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Bilirubin Metabolism (bilirubin (sources: (breakdown of Hgb (dead RBCs) by…

- - - - passive diffusion
      - receptor-mediated endocytosis
    - - via uridine 5'-diphosphate glucuronyl transferase (UDPGT)
      - adds 1-2 glucuronide >> bilirubin mono- or di-glucuronide = conjugated bilirubin
  - - - multi-step hydrogenation
        
        urobilinogen
        
        majority reabsorbed
        
        urinary urobilinogen usually elevated in hyperbilirubinemia
        
        kidney >> urine as urobilin (2-5%)
        
        entero-hepatic circulation >> liver >> bile
        
        collective term for:
        
        stercobilinogen >> stercobilin (red-brown)
        
        mesobilinogen >> mesobilin
        
        urobilinogen (colorless) >> urobilin (yellow-orange)
        
        small amount remaining metabolized >> stercobilin (red-brown) >> feces
      - oxidation
        
        mesobilifuscins (brown)
    - - conjugation allows for bilirubin excretion;
        unconjugated does not reach gut except in neonates or disease
      - can be filtered by glomerulus & excreted in urine (H2O-soluble): inc. serum conjugated bilirubin >> inc. urinary bilirubin
    - - reabsorbed >> entero-hepatic circulation >> liver >> bile
- - - - physiologic neonatal jaundice
        
        Treatments
        
        phototherapy
        
        "bili light" for newborns w/ elevated unconjugated bilirubin
        
        more easily excreted in urine & bile
        
        light converts unconjugated to conjugated bilirubin
        
        phenobarbitone (inducing agent)
        
        albumin infusion
        
        exchange transfusion
        
        high level of hemolysis (fetal Hgb >> adult Hgb)
        
        inc. unconjugated bilirubin d/t
        
        low UDPGT soon after birth
        
        undeveloped intestinal flora
        
        canalicular mechanisms immature
        
        most neonates develop mild case days 2-5 after birth
        
        normalize w/in 2 weeks
        
        risk for kernicterus
        
        maternal-fetal blood group incompatibility (Rh, ABO)
        
        breast milk jaundice
        
        end of 1st week of life
        
        chemicals in breast milk (-) UDPGT
        
        usually harmless; resolves spontaneously
      - hemolysis
        
        hemolytic anemia d/t sickle cell, autoimmune, drug-induced
        
        results:
        
        inc. premature release of Hgb from RBCs
        
        rate of cell destruction (w/ release of unconjugated bilirubin) overcomes liver clearance >> inc. serum levels
        
        dark urine d/t inc. urobilinogen
        
        dark brown feces d/t inc. stercobilinogen
        
        most common hyperbili. in newborns w/ immature liver & dec. UDPGT activity
        
        ~1.5-3.0 mg/dL in adults =
    - - Crigler-Najjar Syndrome
        
        Type I
        
        rare, serious homozygous mutation >> complete absence of UDPGT
        
        severe elevation (5-20+ mg/dL)
        
        kernicterus in infants >> death w/in first year
        
        Tx: early liver transplant
        
        no response to phenobarbital (+ CYP450 enzyme)
        
        Type II
        
        less severe heterozygous mutation >> partial UDPGT deficiency
        
        kerincterus rare; affected survive to adulthood
        
        responds to phenobarbital
      - Gilbert's Syndrome
        
        3-5% of population
        
        mild elevation (1.5-3 mg/dL); rarely serious - only shows when stressed
        
        d/t enzyme mutation (UDPGT gene) >> dec. activity
        
        results:
        
        compensatory hemolysis
        
        impaired uptake
        
        impaired conjugation
        
        aka familial non-hemolytic non-obstructive jaundice
  - - - Dubin-Johnson Syndrome
        
        results:
        
        accumulates in hepatocytes >> backs up into circulation
        
        dark, greenish-black pigmentation of liver; biopsy reveals dark brown melanin-like pigment in hepatocytes & Kupffer cells
        
        no elevation of ALT, AST
        
        impaired excretion of various conjugated anions & bilirubin
        
        inborn error of metabolism >> defect of ATP-binding cassette
        
        total = 2-5 mg/dL
        
        benign, autosomal recessive mutation in MRP2
      - Rotor's Syndrome
        
        rare, relatively benign autosomal recessive
        
        similar to Dubin-Johnson w/o liver pigmentation
        
        main symptom: non-itching jaundice
    - - biliary obstruction
        
        cholelithiasis (bilirubin or cholesterol) blocking CBD is most common in adults
        
        90% conjugated (of total)
        
        results:
        
        conjugated backs up >> dark urine
        
        clay-colored, fatty stools d/t absence of stercobilinogen
        
        no bilirubin reaches GI tract >> no urobilinogen or stercobilin
        
        inflammation of biliary tract >> elevation (>5mg/dL )
        
        gram negative sepsis >> mild elevation (2-3 mg/dL)
        
        carcinoma of bile duct, head of pancreas, ampulla
  - - - hepatitis
        
        hepatocyte damage or destruction d/t viral infections, drugs
        
        results:
        
        impaired conjugation and/or
        
        blockage of excretion of conjugated
        
        hepatitis B total = 5-10 mg/dL
      - dark urine d/t inc. bilirubin & urobilinogen
      - pale-colored stools d/t reduced stercobilinogen
      - inc. activities of alanine & aspartate transaminases
      - inc. fecal fat (40-50%) >> bulky, foul smelling
      - alcoholic cirrhosis
        
        dec. excretion of bilirubin into bile
  - - - XS bilirubin production
      - dec. hepatocyte uptake
      - impaired bilirubin conjugation
      - impaired bile flow
    - - 15-20 mg/dL
      - form of permanent brain damage d/t XS jaundice d/t polycythemia or Rh incompatibility
      - severe motor dysfxn & retardation >> death
      - bilirubin crosses immature BBB >> precipitates in basal ganglia & other areas >> yellow staining
      - aka bilirubin encephalopathy