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PORPHYRIAS

  • Metabolic disorders of heme synthesis; may be hereditary or acquired

  • Photosensitivity due to exposure of ultraviolet (UV) radiation in the Soret band (400–410 nm)

Classification of Porphyrias: Erythropoietic and Hepatic Forms (Based on the Primary Site of Expression of the Enzymatic Defect)

  • Nonacute porphyrias: porphyria cutanea tarda (PCT), erythropoietic porphyria (EPP), congenital erythropoietic porphyria (CEP), and hepatoerythropoietic porphyria (HEP); most common cutaneous manifestation is photosensitivity

  • Acute porphyrias: acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and δ-aminolevulinic acid (ALA) dehydratase deficiency porphyria (plumboporphyria)

  • Heme biosynthesis

    • Major sites of heme synthesis are bone marrow (85%) and in the liver

    • Initial reaction takes place in the mitochondrion within the cell

    • Condensation of 1-glycine and 1-succinylCoA by ALA synthase: this is the rate-limiting reaction of heme biosynthesis

    • Mitochondrial ALA is transported to the cytosol

    • ALA dehydratase (also called porphobilinogen synthase) dimerizes 2 molecules of ALA to produce porphobilinogen

    • Uroporphyrinogen I synthase, also called porphobilinogen deaminase or PBG deaminase, causes condensation of 4 molecules of porphobilinogen to produce intermediate hydroxymethylbilane

    • Hydroxymethylbilane undergoes enzymatic conversion to uroporphyrinogen III by uroporphyrinogen synthase plus a protein known as uroporphyrinogen III cosynthase

    • In the cytosol, the acetate substituents of uroporphyrinogen (normal uroporphyrinogen III or abnormal uroporphyrinogen I) are decarboxylated by uroporphyrinogen decarboxylase (UROD)

    • The resulting coproporphyrinogen III intermediate is transported to the interior of the mitochondrion, where, after decarboxylation, protoporphyrinogen IX results

    • In the mitochondrion, protoporphyrinogen IX is converted to protoporphyrin IX by protoporphyrinogen IX oxidase

    • Final reaction in heme synthesis takes place in the mitochondrion by ferrochelatase

ERYTHROPOIETIC PORPHYRIAS

Congenital Erythropoietic Porphyria (CEP)

GUNTHER DISEASE

  • Autosomal recessive with complete absence of uroporphyrinogen III synthase (UROS) gene activity; affects uroporphyrinogen III synthase and the production of uroporphyrinogen III

  • Results in massive accumulation and excretion of uroporphyrin I and coproporphyrin I

  • Clinical findings (appear soon after birth)

    • Cutaneous: severe photosensitivity with burning, edema, bullae, mutilating scars, loss of brows/lashes, hypertrichosis, hyperpigmentation/hypopigmentation

    • Ocular: photophobia, kerato conjunctivitis, ectropion, symblepharon, loss of vision

    • Other: gallstones possible, cartilaginous breakdown, red/brown urine, erythrodontia (seen with Wood's lamp), splenomegaly, hemolytic anemia

  • Laboratory findings

    • Urine: uroporphyrin I, coproporphyrin I

    • Stool: coproporphyrin I

    • Blood: plasma-uroporphyrin I, coprophorphyrin I; red blood cell (RBC): uroporphyrin I, coproporphyrin, and some protoporphyrin

  • Other diagnostic tests: urine fluoresces reddish pink

  • Treatment: strict photoprotection, splenectomy, blood transfusions, activated charcoal, hydroxyruea, oral ascorbic acid, and α-tocopherol

Erythropoietic Protoporphyria (EPP)

  • Autosomal dominant, FECH gene mutation results in partial ferrochelatase deficiency

  • Clinical findings

    • Cutaneous (photosensitivity): painful erythematous, edematous plaques after exposure to UV light that may heal with scarring, skin lichenification, waxy, leathery pseudovesicles, and nail changes

    • Hepatic: porphyrin gallstones (early age), liver disease (10% of patients): jaundice, cirrhosis

  • Laboratory findings

    • Urine: normal (protoporphyrin IX is not water soluble)

    • Stool: protoporphyrin

    • Blood (RBC/plasma): protoporphyrin

  • Treatment: ...

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