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Porphyrias
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- 2. •Porphyrias - groupof disorders caused by defects in the biosynthesis of haem. •Phototoxic properties of porphyrins, cause photosensitivity.
- 4. The IRON inhaem useful for electron transfer(respiratory cytochromes), reversible oxygen binding (haemoglobin and myoglobin) and oxidation and reduction reactions (cytochrome P450, catalase)
- 6. • 18 delocalisedelectrons- exited by long wavelength. • Soret band – 408 nm – main absorption peak
- 7. Cutaneous disease only Cutaneous disease andacute attacks Acute attacks only 1. Porphyria cutanea tarda(PCT) Hereditary coproporphyria(HC) Acute intermittent porphyria(AIP) 2. Congenital erythropoietic porphyria(CEP) Variegate porphyria(VP) 3. Erythropoietic protoporphyria(EPP)
- 8. CONGENITAL ERYTHROPOIETIC PORPHYRIA •Guntherdisease •severe ,rare childhood porphyria - lifelong mutilating photosensitivity and haematological disease. •AR •inherited deficiency of uroporphyrinogen ɪɪɪ cosynthase
- 9. • Uroporphyrinogen ɪɪɪcosyntase is required to form type ɪɪɪ porphyrin isomers. • Its absence- formation of type ɪ isomers - cannot participate in haem formation, • Accumulates in erythroid cells and leaks into plasma.
- 10. Clinical features •hydrops fetalisto mild forms •brown discoloration of amniotic fluid or pink/ brown porphyrin staining of nappies (fluoresce red‐orange- Wood’s light). •Severe photosensitivity in neonatal period → blisters developing •Photomutilation- onycholysis, erosions in terminal phalanges, destructive changes in pinna and nose
- 11. •Repeated inflammation withvesicles and bullae, with secondary infection → mutilating scarring - face and hands •A diffuse pseudosclerodermatous thickening of exposed skin with microstomia and sclerodactyly‐like changes. •Hypertrichosis - upper arms, temples and malar region
- 12. •Eyes . Keratoconjunctivitis,blepharitis, cataracts, corneal ulcers, scars •Bones and teeth . When teeth emerge, stained brown( fluoresce under Wood’s). Decreased bone density, osteopenia and osteolytic lesions •Haematology . Haemolytic anaemia, Hypersplenism Under violet illumination most normoblasts- red fluorescence localized to their nuclei
- 13. • Red cellsand urine – large amounts of uro and coproporphyrin. • Faeces – coproporphyrin. • Plasma spectrofluorimetry peak – 615 to 620nm.
- 14. TREATMENT •Hypertransfusion - tomaintain polycythaemia→ inhibits Hb production and ↓ses porphyrin formation •Allogeneic bone marrow transplantation from an HLA‐compatible donor treatment of choice
- 15. Genetic counselling • Forparents of an affected child, the chance of future offspring suffering - 25%. •The diagnosis before birth by measuring the uroporphyrin I concentration in amniotic fluid, increased as early as 16 weeks in utero
- 16. PORPHYRIA CUTANEA TARDA •characterizedby fragility and blistering of exposed skin. • acquired and associated with liver disease. •It does not cause acute attacks. •deficiency of UROD uroporphyrinogen decarboxylase.
- 17. TYPES Type 1 –sporadic enzyme deficiency is acquired and restricted to hepatocytes due to inhibition of normal UROD Type 2 – familial enzyme deficiency is hereditary, present in all tissues with UROD gene mutation Type 3 – hereditary enzyme deficiency localised to liver. Type 4 – toxic porphyria- halogenated hydrocarbons, hexachlorobenzene.
- 18. UROD inactivated byUroporphomethene, CI (formed oxidation of uroporphyrinogen ) The inhibitor generated in liver by ROS accumulated uroporphyrin diffuses into surrounding tissues→ phototoxic reaction in the upper dermis This leads to lysis of cells in the superficial dermis with formation of vacuoles which produce blister cavity under the basal lamina
- 19. •Type 1 –adult ; type 2 – childhood •Fragility and blistering in exposed sites •Lesions resolve leaving atrophic scars, milia, mottled hyper or hypo pigmentation •Scarring alopecia, hypertrichosis, melasma like hyperpigmentation, onycholysis, solar elastosis,Morphoea‐like plaques, cicatricial conjunctivitis
- 20. HEPATOERYTHROPOIETIC PORPHYRIA(HEP) •Homozygous formof familial PCT. •90% reduction in UROD activity. •Severe disease similar to CEP with phototoxicity during infancy
- 21. RISK FACTORS FORTHE DEVELOPMENT OF PCT
- 22. INVESTIGATIONS •PCT- urine –uroporphyrin •A plasma spectrofluorimetry peak - 615–620 nm. •Faeces - Isocoproporphyrin few patients with VP have the PCT urine pattern (‘dual porphyria’) • HEP- additional finding → raised red cell Zinc‐protoporphyrin, and lower red cell UROD activity
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- 25. •Photoprotection sunscreens – titanium dioxideor zinc oxide, (with added iron oxide) filter films for car and home windows, gloves, hats and clothes
- 26. Specific treatments •Venesection Around 500mL of blood removed every week/2 weeks, ↓ transferrin saturation to 15%, Hb to 11–12 g/dL and plasma ferritin to ˂ 25 μg/L •Excision and grafting - ulcerated sclerodermoid lesions •Desferrioxamine – rapidly chelates hepatic iron •Low dose chloroquine- complexes with uroporphyrin and excretes in bile. •Dose-125mg or 250mg weekly twice
- 28. ERYTHROPOIETIC PROTOPORPHYRIA •Hereditary •painful, lifelong photosensitivity •Withoutblistering •Deficient activity of ferrochelatase enzyme. •Gain‐of‐function mutations in ALAS‐2 (the first enzyme in the pathway) •Common in 1st year of life
- 29. Mutation in ferrochelatasegene Accumulation of protoporphyrin in RBC Porphyrin laden cells pass dermal vessels and are expose to soret wavelength Acute injury to endothelium by singlet oxygen and hydroxyl radical.
- 30. CLINICAL FEATURES •Immediate painon exposure to bright sunlight •Pts describe discomfort, tingling or itching over dorsae of hands and face •partial relief with cold water and wet cloths •Physical sign – erythema and oedema •Patients experience a ‘priming phenomenon’ in which sunlight tolerance is reduced on the day after significant sun exposure
- 31. INVESTIGATIONS •Plasma fluorimetry –peak at 633nm •Red cell- free protoporphyrin •Faeces – protoporphyrin •Urine – normal •Biopsy- deposition of PAS positive hyaline material in walls of blood vessels. •DIF- IgG deposition.
- 32. Management •Photoprotection sun protective clothing. Dihydroxyacetonepaint window films •Oral β‐carotene - dose 180 mg daily in adults (90 mg daily in children) •PUVA and NBUVB- photoprotection by inducing epidermal thickening and pigmentation. •Bone marrow transplantation
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- 34. HEREDITARY COPROPORPHYRIA • rare inheriteddisease •characterized by acute attacks •AD •Inherited deficiency of coproporphyrinogen oxidase •puberty
- 35. CLINICAL FEATURES •Skin -10–20% - fragility and blistering in sun‐exposed areas, Prominent hypertrichosis, pigmentation •Harderoporphyria – jaundice, anemia, hepatosplenomegaly in neonates
- 36. INVESTIGATIONS •615–620 nm peak- plasma spectrofluorimetry •increased uro‐ and coproporphyrin – urine •increased coproporphyrin - faeces
- 37. VARIEGATE PORPHYRIA •rare inheriteddisease •AD •Deficiency of protoporphyrinogen oxidase. •Accumulation of CPP and PPP inhibits PBG deaminase. •Local accumulation – secondary photoinactivation of UROD
- 38. CLINICAL FEATURES •Begins inadolescence •Mild skin fragility with painful bullae in exposed areas •Lesions heal with scarring and pigmentary abnormalities- pseudoscleromatous changes. •Intercurrent biliary obstruction exacerbates cutaneous disease
- 39. Acute attacks •17% •severity variesfrom mild abdominal pain, vomiting and constipation, to very severe attacks with bulbar palsy and respiratory paralysis.
- 40. INVESTIGATIONS •Plasma spectroflurimetry –peaks around 626nm. •Urine – coproporphyrin and uroporphyrin similar to PCT. •Faeces – copro and protoporphyrin
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- 42. ACUTE INTERMITTENT PORPHYRIA •AD •Deficiencyof porphobilinogen deaminase •Primary or secondary •Triggered by drugs- CYP 450 •Gunter triad – abdominal pain, vomiting , constipation
- 43. Pathogenesis Liver- heme isincorporated into CYP450 proteins Drug or hormone induces P450 Acutely increases hepatic requirement Inability of pathway to respond adequately Secondary accumulation of ALA
- 44. CLINICAL FEATURES •Acute autonomicneuropathy – pain, tachycardia, hypertension, partial ileus. •Confusion, agitation, hallucination- abnormal behaviour •Motor neuropathy - Respiratory muscle paralysis - death
- 45. MANAGEMENT •Urine – PBGexcretion •Treatment – safe drugs •Analgesia, sedatives, antiemetics and hydration •IV hematin or haem arginate – suppress hepatic ALA synthase activity
- 47. PSEUDOPORPHYRIA •non‐porphyric dermatosis •clinically andhistologically indistinguishable from PCT •Porphyrin concentrations - normal •clinical presentations of drug‐induced photosensitivity: Also, non‐drug‐related causes.
- 48. Causes •Photosensitizing drugs •Hemodialysis •Sunbeds –UVA tanning beds
- 49. Photosensitizing drugs •NSAIDs- naproxen,ketoprofen, mefanamic acid. •Nalidixic acid •Tetracyclines- minocycline •Furosemide •Isotretinoin •Dapsone
- 50. Clinical features •vesicles, bullae,fragility, milia and scarring on exposed skin - dorsal hands, face, chest •Diagnosis – Normal porphyrin conc in plasma, urine and faeces. •Treatment – stop offending drug, sunbed usage.
- 53. CASE #1 45y malealcoholic house painter with c/o blisters on hands and tight skin.
- 54. Urine: Elevated Uroporphyrin >Coproporphyrins Feces: elevated Isocopro RBC: nl CBC: wbc=8, Hg=16, Hct=50, Plt=250 LFT: elevated PORPHYRIA CUTANEA TARDA
- 55. Case #3 Mother comesin with 3yr old child. She says used to cry after going out in the sun.He would often turn red and blister afterwards. you notice sclerodermoid changes of the face along with excessive hair growth along the temples. Mother states that both she and the father have problems with Blistering of their hands with extensive sun exposure.
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- 57. Case scenario #4 40ywoman from S.Africa. C/o blisters and scarring of the hands Since age of 20. Recently admitted to the GI service for N/V/D with abdominal pain. Urine: Copro > Uro (opposite of PCT) Variegate Porphyria
- 58. Case #5 3yo femalewho cries when she Goes outside, and Then runs inside to stand in front of AC vent. She now presents to you with elliptical scars on the face and pebbling of the nose and hands Erythropoietic protoporphyria