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Updated: Jan 31 2020

Heme Metabolism

  • Heme sythesis
    • Functions
      • hemoglobin
      • cytochrome b4
      • P450
    • Location of synthesis
      • involves both the mitochondria and the cytosol
      • occurs in nearly every cell
        • occurs in RBC progenitor cells
          • CANNOT occur in RBCs because they lack mitochondria
    • Pathway
      • ALA synthase is rate limiting enzyme (see above)
    • Deficiencies in heme synthesis
      • hemin
        • occurs when Fe3+ is incorporated instead of Fe2+
      • porphyria
        • causes
          • symptoms due toxic accumulation of pathway intermediates
            • aminolevulinic acid (ALA) causes neurological symptoms
            • protoporphyrins cause photosensitivity
              • conjugated structure what absorbs light energy and forms free radicals
          • symptoms worsened by
            • sunlight
            • P450 inducing drugs
              • stimulate the heme synthesis pathway to ↑ production
              • ex.) barbiturates, alcohol
        • treatment
          • limit exposure to sun and P450 inducing substances
          • hemin
            • inhibits new heme production
        • types
          • porphyria cutanea tarda
            • deficiency in uroporphyrinogen decarboxylase
            • AD
            • late onset (4th or 5th decade)
              • symptoms often noticed with alcohol consumption
            • presentation
              • photosensitivity
              • hyperpigmentation
                • body's attempt to protect the skin
              • dark red/brown colored urine
          • acute intermittent porphyria
            • deficiency in porphobilinogen deaminase
            • AD
            • late onset
            • presentation
              • NO photosensitivity
              • episodic psychological symptoms (paranoia, anxiety, depression)
              • vague abdominal pain
                • patients can present with a history of laparoscopies
              • dark red/brown colored urine
                • ALA and porphobilinogen (PBG) present in urine during symptoms
      • poisoning
        • lead
          • induced deficiency in ALA dehydratase and ferrochelatase
            • both enzymes are Zn2+ dependent metalloenzymes
            • Pb2+ replaces the Zn2+ at the active site
          • presentation
            • ↓ in IQ
            • microcytic anemia with coarse basophilic stippling
            • abdominal pain
            • ↑ in ALA without ↑ in PBG
              • differentiates from porphyrias
            • lead lines in bone and teeth xrays
            • nephrotoxicity
              • deposition in nuclei of proximal renal tubular cells
        • hexachlorobenzene
          • induced deficiency in uroporphyrinogen decarboxylase
          • presentation
            • hypertrichosis (↑ body hair coverage)
          • found in (now banned in USA) pesticides
      • iron deficiency
        • iron incorporated in the final step
        • result is microcytic hypochromic anemia
        • see Trace metals topic
      • vitamin B6 deficiency
        • rate limiting enzyme (ALA synthase) requires
        • most commonly due to isoniazid therapy
        • see Vitamins topic
  • Degradation of Heme
    • Function
      • rid body of hemoglobin removed from degraded RBCs
    • Location of degradation
      • spleen
        • site of RBC destruction
      • liver
        • site of bilirubin conjugation
      • intestine
        • conversion by normal gut flora
    • Pathway
  • Bilirubin
    • Properties
      • insoluble
        • must travel in blood bound to albumin
      • conjugation
        • direct (conjugated)
          • glucuronate group added
            • soluble
        • indirect (unconjugated)
          • glucuronate group not yet added
            • insoluble
    • Modified forms
      • urobilinogen
        • gives urine yellow color
      • stercobilin
        • gives feces brown color
          • with a blocked bile duct no stercobilin in feces and it is clay colored
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