Download - Cutaneous porphyrias
DR. SHITI BOSE CMC
CUTANEOUS PORPHYRIAS
Definition
• Metabolic ds with defect in enzymes heme biosynthesis
• Porphyrins are phototoxic
• Most porphyrias are inherited
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
Heme biosynthesis pathway and associated diseases
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)
Genetic aspects Porphyrias Protein products Mode of
inheritanceAIP Porphobilinogen deaminase
(PBGD), 11q23.3AD
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 ADHEP Uroporphyrinogen
decarboxycalase (UROD), 1p 34AR
VP Protoporphyrinogen oxidase (PPOX), 1q 22-23
AD
HC Coproporphyrinogen oxidase (CPO), 3q12
AD
Cutaneous Porphyrias
PORPHYRIA CUTANEA TARDA (PCT)
Most common UROD DEFECIENCY
4 types : 1. Type I (sporadic): 75% acquired hepatocytes- UROD inhibition/defncy
2. Type II (hereditary/familial) : 25% AD all tissues: UROD gene mutation. Low penetrance.
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
Hypertrichosis (face) and solar elastosisMorphea –like plaquesScalp: scarring alopeciaNails: photoonycholysis
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
malignanciesSideroblastic anemia
Differential diagnosisVariegate porphyriaEpidermolysis bullosa acquisitaHydroa vacciniformisDrug induced and renal pseudoporphyriasPMLESclerodermaLate onset Gunther’s syndrome.
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
Dark urine
Increased urinary uroporphyrins and fecal coproporphyrins.
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
C/F:Hydrops fetalisPink/Brown discoloration –amniotic fluid /
nappies–> red-orange-- Wood’s lamp
Severe photosensitivity
Milder late onset form
Other systems involved
Eyes: blepharitis, keratoconjuctivitis, corneal ulcers
Bones & teeth: Erythrodontia (flourescence under wood’s lamp)
Osteopenia,osteolytic lesions, maxillary hyperplasia, pathological fractures. Impaired Vit D synthesis
Hematology: hemolytic anemia hydrops fetalisBM normoblastic hyperplasia red flourescence
Hepatosplenomegaly
Differential diagnosis:Epidermolysis bullosa dystrophicaHEPVPLate onset CEP PCT.
Erythropoietic protoporphyria (EPP)
2nd most common after PCT
AD with incomplete penetrance, AR rare
Ferrochelatase defeciency protoporphyrin in RBC phototoxicity
C/F:Pain on exposure to sun –1st 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.
Priming Severe : petechiae ,vesicles (similar to
CSVV),urticarial,eczematous
Skin over MCP,IPJ hardened, “pebbly skin”-face
Scarring(waxy,shallow, linear,punctate)
Photoonycholysis.
Hematological :mild hypochromic microcytic/normocytic anemia (25%)
Liver: Cholelithiasis (12%)- protoporphyrin accumulation.
Cirrhosis
Appearance of coproporphyrin in urine—significant liver damage.
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.
Rare variants: Homozygous form Harderoporphyria
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
C/F:Skin: 70% .post puberty. features similar to PCT.
No worsening in summers.
Hormonally induced hepatic dysfunction exacerbate ds.
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.
Differential diagnosis:PCTLate onset CEPHCPseudoporphyria
Approach to a patient with Cutaneous PorphyriaFragility/blistering on sun exposed sites
Measure urine uro &Copro’gen (plasma Porphyrins in pts with renal failure If Normal: 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 HCPVP: Plasma flourescence at 626 nm.
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 vacciniformeElevated: Erythropoietic protoporphyria
Wood’s lamp examination showing bright pink flourescence of urine
Wood’s lamp examination showing pink flourescence of teeth in porphyrias.
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 PROTOPORCOPRO III
NORMAL Peak at 626 nm
EPP NORMAL PROTOPOR FREE PROTOPOR
Peak at 626-634nm
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.
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
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 <25μg/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
EPP • Photoprotection and sun avoidance
• Oral β carotene : 30-90 mg/day in children 60-180 mg/day in adults maxm plasma levels of 600-800μgm/dl. Administer in spring,summer
• Cholestyramine or charcoal: Prevents enterohepatic circuln, & increase hepatic excretion
CEP • Photoprotection and sun avoidance
• Change day-night rhythm
• Splenectomy (reduces hemolysis & plt consumption)
• BMT or stem cell transplant
HEP • Photoprotection and sun avoidance
• Change day-night rhythm
• Therapeutic approaches used for PCT are not very effective.
Pseudoporphyrias
Clinical & HPE similar to PCT
Chronic renal failure/Haemodialysis
Drug induced NSAIDS Antibiotics Diuretics Retinoids Msc Naproxen Nalidixic acid Furosemi
deIsotretinoin
OCP
Ketoprofen Tetracycline Hydrochlorthiazide
Etretinate Dapsone
Mefenemic acid
Ampicillin /sulbactam with cefexime
Cyclosporine
CelecoxibRofecoxib