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1. PORPHYRIAS
Preksha Mehta

2. INTRODUCTION
• The porphyrias are 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. BIOSYNTHESIS OF HAEM

4. CUTANEOUS NON-CUTANEOUS
• Porphyria cutanea 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-ACUTE PORPHYRIAS
• 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 HEPATIC GROUP
• Congenital erythropoietic
porphyria
• Erythropoietic
protoporphyria
• All the others

7. PATHOGENESIS OF SKIN DISEASE

8. • The type of 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 ACUTE PORPHYRIC 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 I PCT - 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
• Increased photosensitivity 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 urinary excretion 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-spectrum sunscreens, 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 alcohol ingestion
• Stop estrogen therapy
• Measurement of urinary porphyrin excretion to monitor therapeutic
outcome
• Deferasirox

23. • Phlebotomy: 400–500 ml 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
• Acute photosensitivity 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 patients without 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 in free 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 accumulation of 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 (an analogue 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 of onset: 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
• Severe cutaneous 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, red or 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-spectrum sunscreens, protective clothing)
• Strict avoidance of sunlight exposure
• Change day–night rhythm

47. • Frequent blood transfusions 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
• Dark urine 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 levels of 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-spectrum sunscreens, 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 those conditions 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 4 or 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-induced pseudoporphyria - 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 attacks can 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 OF AN 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 porphyric attacks 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
• Cutaneous and 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 acute attacks, 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 levels of 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 clinical symptoms 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 ACUTE PORPHYRIAS
CUTANEOUS SYMPTOMS (VP, HCP)
• Photoprotection - broad-spectrum sunscreens, protective clothing
• Avoidance of sunlight exposure and trauma

71. ACUTE ATTACKS
• Identification and 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 administration of 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 by Bolognia 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. THANK YOU