BILIARY SECRETION: - BDG actively transported across canalicular membrane by MRP-2 (multidrug resistance protein 2) - This is the RATE-LIMITING STEP of hepatic bilirubin metabolism - Enters bile canaliculi → bile ducts → small intestine STEP 6 - INTESTINAL METABOLISM: - Conjugated bilirubin (BDG) reaches terminal ileum/colon - Intestinal bacteria (β-glucuronidase) deconjugate bilirubin - Gut bacteria reduce bilirubin → Urobilinogen (colorless) - Urobilinogen → Stercobilinogen → Stercobilin (brown color of stool, oxidized) STEP 7 - ENTEROHEPATIC CIRCULATION: - ~20% urobilinogen reabsorbed from gut into portal blood - Most re-excreted by liver back into bile - Small amount (~1-4 mg/day) escapes into systemic circulation → filtered by kidneys → Urobilin in urine (yellow color) Include a side box labeled "CLINICAL CORRELATIONS": - Prehepatic jaundice: excess heme breakdown → excess unconjugated bilirubin - Hepatic jaundice: impaired uptake/conjugation → unconjugated hyperbilirubinemia (Crigler-Najjar, Gilbert syndrome) - Posthepatic jaundice: impaired excretion → conjugated hyperbilirubinemia (Dubin-Johnson, Rotor syndrome, cholestasis) Use color coding: yellow for bilirubin boxes, green for intestinal steps, pink for blood/plasma steps, blue for hepatocyte steps. Clear arrows between steps.