Cutaneous porphyrias

porphyrias

1. Dr. Shiti Bose CMC CUTANEOUS PORPHYRIAS

2. Definition Metabolic ds with defect in enzymes heme biosynthesis Porphyrins are phototoxic Most porphyrias are inherited

3. Photochemistry of porphyrins Heme : insertion of ferrous iron into porphyrin molecule . Porphyrins absorb photons of 408 nm (visible light) SORET BAND Singlet state release energy(red flourscence ) ground state Or change to longer lived excited Triplet state

4. Heme biosynthesis pathway and associated diseases

5. Classification of Porphyrias ACUTE CUTANEOUS CUTANEOUS AND ACUTE Acute intermittent porphyria (AIP) Porphyria cutanea tarda (PCT) Hereditary coproporphyria (HC) Congenital erythropoietic porphyria (CEP) Variegate porphyria (VP) Plumboporphyria /Doss Porphyria (ALA dehydratase def porphyria) Erythropoietic protoporphyria (EPP) Hepatoerthropoietic porphyria (HEP)

6. Genetic aspects Porphyrias Protein products Mode of inheritance AIP Porphobilinogen deaminase (PBGD), 11q23.3 AD Plumboporphyria Aminolevulinic acid dehydratase (ALAD), 9q34 AR PCT Uroporphyrinogen decarboxycalase (UROD), 1p34 AD (25% CASES),rest acq CEP Uroporphyrinogen III cosynthase (UROS), 10 q 25.5-26.3 AR EPP Ferrochelatase (FECH), 18q21.3 AD HEP Uroporphyrinogen decarboxycalase (UROD), 1p 34 AR VP Protoporphyrinogen oxidase (PPOX), 1q 22-23 AD HC Coproporphyrinogen oxidase (CPO), 3q12 AD

7. Cutaneous P orphyrias PORPHYRIA CUTANEA TARDA (PCT) M ost common UROD DEFECIENCY 4 types : 1. T ype I (sporadic) : 75% acquired hepatocytes- UROD inhibition/ defncy 2. Type II (hereditary/familial) : 25% AD all tissues: UROD gene mutation. Low penetrance.

8. 3. Type III (hereditary , but normal RBC UROD,localized to liver) 4. Type IV (toxic): alcohol,estrogens , hexachlorobenzene C/F: Sporadic- middle age, familial- younger Skin fragility - sun exposed areas Painful bullae  crust atrophic scars & milia ,hypo/ hyperpigmn

9. Hypertrichosis (face) and solar elastosis Morphea –like plaques Scalp: scarring alopecia Nails: photoonycholysis

10. Triggering factors: Estrogen Haemochromatosis (20-60%) Hep C (70-90%) , Hep B, Hep A Alcohol (30-90%- 40g/day) SLE Polychlorinated hydrocarbons Dermatomyositis Haemodialysis Iron NIDDM Thallesemia Tamoxifen Haematological malignancies Sideroblastic anemia

11. Differential diagnosis Variegate porphyria Epidermolysis bullosa acquisita Hydroa vacciniformis Drug induced and renal pseudoporphyrias PMLE Scleroderma Late onset Gunther’s syndrome.

12. Cutaneous porphyrias contt HEPATOERYTHROPOIETIC PORPHYRIA (HEP) Homozygous form of familial PCT Upto 90% decrease in UROD activity Severe disease (similar to CEP)  pain,blisters , scarring on exposure to sun in infancy Hypertrichosis , flourescent teeth, eye involvement, shortened distal phalynges D ark urine Increased urinary uroporphyrins and fecal coproporphyrins .

13. CONGENITAL ERYTHROPOIETIC PORPHYRIA /GUNTHER’S DISEASE Severe rare childhood porphyria Photosensitivity & hematological disease AR - UROS  inc type I isomers porphyrins in RBC leak into plasma < 100 cases worldwide

14. C/F: Hydrops fetalis Pink/Brown discoloration –amniotic fluid / nappies–> red-orange-- Wood’s lamp Severe photosensitivity Milder late onset form

15. Other systems involved Eyes : blepharitis , keratoconjuctivitis , corneal ulcers Bones & teeth : E rythrodontia ( flourescence under wood’s lamp) O steopenia,osteolytic lesions, maxillary hyperplasia, pathological fractures. Impaired Vit D synthesis Hematology : hemolytic anemia  hydrops fetalis BM normoblastic hyperplasia red flourescence Hepatosplenomegaly

16. Differential diagnosis: Epidermolysis bullosa dystrophica HEP VP Late onset CEP  PCT.

17. Erythropoietic protoporphyria (EPP) 2 nd most common after PCT AD with incomplete penetrance, AR rare Ferrochelatase defeciency  protoporphyrin in RBC phototoxicity

18. C/F: Pain on exposure to sun –1 st year of life. Few minutes to 2 hrs – discomfort,tingling,itching Beyond that– severe burning pain relieved with cold water Edema > erythema . 15% may have no signs.

19. Priming Severe : petechiae ,vesicles (similar to CSVV ), urticarial,eczematous S kin over MCP,IPJ hardened, “pebbly skin”-face Scarring( waxy,shallow , linear,punctate ) Photoonycholysis .

20. Hematological :mild hypochromic microcytic/normocytic anemia (25%) Liver : C holelithiasis (12%)- protoporphyrin accumulation. Cirrhosis Appearance of coproporphyrin in urine—significant liver damage.

21. Cutaneous porphyrias along with acute symptoms Hereditary coproporphyria (HC) Rare .Appears puberty onwards. AD. Coproporphyrinogen oxidase defeciency . Skin affected in 10-20%--features indistinguishable from PCT and VP Triggered by intercurrent liver disease. R are variants: Homozygous form Harderoporphyria

22. Variegate porphyria Rare. AD. Protoporphyrinogen oxidase defeciency (activity reduced by 50%) Skin fragility ,blistering with acute attacks  as accumulated copro’gen and proto’gen may also inhibit PBG deaminase . Skin lesions due to hydrophilic uroporphyrins in skin

23. C/F: Skin: 70% .post puberty. features similar to PCT. No worsening in summers. Hormonally induced hepatic dysfunction  exacerbate ds.

24. Acute attacks : Female: male:: 3:1 between 20-40 yrs in 70% abd pain,vomiting /constipation bulbar & resp palsy Homozygous VP : < 20% activity of proto’gen oxidase.

25. Differential diagnosis: PCT Late onset CEP HC P seudoporphyria

26. Approach to a patient with Cutaneous Porphyria Fragility/blistering on sun exposed sites Measure urine uro & Copro’gen (plasma Porphyrins in pts with renal failure If N ormal : Consider pseudoporphyrias (drug/renal) Consider Lupus Erythematosis Borderline elevation : evidence of CRF (dialysis) Elevated : Consider porphyrias : Measure stool porphyrins to d/f between PCT from VP or HCP VP: Plasma flourescence at 626 nm.

27. Immediate burning sensation,edema,erythema &/or erosions Measure erythrocyte protoporphyrin (Zn protoporphyrin (but not free),maybe elevated in IDA,Pb poisoning. If Normal: check medication/phototoxic chemicals consider Solar urticaria , hydroa vacciniforme Elevated: E rythropoietic protoporphyria

28. Wood’s lamp examination showing bright pink flourescence of urine Wood’s lamp examination showing pink flourescence of teeth in porphyrias .

29. Biochemical findings Cutaneous porphyrias Urine Faeces Red cell Plasma flourimetry CEP URO I, COPRO I COPRO I URO I,COPRO I, Zn & free PROTO Peak at 615-620nm PCT URO III, hepato & carboxy POR ISOCOPRO,hepato & carboxy POR NORMAL Peak at 615-620nm HC COPRO III COPRO III NORMAL Peak at 615-620nm VP COPRO III PROTOPOR COPRO III NORMAL Peak at 626 nm EPP NORMAL PROTOPOR FREE PROTOPOR Peak at 626-634nm

30. Histopathological changes Histopathological findings EPP BULLOUS PORPHYRIAS HPE: Homogeneous material PAS positive ,diastase resistant in upper dermal and papillary vascular plexus –vessel changes more pronounced in EPP Similar changes ,but more pronounced in basement membrane zone. Subepidermal bulla with split in lamina lucida and “ festooning ’’ IF : Ig G in a similar distribution EM : Reduplication of vascular basal lamina & presence of masses of fibrillar material ,mainly around blood vs.

31. Liver biopsy : in PCT  incr stainable iron, fatty change,intracellular porphyrin crystals Lobular necrosis :50% Cirrhosis :15% Hepatocellular CA :3% Liver function tests, USG ,serum alfa protein

32. Treatment PCT Photoprotection and sun avoidance . Cease /treat triggers (alcohol/estrogen/viral infn ) Phlebotomy : 4oo—500ml/ wk x 3-6 mo ( Hb <12g%,transferrin sat 15%,plasma ferritin <25 μ g/L) Low dose OH chloroquin or chloroquin 125 or 200 mg twice a week for 6-12 months,until porphyrin excretion is WNL Desferroxamine Erythropoietin (DOC in renal failure) Monitor urine porphyrin excretion

33. EPP Photoprotection and sun avoidance Oral β carotene : 30-90 mg/day in children 60-180 mg/day in adults maxm plasma levels of 600-800 μ gm /dl. Administer in spring,summer Cholestyramine or charcoal : Prevents enterohepatic circuln , & increase hepatic excretion

34. CEP Photoprotection and sun avoidance Change day-night rhythm Splenectomy (reduces hemolysis & plt consumption) BMT or stem cell transplant

35. HEP Photoprotection and sun avoidance Change day-night rhythm Therapeutic approaches used for PCT are not very effective.

36. Pseudoporphyrias Clinical & HPE similar to PCT Chronic renal failure/ Haemodialysis Drug induced NSAIDS Antibiotics Diuretics Retinoids Msc Naproxen Nalidixic acid Furosemide Isotretinoin OCP Ketoprofen Tetracycline Hydrochlorthiazide Etretinate Dapsone Mefenemic acid Ampicillin / sulbactam with cefexime Cyclosporine Celecoxib Rofecoxib