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Porphyrias ...heme metabolism, pathophysiology, classification
The document discusses porphyrias, which are a group of disorders caused by defects in heme biosynthesis, classified into hepatic and erythropoietic types. It details various types of porphyrias, their symptoms, diagnostic methods, treatment options, and complications associated with the conditions. The document emphasizes the importance of recognizing precipitating factors and provides information on clinical presentations, differential diagnoses, and specific management strategies.
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Porphyrias ...heme metabolism, pathophysiology, classification
- 1. Dr.Spandana Kanaparthi Mediciti InstituteOf Medical Sciences
- 2. The term porphyria- derived from the Greek word "porphyra", meaning "purple pigment" The porphyrias -group of disorders - defects in the biosynthesis of heme
- 3. Heme -iron porphyrin Heme biosynthesis - in most mammalian cells except mature RBC - lack mitochondria 85% of heme synthesis -in erythroid precursor cells in the bone marrow and the majority of the remainder in hepatocytes Examples - Hemoglobin, Myoglobin, Cytochrome C, Catalase, Tryptophan pyrrolase
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- 9. Depending onthe site of overproduction and accumulation, they are classified as hepatic and erythropoietic porphyrias. Hepatic porphyrias-adult life 1. Acute intermittent porphyria(AIP) 2. Hereditary coproporphyria(HC) 3. Variegate porphyria(VP) 4. ALA Dehydratase deficient porphyria(ADP)/Plumboporphyria 5. Porphyria cutanea tarda(PCT) AD AR Sporadic
- 10. Erythropoietic porphyrias: atbirth/early childhood 1. Erythropoietic porphyria(EPP) 2. Congenital erythropoietic porphyria(CEP) 3. X-linked protoporphyria(XLP) Hepatoerythropoietic porphyria(HEP) AR AR
- 11. Also classifiedas acute and non- acute(cutaneous): Acute-AIP,HC,VP, ADP Cutaneous- PCT, CEP, EPP, HEP
- 12. If theenzymatic defects-in the initial steps- early metabolic intermediates accumulate – neurovisceral symptoms If the enzymatic defects - in the final steps- sunlight-induced cutaneous lesions due to porphyrin accumulation in the skin
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- 16. HMB synthaseactivity less than 50% Precipitating factors-steroids, porphyrinogenic drugs, alcohol, low calorie diet(hPGC 1α ), hormones C/F:Neurovisceral symptoms Visceral symptoms: Abdominal pain Nausea, vomiting, Constipation, Abd. distension Hypertension and tachycardia
- 17. Barbiturates Carabamazepine Chloroquine Dapsone Diclofenac Erythromycin Sulfonul ureas PORPHYRINOGENIC DRUGS Ethylalcohol Phenytoin Furosemide Griseofulvin OCPs Rifampicin Sodium Valproate
- 18. Neuropsychiatric symptoms oMotor- proximal muscles initially o DTR decreased or absent o Sensory-Paresthesias and loss of sensations o Mental- Anxiety, insomnia, depression, hallucinations, paranoia o Seizures
- 19. oElectrolyte imbalance- hyponatremia Infants(homozygous)- developmentaldelay, bilateral cataract, hepatosplenomegaly – die at an early age.
- 20. Diagnosis: o Increasedlevels of plasma and urinary ALA and PBG - elevated for longer period. o Fecal porphyrins-Normal, unlike HC and VP. o Enzyme assay and Mutation analysis
- 21. Treatment: •IV Hemin 3-4mg/Kg(lyophilizedhematin / heme albumin/ heme arginate) daily for 4 days. •IV Glucose(Carb. loading)-300g/day. •Narcotic analgesics for pain, •Avoidance of precipitating factors
- 23. Complications: o Renalfailure o Hepatocellular Ca.(Hepatic imaging yearly) D/D: o Acute appendicitis o Dysmenorrhoea o Cholecystitis o Peripheral neuropathy
- 24. A rareacute hepatic porphyria. The symptomatic patients are homozygous with <10% of ALAD activity. C/F:Neurovisceral symptoms with earlier age of onset
- 25. Diagnosis: Elevated levelsof plasma and urinary ALA and urinary coproporphyrin III Enzyme assay(ALAD activity less than 10%) Gene mutation analysis Prenatal diagnosis
- 26. Differential Diagnosis Hereditary Tyrosinemia type I Lead intoxication Treatment: similar to that of AIP. Infants-hyperalimentation and periodic blood transfusions(no response to IV hemin)
- 27. COPRO oxidase<50% Neurovisceral and cutaneous photosensitivity together or separately. C/F: Identical to those of AIP but less severe. More common in women. Blistering skin lesions
- 28. Diagnosis: COPROIII – in the urine and feces(symptomatic) Urinary ALA and PBG levels during acute attack but revert to normal more quickly. Mutation analysis Enzyme assay Treatment: Same as AIP.
- 29. Results fromdeficient activity of PROTO oxidase. Presents with neurologic symptoms, photosensitivity or both. C/F:Acute attacks- similar to those of AIP. Blistering skin lesions- similar to those of PCT.
- 30. Diagnosis: UrinaryALA and PBG-return to normal Persistant in fecal protoporphrin and COPRO III and urinary COPRO III plasma porphyrins(esp. In cutaneous lesions) Fluorescence spectroscopy Enzyme assay & mutation analysis
- 31. Treatment: IVHemin Avoid sun exposure
- 34. The mostcommon Sporadic/familial Hepatic URO decarboxylase (with ≤20% )
- 35. C/F: Blistering skinlesions-rupture and crust-atrophy, scarring Numerous milia , Hypertrichosis-light & porphyrins Hyperpigmentation
- 37. Other skin changes: Heliotroperash Sclerodermoid plaques
- 38. Diagnosis: o Plasma/urinary/fecalPorphyrins o Urinary ALA and PBG-normal o Fluorometric studies o Isocoproporphyrins in feces Treatment: o Phlebotomy- 450ml/1-2 wks o Antimalarials- 125mg chloroquine twice weekly for abt 6-12 months
- 39. Second mostcommon porphyria in adults. The most common EP in children. C/F: Non-blistering photosensitivity Urticarial lesions Small, atrophic pitted scars
- 40.
- 41. DIAGNOSIS Elevated levels oferythrocyte protoporphyrin(free) Fluorescence microscopy-red fluorescence Enzyme assay Mutation analysis
- 42. Treatment: Avoidsunlight exposure Oral beta carotene Cholestyramine Plasmapheresis and IV hemin
- 43. Gunther’s disease C/F: • Bullae and vesicles • Hypo/hyperpigmentation • Hypertrichosis • Secondary infections • Brown teeth • Hemolysis---- Anemia
- 45. Diagnosis: URO& COPRO COPRO I in feces Enzyme assay Mutation analysis Treatment: Blood transfusions for anemia
- 46. Systemic UROD-Early childhood Dark red urine- first sign Asso. with ocular manifestation C/F: Photosensitivity Hyperpigmentation Hypertrichosis Scleroderma like scarring
- 47. Diagnosis: Increasedfecal conc. of coproporphyrin Elevated RBC Zn-protoporphyrin levels Increased uro and coproporphyrin(RBC , Urine) Treatment: Photoprotection
- 49. Defects inthe erythroid gene ALAS Decreased activity—X linked sideroblastic anemia. Increased activity- X-linked form of EPP, known as X-linked protoporphyria (XLP). (Free PROTO= Zn-PROTO)
- 50. XLSA- C/F:Males,during infancy Refractory hereditary anemia, pallor, weakness Diagnosis: Bonemarrow- Hypercellular with shift to left Prussian blue-sideroblasts Urinary ALA/PBG & Urinary and fecal porphyrins – Normal
- 51. Mutation Analysis Treatment: Pyridoxine Blood transfusion
- 52. •NEUROVISCERAL SYMPTOMS • URINARYALA & PBG ALA N PBG ALA PBG porphyrins AIP HC VC Urinary Copr III U & C Copr III plasma N/ fecal N Copr III Copro & Proto ALAD Urinary Porph (Copr III )
- 53. CUTANEOUS LESIONS Blistering Non-blistering Plasmaporphyrins Porph PCT/HEP HC/VP CEP Urine Uro/hep.co2 C-III U-I C-I Fecal Isocopr C-III C, P Copr I RBC U-I C-I Plasma porphyrins Porph EPP XLP Urine N N Fecal Proto N RBC Proto (F) P(Z=F)
Editor's Notes
- #3 Porphyra-a reference to the color of the porphyrins.
- #10 Hepatic porphyrias-present in adult life with acute attacks of neurologic manifestations.
- #11 Erythropoietic porphyrias: present at birth or in early childhood.
- #13 Depend on the step in which the enzymatic defect occurs
- #17 HTN & tachycard-secondary to sympathetic hyperactivity, stimulated by extreme pain ALAS1 gene regulated by PPAR ꝩ coactivator 1α Hepatic PGC 1α induced by fasting which induces ALAS transcription and increased heme biosynthesis
- #19 Seizures- due to neurologic effects or hyponatremia Treatment of seizures is difficult because most antiseizure drugs can exacerbate AIP (clonazepam may be safer than phenytoin or barbiturates).
- #20 Hyponatremia - hypothalamic involvement and inappropriate vasopressin secretion / from electrolyte depletion due to vomiting/diarrhea/poor intake/excess renal sodium loss.
- #21 Treatment: IV Hemin-1st line therapy 3-4mg/Kg Given as lyophilized hematin / heme albumin/ heme arginate - infused daily for 4 days. Heme arginate and heme albumin-preferred- chemically stable and less side effects(phlebitis, anticoag. effect) IV Glucose(Carb. loading)-300g/day. Narotic analgesics for pain, Avoidance of precipitating factors
- #25 It is a rare AR acute hepatic porphyria. Usually asymptomatic(<50% ALAD activity) Prenatal diagn. by determination of ALAD activity/gene mutation in cultured chorionic villi or amniocytes.
- #27 Hereditary Tyrosinemia type I- fumaryl aceto acetase def.- accumulation of succinyl acetone-structurally similar to ALA. Lead intoxication-inhibits ALAD. Hence ADP is also known as Plumboporphyria. Treatment: Infants-hyperalimention and periodic blood transfusions(no response to IV hemin)
- #28 Cutaneous symptoms less common than in VP.
- #31 Urinary ALA and PBG-return to normal more quickly than AIP.
- #35 Generation of uroD inhibitor in the liver which forms uroporphomethene in the presence of iron/oxidative stress HEP-systemic deficiency UROD-in childhood C/F: Blistering skin lesions-back side of hands.also on forearm face legs feet Milia-fingers and hands Neuro features absent
- #38 URO I stimulates collagen syn. In human skin fibroblasts
- #39 Porphyrins increased in liver, plasma, urine, stool Phlebotomy-reduce hepatic iron. A unit (450 mL) of blood can be removed every 1–2 weeks.Aim -gradually reduce excess hepatic iron until the serum ferritin level reaches the lower limits of normal. Because iron overload is not marked in most cases, remission may occur after only five or six phlebotomie PCTpts with hemochromatosis may require more rx Monitoring of total plasma porphyrin concentration, which becomes normal some time after the target ferritin level is reached. Hemoglobin levels or hematocrits and serum ferritin ( to prevent development of iron deficiency and anemia.) After remission, continued phlebotomy may not be needed. Plasma porphyrin levels are
- #40 Burning ,stinging,pruritus-photosensitive sympts
- #41 Erythematous and edematous with purpuric rash Old knuckles-thickening/wrinkling of skin over knuckles and fingers(MCP and IP joints)