Porphyria | Anatomy2Medicine
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Porphyria

Heme metabolism

    • Heme
      • consists of a porphyrin ring coordinated with iron
      • found mainly in hemoglobin
      • it is also present in myoglobin and the cytochromes.
    • Heme synthesis
      • In the first step of heme synthesis, glycine and succinyl coenzyme A (CoA) condense to form delta-aminolevulinic acid (d-ALA).

 

  • Enzyme :delta-aminolevulinic acid synthase

 

        • Pyridoxal phosphate is the cofactor
        • Glycine is decarboxylated in this reaction.
        • Heme regulates its own production by repressing the synthesis of delta-ALA synthase in the liver
      • Two molecules of delta-ALA condense to form the pyrrole porphobilinogen.
        • Enzyme : delta-aminolevulinic acid dehydrogenase.
      • Four porphobilinogens form the first in a series of porphyrins; these are hydroxymethylbilane, uroporphyrinogen III, coproporphyrinogen III, and protoporphyrinogen IX.
      • The porphyrins are altered by decarboxylation and oxidation, and protoporphyrin IX is formed.
      • Protoporphyrin IX binds iron (Fe2+), forming heme.
        • Iron obtained from the diet is transported via transferrin and is stored as ferritin in the bone marrow
        • Vitamin C increases the uptake of iron from the intestinal tract.
        • Ceruloplasmin, a protein that contains copper, is involved in the oxidation of iron such that it can be carried by transferrin.
        • Excess iron is stored as hemosiderin.
      • Erythropoietin induces heme synthesis in bone marrow.
      • Heme stimulates synthesis of the protein globin by maintaining the translational initiation complex on the ribosome in its active state
      • Defects in the biosynthesis of heme result in a group of disorders known as porphyrias
    • Heme degradation
      • Red blood cells life span is about 120 days

 

  • Senescent RBCs are phagocytosed by cells of the reticuloendothelial system.
  • Globin is released and converted to aminoacids.

 

      • Heme is degraded to bilirubin,which is excreted in the bile.
      • Heme is oxidized and cleaved to produce carbon monoxide and biliverdin, a green pigment
      • Iron is released, oxidized, and returned by transferrin to the iron stores of the body.
      • Bilirubin
        • produced by reduction of biliverdin
        • carried by the protein albumin to the liver.
      • In the liver, bilirubin reacts with uridine diphosphate (UDP)-glucuronate to form bilirubin monoglucuronide, which is converted to the diglucuronide.
        • Formation of the diglucuronide increases the solubility of the pigment, and bilirubin diglucuronide is secreted into the bile.

 

  • Bacteria in the intestine convert bilirubin to urobilins and stercobilins, which give feces its brown color.

 

Applied aspects :

    • Lead poisoning.
      • delta-ALA dehydrogenase is inhibited by lead.
      • results in the anemia
      • Accumulation of lead leads to abdominal pain and encephalopathy with cognitive and motor impairment.
    • Crigler-Najjar syndrome

 

  • deficiency of bilirubin uridine diphosphate gluconyl transferase (UDP-GT).

 

      • Type I results from a complete absence of the gene,

 

  • Type II, a benign form, results from a mutation causing a partial deficiency of the gene

 

  • Gilbert syndrome
    • common and benign disorder (2% to 10% of the population)
    • results from decreased activity of UDP-GT.
    • Occasional bouts of mild jaundice with increased physiologic stress occur during hemolysis or hepatocellular injury.

Porphyrias

 

  • Porphyria cutanea tarda

 

      • Enzyme deficient :Uroporphyrinogen decarboxylase
      • Autosomal dominant disorder
      • Most common porphyria. (MCQ)
      • It results in photosensitivity with vesicles and bullae on skin of exposed areas.

 

  • delta-ALA dehydrogenase porphyria

 

      • Enzyme deficient : delta-ALA dehydrogenase
      • Autosomal recessive disorder
      • characterized by acute attacks of abdominal pain and neuropathy.

 

  • Acute intermittent porphyria

 

      • Enzyme deficient :Hydroxymethylbilane synthase (porphobilinogen deaminase)
      • Autosomal dominant disorder
      • periodic attacks of abdominal colic, peripheral neuropathy, psychiatric disorders, and tachy- cardia

 

  • Attacks are precipitated by drugs such as gonadal steroids, barbiturates, and alcohol.
  • Congenital erythropoietic porphyria

 

      • Enzyme deficient :Uroporphyrinogen III cosynthase
      • Autosomal recessive disorder
      • photosensitivity. ,hemolytic anemia and splenomegaly.

 

  • Hereditary coproporphyria

 

      • Enzyme deficient :Coproporphyrinogen oxidase
      • An autosomal dominant disorder
      • presents with photosensitivity and neurovisceral symptoms, like colic.

 

  • Variegate porphyria

 

      • Enzyme deficient :Protoporphyrinogen oxidase
      • An autosomal dominant disorder
      • presents with photosensitivity along with neurologic symptoms and developmental delay in children.

 

  • Erythropoietic protoporphyria

 

      • Enzyme deficient :Ferrochelatase
      • Autosomal dominant disorder
      • characterized by photosensitivity with skin lesions after brief sun exposure.

 

  • Patients may also have gallstones and mild liver dysfunction.