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![CONGENITAL ERYTHROPOIETIC PORPHYRIA (CEP)
[GÜNTHER DISEASE]
• AR inherited disorder that results from markedly decreased catalytic
activity of uroporphyrinogen III synthase, the 4th enzyme in heme
biosynthesis.
• Age of onset: infancy/1st decade of life](https://image.slidesharecdn.com/porphyrias-230424110529-df68d97d/85/PORPHYRIAS-pptx-38-320.jpg)
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PORPHYRIAS.pptx
- 1.
- 2. INTRODUCTION • The porphyriasare metabolic disorders, each arising from hereditary deficiency of one of the eight enzymes of the porphyrin-heme biosynthetic pathway • Erythropoietic and hepatic forms • Cutaneous and non-cutaneous forms • Acute and non-acute forms
- 3.
- 4. CUTANEOUS NON-CUTANEOUS • Porphyriacutanea tarda • Erythropoietic protoporphyria • Variegate porphyria • Hereditary coproporphyria • Congenital erythropoietic porphyria • Hepatoerythropoietic porphyria • X-linked dominant protoporphyria • Acute intermittent porphyria • ALA dehydratase deficiency porphyria
- 5. ACUTE PORPHYRIAS NON-ACUTEPORPHYRIAS • Acute intermittent porphyria • Variegate porphyria • Hereditary coproporphyria • ALA-D deficiency porphyria • Porphyria cutanea tarda • Erythropoietic protoporphyria • Congenital erythropoietic porphyria • Hepatoerythropoietic porphyria • X-linked dominant protoporphyria
- 6. ERYTHROPOIETIC GROUP HEPATICGROUP • Congenital erythropoietic porphyria • Erythropoietic protoporphyria • All the others
- 7. PATHOGENESIS OF SKINDISEASE
- 8. • The typeof cellular damage depends on the solubility and tissue distribution of the porphyrins. • Accumulation of water-soluble uro- and coproporphyrins leads to blistering. (cutaneous porphyrias e.g. porphyria cutanea tarda, variegate porphyria) • Accumulation of lipophilic protoporphyrins leads to an immediate cutaneous burning sensation, erythema and edema. (erythropoietic protoporphyria)
- 9. PATHOGENESIS OF ACUTEPORPHYRIC ATTACK • ALA dehydratase deficiency porphyria and acute intermittent porphyria • Not associated with cutaneous findings - their substrates, ALA and porphobilinogen (PBG), respectively, are non-phototoxic porphyrin precursors • Life-threatening acute neurologic attacks - ALA and PBG are extremely neurotoxic. Lacking appropriate barrier protection, the autonomic and peripheral nervous systems are particularly susceptible to the toxic effects.
- 10. PORPHYRIA CUTANEA TARDA(PCT) • Most common type • Decreased activity of uroporphyrinogen decarboxylase, the 5th enzyme in heme biosynthesis • Age of onset : 3rd to 4th decade
- 11. • Type IPCT - sporadic (acquired) variant, dysfunctional enzyme is exclusively expressed in the liver. • Type II PCT – AD familial (hereditary) variant, enzymatic defect is detected in all tissues. • Type III PCT - typical clinical and biochemical features of overt PCT but with normal uroporphyrinogen decarboxylase activity in their RBC.
- 12. TRIGGERING FACTORS • Alcohol(MC) • Estrogens • Polychlorinated hydrocarbons • Dialysis in patients with renal failure • Iron • Hepatitis C • HIV
- 13. CUTANEOUS MANIFESTATIONS • Increasedphotosensitivity and skin fragility • Blistering, erosions, crusts, milia and scars in sun-exposed sites • PIH • Hypertrichosis • Scarring alopecia • Morpheaform and sclerodermoid changes
- 17. INVESTIGATIONS • HPE -subepidermal blisters with a characteristic festooning of dermal papillae (due to the deposition of PAS-positive glycoproteins in and around the wall of vessels localized in the upper dermis) • DIF - immunoglobulins (IgG > IgM), complement and fibrinogen at the DEJ and around blood vessels of the papillary dermis.
- 19. • Increased urinaryexcretion of uroporphyrin (type I isomers > type III isomers), hepta-carboxylated porphyrins (type III isomers > type I isomers) and coproporphyrin • Increased excretion of isocoproporphyrin in the feces (exclusive to PCT and hepatoerythropoietic porphyria) • Historical tests • Urine, under Wood’s lamp illumination shows pink to red fluorescence • Urine turns red to brown after several hours of exposure to natural light
- 21. TREATMENT • Photoprotection (broad-spectrumsunscreens, protective clothing) • Titanium dioxide and zinc oxide (primary wavelengths that induce the porphyrias are in the visible 400–410 nm range) • Avoidance of sunlight exposure and trauma
- 22. • Cease alcoholingestion • Stop estrogen therapy • Measurement of urinary porphyrin excretion to monitor therapeutic outcome • Deferasirox
- 23. • Phlebotomy: 400–500ml every 2 weeks over 3–6 months • MOA - reduces iron stores, thereby improving heme synthesis by reducing iron-induced inhibition of uroporphyrinogen decarboxylase activity. • Low-dose hydroxychloroquine or chloroquine: 200 mg or 125 mg twice weekly respectively, over 6–12 months • MOA - accelerating hepatic elimination and urinary excretion of porphyrins, and they may also inhibit porphyrin synthesis.
- 24. ERYTHROPOIETIC PROTOPORPHYRIA (EPP) •EPP is due to a semi-dominantly inherited deficiency of ferrochelatase, the last enzyme in the heme biosynthetic pathway. • Combined, a mutation in allele A plus the polymorphism in allele B lead to a marked reduction in ferrochelatase activity that is 15–25% of normal. • Cutaneous photosensitivity that typically manifests during early childhood.
- 25. CLINICAL FEATURES • Acutephotosensitivity episodes - intense burning, stinging and pruritus of sun-exposed skin (nose, cheeks and dorsal hands) • F/b erythema, oedema, crusts, petechiae and then wax-like scarring • Blistering usually does not occur
- 26. • In patientswithout recent sun exposure - scars on the nose and lips • In rare patients with AR inherited form of EPP - palmar keratoderma • Adult-onset EPP (late-onset EPP) - very unusual, history of myeloproliferative disorder or myelodysplastic syndrome
- 30. INVESTIGATIONS • HPE -vacuolization of epidermal cells is seen in acute lesions. Intercellular edema, vacuolization and lysis of endothelial cells within superficial dermal blood vessels. • In older lesions (e.g. areas of waxy scarring), eosinophilic PAS-positive deposits are observed around blood vessels. • Ultrastructurally - thickening and degeneration of capillary basement membranes
- 32. • Increase infree protoporphyrin levels in erythrocytes, plasma, feces and other tissues such as the liver. • Historically, microscopic examination of a blood smear via UV illumination was performed to detect erythrocyte fluorescence.
- 33. • Rapid accumulationof protoporphyrin within the liver and biliary system • development of cholestasis • hepatic damage and progressive (even fatal) liver failure
- 34. TREATMENT • Photoprotection, e.g.broad-spectrum sunscreens, protective clothing • Avoidance of sunlight exposure (common window glass does not provide protection) • Oral β-carotene: 30–90 mg/day in children; 60–180 mg/day in adults. (MOA - reduces photosensitivity by decreasing the formation of free radicals that occurs during the cutaneous photoreaction)
- 35. • Afamelanotide (ananalogue of melanocyte stimulating hormone) : 16 mg every 60 days as a resorbable implant, may increase tolerance to light exposure • NBUVB • Cholestyramine or charcoal : to reduce enterohepatic recirculation of porphyrins and bile acids in order to enhance hepatic porphyrin excretion
- 36. X-LINKED DOMINANT PROTOPORPHYRIA (XLDPP) •Gain-of-function mutations in ALAS2 on the X chromosome. • This gene encodes the erythroid tissue-specific isoform of the 1st enzyme in the heme biosynthetic pathway, δ-aminolevulinic acid synthase 2. • The resultant increase in synthetase activity eventually leads to an overproduction of protoporphyrin IX and a clinical phenotype that is indistinguishable from EPP.
- 37. • Age ofonset: early childhood • However, the percentage of patients at risk for potentially fatal liver disease appears to be higher than in classic EPP. • Higher total protoporphyrin levels in erythrocytes (as compared to EPP due to ferrochelatase deficiency), with 40% being zinc protoporphyrin.
- 38. CONGENITAL ERYTHROPOIETIC PORPHYRIA(CEP) [GÜNTHER DISEASE] • AR inherited disorder that results from markedly decreased catalytic activity of uroporphyrinogen III synthase, the 4th enzyme in heme biosynthesis. • Age of onset: infancy/1st decade of life
- 39. CLINICAL FEATURES • Severecutaneous photosensitivity, blistering, erosions, crusts and ulcerations • F/B extensive scarring and deformation • MC site : hands • Face : a loss of eyebrows and eyelashes, severe mutilation of cartilaginous structures (nose)
- 40. • erythrodontia • acro-osteolysis •skeletal abnormalities (demineralization) • Hematologic involvement, ranging from mild forms of hemolytic anemia to intrauterine hydrops fetalis and hepatosplenomegaly
- 44. INVESTIGATIONS • Pink, redor violet staining of diapers - early clue to the diagnosis • Biochemically, there is increased urinary excretion of uroporphyrin I and coproporphyrin I plus elevated levels of coproporphyrin I in the stool.
- 46. TREATMENT • Photoprotection (broad-spectrumsunscreens, protective clothing) • Strict avoidance of sunlight exposure • Change day–night rhythm
- 47. • Frequent bloodtransfusions can suppress erythropoiesis, thereby decreasing porphyrin production and photosensitivity. • Concomitant administration of deferoxamine or deferasirox can reduce the resulting iron overload. • Splenectomy (reduces hemolysis and platelet consumption) • Bone marrow or hematopoietic stem cell transplantation leads to marked reduction of porphyrin levels and photosensitivity (curative)
- 48. HEPATOERYTHROPOIETIC PORPHYRIA (HEP) •AR variant of hereditary PCT • Due to decrease in uroporphyrinogen decarboxylase activity • Presents during early childhood
- 49. CLINICAL FEATURES • Darkurine in the diapers - initial clinical finding • Severe cutaneous photosensitivity, blistering, pruritus, hypertrichosis, hyperpigmentation and scleroderma-like scarring • If the clinical course is severe, the symptoms closely resemble those observed in CEP, but not usually associated with hematologic abnormalities (severe anemia).
- 51. INVESTIGATIONS • Urinary levelsof uroporphyrin and hepta-carboxylated porphyrins are elevated • Fecal levels of coproporphyrin and isocoproporphyrin are elevated • Increased levels of zinc-chelated protoporphyrin within RBC
- 52. TREATMENT • Photoprotection (broad-spectrumsunscreens, protective clothing) • Strict avoidance of sunlight exposure and trauma • Change day–night rhythm • Therapeutic approaches used in PCT (phlebotomy, antimalarials) are not effective
- 53. PSEUDOPORPHYRIA • Encompasses thoseconditions that clinically resemble PCT • But do not have biochemical abnormalities in porphyrin metabolism like PCT • Skin fragility, erosions, blisters and scarring • Sites - dorsal aspect of the hands, face, extensor surfaces of the legs
- 54. ASSOCIATION • Stage 4or 5 CKD or in those undergoing renal dialysis • Ingestion of specific drugs: • NSAIDs (naproxen, nabumetone, ketoprofen) • Furosemide • Antibiotics (nalidixic acid, tetracycline) • Retinoids • Use of tanning beds
- 56. TREATMENT • For drug-inducedpseudoporphyria - discontinuation of exposure to the suspected precipitant • Sun protection
- 57. THE ACUTE PORPHYRIAS •AIP, VP, HCP and ALA-D deficiency porphyria • VP and HCP also have cutaneous findings that are clinically indistinguishable from those of PCT. • So VP and HCP are also referred to as neurocutaneous porphyrias.
- 58. • Acute attackscan be precipitated by: Porphyrinogenic drugs (antimalarials, tetracyclines, sulfonamides) Alcohol Hormonal changes Recurrent or chronic infections Reduced caloric intake due to fasting or diets
- 59. POSSIBLE MANIFESTATIONS OFAN ACUTE PORPHYRIC ATTACK GASTROINTESTINAL AND METABOLIC NEUROLOGIC CARDIAC AND PULMONARY • Colicky abdominal pain • Nausea and vomiting • Constipation • Obstipation • Hyponatremia • Paresthesias • Motor and sensory peripheral neuropathy (para- and tetraplegia) • Seizures • Muscle pain • Back pain • Encephalopathy • Paralysis • Anxiety • Acute psychosis • Coma • Tachycardia • Hypertension • Respiratory paralysis
- 60. ACUTE INTERMITTENT PORPHYRIA(AIP) • MC type of acute porphyria • AD inherited disorder • Deficiency of porphobilinogen deaminase/hydroxymethylbilane synthase, the 3rd enzyme in heme biosynthesis • Age of onset : 2nd to 4th decade of life
- 61. • Acute porphyricattacks that may be precipitated by the various trigger factors • No photosensitivity or cutaneous manifestations • Elevated urinary levels of the porphyrin precursors ALA and PBG can be detected during an acute attack.
- 62. VARIEGATE PORPHYRIA (VP) •AD inherited deficiency of protoporphyrinogen oxidase, the 7th enzyme in the pathway of heme biosynthesis. • Age of onset : 2nd to 3rd decade of life
- 63. CLINICAL FEATURES • Cutaneousand neuropsychiatric symptoms can occur separately or simultaneously in affected individuals. • Clinically, the skin findings in VP cannot be differentiated from those observed in PCT. • Acute attacks observed in VP are identical to AIP.
- 65. INVESTIGATIONS • During acuteattacks, elevated urinary levels of ALA and PBG are encountered. • However, during periods of remission, urinary ALA and PBG levels may be within normal range. • Therefore, additional biochemical analyses of fecal porphyrins are mandatory in order to establish the diagnosis of VP.
- 66. • Elevated levelsof stool protoporphyrin and coproporphyrin can be detected (protoporphyrin > coproporphyrin) - also be detected during periods of remission between attacks. • Plasma fluorescence emission peak of 624–626 nm is seen only in symptomatic patients, including those with cutaneous involvement.
- 67. HEREDITARY COPROPORPHYRIA (HCP) •AD • Deficiency of coproporphyrinogen oxidase, the 6th enzyme in the porphyrin-heme biosynthetic pathway
- 68. • The clinicalsymptoms are similar to those encountered in VP. • However, in contrast to VP, coproporphyrin > protoporphyrin in the stool.
- 69. AMINOLEVULINIC ACID DEHYDRATASE(ALA-D) DEFICIENCY PORPHYRIA • Plumboporphyria • AR • Presents during early childhood or adulthood with acute neurologic symptoms that resemble AIP
- 70. TREATMENT FOR ACUTEPORPHYRIAS CUTANEOUS SYMPTOMS (VP, HCP) • Photoprotection - broad-spectrum sunscreens, protective clothing • Avoidance of sunlight exposure and trauma
- 71. ACUTE ATTACKS • Identificationand elimination of precipitating factors (porphyrinogenic drugs, alcohol, hormones) • Monitoring in intensive care unit and input from porphyria specialists • Adequate pain therapy, e.g. with opioid analgesics • Adequate therapy of nausea and vomiting, e.g. with ondansetron, promethazine
- 72. • Intravenous administrationof heme arginate or hemin MOA - Heme arginate reduces the overproduction of porphyrin precursors via a negative feedback mechanism in which the increased activity of ALA synthase, the rate-limiting enzyme in heme biosynthesis, is repressed. • If necessary, until heme preparations become available, intravenous glucose infusions • Measurement of urinary porphyrin excretion during the acute attack (daily, if possible)
- 76. REFERENCES • Dermatology byBolognia 4th edition • Rook’s textbook of dermatology 9th edition • Hurwitz clinical pediatric dermatology 5th edition • Fitzpatrick’s dermatology 9th edition • IADVL textbook of dermatology 4th edition • Andrews’ diseases of the skin 13th edition • Habif’s clinical dermatology 7th edition
- 77.
Editor's Notes
- #3 leading to a pathologic accumulation and excess excretion of porphyrins and/or porphyrin precursors.
- #8 Soret wavelength light (408 nm), so the same strategy for photoprotection applies to them all,
- #9 as is seen in most of the cutaneous porphyrias (e.g. porphyria cutanea tarda, variegate porphyria).
- #18 (non-antigen-specific) Ig
- #22 primary wavelengths that induce the porphyrias are in the visible 400–410 nm range, sunscreens are limited in their photoprotective efficacy, with the exception of titanium dioxide and zinc oxide.
- #24 While the therapeutic goal is to reduce serum ferritin levels to the lower limit of the reference range, care should be taken to avoid inducing anemia. Phlebotomy usually leads to resolution of skin fragility and blistering within 2–4 months. However, normalization of urinary porphyrin concentrations will usually take longer (about 12 months).
- #25 Skin symptoms can develop within minutes of sun exposure, often starting early in the springtime, continuing throughout the summer, and diminishing during fall and winter. Window glass does not protect the patient. Patients suffering from EPP often report that the only way to relieve the burning and stinging sensations is to cool the affected skin under cold water.
- #62 ALA levels range from 5 to 20 times normal and PBG levels are increased to as high as 20- to 50-fold normal
- #71 Although it is conceivable that chloroquine and hydroxychloroquine might be helpful in decreasing the associated photodermatoses, these antimalarials belong to the group of drugs considered to be potential inducers of acute porphyric attacks. Thus, their use is not recommended.