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