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DOM Morning Report: Porphyria

Objectives. To know the first/rate-limiting enzyme in the heme pathwayTo recognize factors that can precipitate acute attacksTo understand the symptoms associated with overproduction of heme intermediates and the excretion thereof. Background. Uncommon and complexDeficiencies in activity of enzym

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DOM Morning Report: Porphyria

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    1. DOM Morning Report: Porphyria Week of November 10, 2008

    2. Objectives To know the first/rate-limiting enzyme in the heme pathway To recognize factors that can precipitate acute attacks To understand the symptoms associated with overproduction of heme intermediates and the excretion thereof

    3. Background Uncommon and complex Deficiencies in activity of enzymes in heme biosynthetic pathway Genetic Acquired

    4. Background Enzymatic deficiencies ? Excess metabolic intermediates ? Produced Excreted Accumulation in tissues ? Symptoms Neurovisceral Photocutaneous

    5. Background Identification of metabolites ? diagnosis Red cells Plasma Urine Feces

    6. History Classification Hepatic or erythroid Major site of production and accumulation Acute, chronic, or cutaneous Based on clinical signs and symptoms Now well-defined at molecular level Specific enzyme deficiency Tissues involved

    7. Heme Synthesis Initial and rate limiting step Glycine + succinyl-coenzyme A ? delta-aminolevulinic acid (ALA) Catalyzed by ALA synthase (ALAS) Required cofactor = pyridoxal-5-phosphate Feedback inhibition ? hepatic ALAS activity ? acute attack ? hepatic heme concentration ? remission

    8. Toxicity Neurovisceral complaints (Acute intermittent porphyria - AIP) Abdominal pain Vomiting Constipation Muscle weakness Mental symptoms Limb, head, neck, or chest pain Hypertension Tachycardia Convulsion Sensory loss Fever Respiratory paralysis Diarrhea

    9. Toxicity Precipitating factors Drugs Barbiturates Sulfonamide antibiotics Nutritional factors Reduced caloric intake Smoking Infections, surgery, and stress

    10. Toxicity Photosensitivity When porphyrins absorb light ? Excited energy state ? Formation of oxygen free radicals Often begins in childhood Affects sun-exposed areas Generally worse in spring and summer

    11. Toxicity Symptoms Itching Painful erythema Swelling Secondary infection is common

    12. Toxicity Hemolytic anemia Homozygous erythroid disease Congenital erythropietic porphyria (CEP) Hepatoerythropoietic porphyria (HEP) Erythropoietic porphyria (EPP) Splenomegaly Production of pigment-laden gallstones Compensatory expansion of marrow

    13. Excretion Pattern Neurovisceral complaints Water soluble porphyrin precursors ALA Porphobilinogen (PBG) Urine collection required for diagnosis AIP Hereditary corpoporphyria (HCP) Variegate porphyria (VP)

    14. Excretion Pattern Photosensitivity Excess production of uroporphyrin Water soluble Diagnosed by urine collection CEP HEP Porphyria cutanea tarda (PCT)

    15. Excretion Pattern Overproduction of protoporphyrin Virtually water-insoluble, but soluble in lipids Diagnosed by fecal collection and plasma porphyrin analysis VP EPP

    16. Diagnosis Clinical suspicion ? major complications Neurovisceral complaints Photosensitivity Hemolytic anemia

    17. Diagnosis Neurovisceral complaints Suggestive of hepatic disease ADP (ALA dehydratase porphyria) AIP HCP VP 24 hour urine ? ALA ? PBG

    18. Diagnosis Photosensitivity Suggestive of cutaneous/erythroid disease CEP PCT HEP HCP VP EPP

    19. Diagnosis 24 hour urine ? Porphyrin concentration Fecal or plasma porphyrin analysis

    20. Treatment Photocutaneous disease Mostly preventive (acute sxs irreversible) Avoidance of sun exposure Use of sunscreens Oral beta-carotene Charcoal Cholestyramine Phlebotomy Chloroquine

    21. Treatment Modifying underlying disease Hepatitis C, Hemochromatosis, Chemo Hypertransfusion, myelosuppression, stem cell or liver transplantation

    22. Treatment Neurovisceral disease Acute attack Supportive care Cessation of medications Treatment of intercurrent illnesses/infections Airway and respiratory support Free water restriction Pain control and/or sedation

    23. Treatment Intravenous heme preparations Hemin (Panhematin) Heme arginate Fewer side effects Investigational in US

    24. Treatment Prevention of future attacks Avoidance of provocative agents Updated list at www.porphyriafoundation.com Knowledge is incomplete LHRH agonists to interrupt menstrual cycle Smoking cessation Prompt treatment of infection Stress reduction Avoidance of reduced calorie intake

    25. Managing Other Conditions Choice of surgical medications Choice of antineoplastic agents Maintenance during acute illness Caloric intake Electrolyte balance

    26. Managing Other Conditions Symptom control Anticonvulsants Sedatives Pain medications Antiemetics Skin care to prevent infection/breakdown

    27. Objectives Revisited First/rate-limiting step in heme synthesis Glycine + succinyl-coenzyme A ? delta-aminolevulinic acid (ALA) Catalyzed by ALA synthase (ALAS) Events precipitating acute attack Drugs Reduced caloric intake Smoking Stress

    28. Objectives Revisited Symptom and excretion patterns Neurovisceral Urinary Cutaneous Urinary and fecal

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