Porphyrias

• The porphyrias are rare disorders, occurring in all races and both sexes.
• Some forms appear during infancy; other variants usually do not present until puberty or adulthood.
• Prevalence rates vary from 0.1 to 10 per 100 000 individuals.
• Precise prevalence of the various porphyrias is not known, due primarily to:
• Geographic differences.
• Likelihood of underdiagnosis.
• Incomplete penetrance of the dominantly inherited porphyrias.

• The porphyrias result from dysfunction of enzymes involved in heme biosynthesis.
• The different types can be classified into either acute versus non-acute or cutaneous versus non-cutaneous forms.
• Cutaneous symptoms exclusively involve sun-exposed areas of the body.
• Life-threatening neurologic attacks can occur in the acute porphyrias.
• Diagnosis of specific types of porphyria may at times be difficult because clinical symptoms are often nonspecific and biochemical findings can overlap.
• The genetic bases of the porphyrias have been well characterized, facilitating accurate molecular diagnosis and genetic counseling.

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• The porphyrias are metabolic disorders, each arising from a predominantly hereditary deficiency of one of the eight enzymes of the porphyrin–heme biosynthetic pathway.
• Traditionally subdivided into erythropoietic and hepatic forms, according to the major site of expression of the enzyme deficiency.
• From a dermatologist's perspective, classified into cutaneous and non-cutaneous forms.
• From a general clinician's point of view, more appropriate to classify into acute and non-acute forms, emphasizing presence or absence of potentially life-threatening acute neurologic attacks — this is the classification the chapter adheres to.
• Porphyrias are of particular dermatologic interest because most forms have characteristic cutaneous manifestations that often allow a presumptive diagnosis.
• Laboratory tests are then used to confirm the suspected diagnosis.
• Genetic defects underlying the porphyrias have been well characterized, facilitating molecular diagnosis and genetic counseling for affected families.

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• 1874: Schultz described a man with cutaneous photosensitivity accompanied by excretion of wine-red urine.
• Baumstark: subsequently detected urinary pigments, naming them "urorubrohaematin" and "urofuscohaematin."
• Günther (1911): established the first classification of the porphyrias, recognizing them as hereditary metabolic disorders characterized by increased porphyrin excretion; distinguished:

1. Haematoporphyria acuta — acute neurovisceral attacks without skin lesions.
2. Haematoporphyria congenita and chronica — cutaneous findings in sun-exposed body areas.

• 1937: terms "acute intermittent porphyria" and "porphyria cutanea tarda" introduced.
• Subsequent descriptions over the following four decades:
• Variegate porphyria — 1953.
• Hereditary coproporphyria — 1955.
• Erythropoietic protoporphyria — 1961.
• Hepatoerythropoietic porphyria — 1969.
• δ-Aminolevulinic acid (ALA) dehydratase deficiency porphyria — 1979.
• Most recently, X-linked dominant protoporphyria was recognized.

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• Pathway begins with glycine + succinyl CoA and proceeds through eight enzymatic steps to heme; occurs partly in the mitochondrion and partly in the cytosol.
• Full pathway (substrate → enzyme → product; disease resulting from enzyme deficiency):

1. Glycine + succinyl CoA → (enzyme: ALA synthase 2, erythroid-specific) → Delta ALA (ALA)**.

• Gain-of-function mutation in this enzyme → X-linked dominant protoporphyria (the exception; all other porphyrias are due to loss-of-function/deficiency).

1. Delta ALA → (enzyme: ALA dehydratase) → Porphobilinogen.

• Deficiency → ALA dehydratase deficiency porphyria.

1. Porphobilinogen → (enzyme: Porphobilinogen deaminase) → Hydroxymethylbilane.

• Deficiency → Acute intermittent porphyria.

1. Hydroxymethylbilane → (enzyme: Uroporphyrinogen III synthase) → Uroporphyrinogen (with non-enzymatic Uroporphyrin I and III also forming).

• Deficiency → Congenital erythropoietic porphyria.

1. Uroporphyrinogen → (enzyme: Uroporphyrinogen decarboxylase) → Coproporphyrinogen (with Coproporphyrin I and III).

• Deficiency (partial) → Porphyria cutanea tarda.
• Deficiency (marked/homozygous) → Hepatoerythropoietic porphyria.

1. Coproporphyrinogen → (enzyme: Coproporphyrinogen oxidase) → Protoporphyrinogen IX.

• Deficiency → Hereditary coproporphyria.

1. Protoporphyrinogen IX → (enzyme: Protoporphyrinogen oxidase) → Protoporphyrin IX.

• Deficiency → Variegate porphyria.

1. Protoporphyrin IX → (enzyme: Ferrochelatase + Fe²⁺) → Heme.

• Deficiency → Erythropoietic protoporphyria.

1. Heme + Globin (or Apoprotein) → Hemoglobin (or Cytochromes).

• Footnotes to Fig. 49.1:
• *X-linked dominant protoporphyria is the exception, as it is due to gain-of-function mutations.
• Erythroid and ubiquitous isoenzymes of ALA synthase are encoded by genes on the X chromosome and chromosome 3**, respectively.

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• Mutations in any of the genes encoding the enzymes in the heme biosynthetic pathway can lead to pathologic accumulation and excess excretion of porphyrins and/or porphyrin precursors, as a result of enzyme dysfunction.
• Except for patients with acquired porphyria cutanea tarda, ALL forms of porphyria are inherited as monogenetic traits.

• No single factor explains the various photosensitivity patterns evoked by porphyrins plus visible and UV radiation.
• Cellular and soluble factors thought to be involved:
• Reactive oxygen species.
• Cell types: erythrocytes, mast cells, polymorphonuclear cells, fibroblasts.
• Soluble mediators: complement system components, factor XII-dependent pathways, eicosanoids.
• Matrix metalloproteinases.
• Most likely, interactions between these factors contribute to development of cutaneous lesions.
• Porphyrins absorb light energy most efficiently within the Soret band (400 to 410 nm) and enter an excited molecular state.
• Less prominent absorption of adjacent UV wavelengths and other minor visible bands also occurs.
• Light-excited porphyrins transfer absorbed energy to oxygen molecules, generating highly reactive oxygen species.
• Cellular/tissue damage from photoactivated porphyrins is believed to result primarily from:
• Formation of reactive singlet oxygen and free radicals.
• Subsequent lipid peroxidation and protein cross-linking.
• Type of cellular damage depends on solubility and tissue distribution of porphyrins:
• Water-soluble uro- and coproporphyrins → blistering (seen in most cutaneous porphyrias, e.g. PCT, VP).
• Lipophilic protoporphyrins → immediate cutaneous burning sensation after light exposure, with erythema and edema (e.g. EPP).

• Two variants NOT associated with cutaneous findings: ALA dehydratase deficiency porphyria and acute intermittent porphyria.
• Dysfunctional enzymes in these two are involved in early steps of heme biosynthesis; substrates ALA and porphobilinogen (PBG) are non-phototoxic porphyrin precursors.
• Both can manifest with life-threatening acute neurologic attacks.
• ALA and PBG, excreted in massive amounts from the liver during an acute attack, are extremely neurotoxic.
• Lacking appropriate barrier protection, the autonomic and peripheral nervous systems are particularly susceptible to toxic effects.
• Porphyrin abnormalities are also observed in: lead poisoning, sideroblastic and hemolytic anemia, iron deficiency, renal failure, cholestasis, liver disease, and gastrointestinal hemorrhage.
• However, associated photosensitivity has only been documented in rare cases of sideroblastic anemia.

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• Cutaneous:
• Porphyria cutanea tarda.
• Erythropoietic protoporphyria.
• Variegate porphyria.
• Hereditary coproporphyria.
• Congenital erythropoietic porphyria.
• Hepatoerythropoietic porphyria.
• X-linked dominant protoporphyria.
• Non-cutaneous:
• Acute intermittent porphyria.
• ALA dehydratase deficiency porphyria.

Acute porphyrias:

• Acute intermittent porphyria: Incidence 0.5–1 per 100 000; age of onset second to fourth decade of life, rarely before puberty; most common acute porphyria worldwide; acute neurologic attacks but NO photosensitivity/cutaneous manifestations.
• Variegate porphyria: Incidence ~1 per 300 in South Africa, relatively rare elsewhere; age of onset second to third decade of life, usually not before puberty; cutaneous manifestations similar to PCT, and acute attacks similar to AIP can occur (neurocutaneous porphyria); founder mutations identified in South Africa and Chile.
• Hereditary coproporphyria: Very rare (<75 cases reported); usually not before puberty; acute attacks similar to AIP; cutaneous manifestations including erythema and blistering in sun-exposed areas can occur (neurocutaneous porphyria).
• ALA-D deficiency porphyria: Extremely rare (<10 cases reported); early and late onset both described; neurologic symptoms similar to AIP can occur; NO photosensitivity/cutaneous manifestations.

Non-acute porphyrias (all can have cutaneous features):

• Porphyria cutanea tarda: Most common porphyria worldwide; onset third to fourth decade of life, usually not before puberty; acquired and hereditary variants exist; moderate to severe photosensitivity; cutaneous findings in sun-exposed areas include skin fragility, erosions, crusts, vesicles and bullae, milia, scarring, hyperpigmentation, and hypertrichosis; indistinguishable from variegate porphyria.
• Erythropoietic protoporphyria: Second-highest incidence of the cutaneous porphyrias; onset early childhood (1 to 4 years), late onset extremely rare; cutaneous manifestations include erythema, edema, crusts, purpura, skin thickening, and waxy scars, primarily on dorsal hands and face; usually no blistering; in ~5% of patients, severe liver disease can occur; cholelithiasis; palmar keratoderma in rare AR form; adult-onset form associated with underlying MPD or MDS.
• Congenital erythropoietic porphyria: Very rare (~170 cases reported); onset infancy/first decade of life; very severe clinical course; sun-exposed sites show vesicles and bullae, erosions, ulcerations, crusts, milia, scarring, hyperpigmentation, and hypertrichosis; mutilation; hemolytic anemia; hepatosplenomegaly; porphyrin deposition in bones and teeth (erythrodontia); pink, red, or violet staining of diapers.
• Hepatoerythropoietic porphyria: Extremely rare (~35 cases reported); onset early infancy; homozygotic or compound heterozygotic variant of PCT; markedly increased photosensitivity and severe clinical course possible; sun-exposed sites show vesicles and bullae, skin fragility, erosions, crusts, milia, scarring, and hypertrichosis; mutilation can occur; diapers stained by darkly colored urine.
• X-linked dominant protoporphyria: Very rare; onset early childhood; skin symptoms indistinguishable from EPP; most recent type of porphyria to be recognized; liver disease appears to occur more frequently than in EPP.
• Abbreviations: ALA-D, aminolevulinic acid dehydratase; AR, autosomal recessive; MDS, myelodysplastic syndrome; MPD, myeloproliferative disorder.

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• Medical evaluation involves up to four steps:

1. Thorough clinical assessment including family history and physical examination, with particular reference to sun-exposed sites.
2. Biochemical measurement of porphyrins and porphyrin precursors in urine, feces, blood, and/or plasma.
3. Determination of activity of specific enzymes (specialized laboratories).
4. DNA mutational analysis (specialized laboratories).

• Difficulties obtaining a definitive diagnosis are primarily a result of overlapping clinical and/or biochemical features.
• Especially true of variegate porphyria and hereditary coproporphyria, which may present with cutaneous lesions similar to PCT and/or neurologic/visceral findings resembling AIP.
• Markedly elevated urinary levels of porphyrin precursors ALA and PBG can be found during an acute attack.
• Asymptomatic "carriers" (harboring mutations) are rarely detected via measurement of urinary porphyrin precursors because levels exhibit significant variability and may be only slightly elevated or even normal between acute attacks (shaded areas).
• Diagnoses based upon enzymatic activity measurements in fibroblasts or lymphocytes are not always conclusive, because an overlap exists between values in patients, asymptomatic carriers, and normal controls.
• Therefore, the ability to detect specific genetic mutations has made a significant impact on precise diagnosis and accurate genetic counseling.

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Acute porphyrias:

Non-acute porphyrias:

• *EPP: Actually semi-dominant inheritance — a mutation in one allele plus a specific intronic polymorphism in the second allele ("hypomorphic" allele; see EPP section below).
• Abbreviations: ALA-D, aminolevulinic acid dehydratase; AD, autosomal dominant; AR, autosomal recessive; XLD, X-linked dominant.

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• Legend: N = normal; NA = not available; + = above normal range; ++ = slightly elevated; +++ = highly elevated; ++++ = very highly elevated; ↑ = increase.

Acute porphyrias:

• Acute intermittent porphyria — Urine: ALA ++ to ++++, PBG ++ to ++++, URO +++, COPRO ++; Feces: URO N to +, COPRO N to +; Erythrocytes PROTO N; Plasma N.
• Variegate porphyria — Urine: ALA ++ to +++, PBG ++ to +++, URO +++, COPRO +++; Feces: URO N, COPRO +++, PROTO ++++; Erythrocytes N; Plasma: peak fluorometric emission 624–626 nm.
• Hereditary coproporphyria — Urine: ALA N to ++, PBG N to ++, URO ++, COPRO ++++; Feces: URO ++, COPRO ++++, PROTO N to +; Erythrocytes N; Plasma: peak fluorometric emission 619 nm.
• ALA-D deficiency porphyrin — Urine: ALA +++, PBG N, URO +, COPRO ++; Feces: URO N, COPRO +, PROTO +; Erythrocytes N, N, ++ (URO, COPRO, PROTO respectively); Plasma: ALA, COPRO & PROTO ↑.

Non-acute porphyrias:

• Porphyria cutanea tarda — Urine: ALA N, PBG N, URO ++++, COPRO ++; Feces: URO ++, COPRO ISOCOPRO; Erythrocytes PROTO N; Plasma: URO ↑.
• Erythropoietic protoporphyria — Urine: ALA N, PBG N, URO N, COPRO N; Feces: URO N, COPRO ++, PROTO ++ to ++++; Erythrocytes: URO N, COPRO N to +, PROTO +++; Plasma: PROTO ↑.
• Congenital erythropoietic porphyria — Urine: ALA N, PBG N, URO ++++, COPRO ++; Feces: URO +, COPRO +++, PROTO +; Erythrocytes: URO ++++, COPRO +++, PROTO +++; Plasma: URO & COPRO ↑.
• Hepatoerythropoietic porphyria — Urine: ALA N, PBG N, URO +++, COPRO ISOCOPRO; Feces: URO N, COPRO ISOCOPRO, PROTO N; Erythrocytes: URO N, COPRO +, PROTO +++; Plasma: URO ↑.
• X-linked dominant protoporphyria — Urine: ALA N, PBG N, URO N, COPRO N; Feces: URO NA, COPRO NA, PROTO NA; Erythrocytes: URO NA, COPRO NA, PROTO ++++† (†Approximately 40% zinc protoporphyrin); Plasma: PROTO ↑.
• Note: In patients with VP or HCP who have no symptoms (cutaneous or systemic), urine porphyrins may not be elevated (shaded areas in original table).
• Abbreviations: ALA, aminolevulinic acid; ALA-D, aminolevulinic acid dehydratase; COPRO, coproporphyrin; ISOCOPRO, isocoproporphyrin; PBG, porphobilinogen; PROTO, protoporphyrin; URO, uroporphyrin.

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1. As screening, measure urinary porphyrins (uro- and coproporphyrins as well as ALA and PBG) — 24-hour collection.
2. If normal in a symptomatic patient → porphyria excluded; consider pseudoporphyria or epidermolysis bullosa acquisita (EBA).
3. If elevated → cutaneous porphyria confirmed; measure stool porphyrins to differentiate between PCT (isocoproporphyrin), VP, and HCP — or perform plasma screening to differentiate.

1. Measure erythrocyte protoporphyrin.
2. If normal → EPP (and XLDPP) excluded.
3. If elevated → EPP (increased free protoporphyrin) or XLDPP (increased free and zinc protoporphyrins, ~40% zinc protoporphyrin) confirmed.

1. Measure urinary porphyrin precursors ALA and PBG.
2. If normal → acute porphyria as etiology of acute neurologic symptoms excluded; measure stool porphyrins to exclude VP or HCP during period of remission (between acute attacks).
3. If elevated → measure stool porphyrins to differentiate between AIP, VP, and HCP.

• Note: Increased zinc protoporphyrin can be seen in iron deficiency anemia, heavy metal intoxication, and anemia of chronic disease.
• These bedside observations (e.g. Wood's lamp urine fluorescence) are neither sensitive nor specific diagnostic tests.

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• Consist of: porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), congenital erythropoietic porphyria (CEP), hepatoerythropoietic porphyria (HEP), and X-linked dominant protoporphyria (XLDPP).
• All present primarily with cutaneous findings.
• Histologic examination of involved skin is not required to confirm a presumptive diagnosis of any cutaneous porphyria, but a biopsy specimen may be obtained to exclude other entities in the differential diagnosis.
• Occasionally, the pathologist may identify histologic features supporting cutaneous porphyria even when the clinician suspected another disorder, e.g. epidermolysis bullosa acquisita.

• Worldwide, PCT is the most common type of porphyria.
• Results from decreased activity of uroporphyrinogen decarboxylase, the fifth enzyme in heme biosynthesis.
• At least two (three) types distinguished:

1. Type I PCT — sporadic (acquired); dysfunctional enzyme exclusively expressed in the liver.
2. Type II PCT — autosomal dominant familial (hereditary); catalytic enzymatic defect detected in all tissues.
3. Type III PCT — described by Elder: families with typical clinical/biochemical features of overt PCT but normal uroporphyrinogen decarboxylase activity in red blood cells.

• In most countries, ratio of type I to type II PCT is currently estimated at approximately 3:1 to 4:1.
• There is increasing evidence that some facets of PCT etiology remain incompletely elucidated.

Clinical features

• Increased photosensitivity and skin fragility.
• Blistering, erosions, crusts, milia, and scars in sun-exposed sites.
• Postinflammatory hyperpigmentation, hypertrichosis, scarring alopecia, and morpheaform and sclerodermoid changes.

Histology

• Vesiculobullae commonly reveal subepidermal cell-poor blisters with characteristic festooning of dermal papillae.
• Festooning is most likely due to deposition of PAS-positive glycoproteins in and around the wall of vessels localized in the upper dermis.
• Direct immunofluorescence microscopy often demonstrates immunoglobulins (mainly IgG; less commonly IgM), complement, and fibrinogen at the dermal–epidermal junction and around blood vessels of the papillary dermis.
• As opposed to autoimmune bullous diseases, these immunoglobulin deposits are presumed to be non-antigen-specific.
• In sclerotic lesions: dermal fibrosis as well as PAS-positive deposits around blood vessels.

Biochemical findings

• 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 — this finding is exclusive to PCT and hepatoerythropoietic porphyria.
• Historically: urine examined under Wood's lamp illumination (in the dark) and after exposure to natural light.
• Urine turns red to brown after several hours of exposure to natural light.
• Urine has pink to red fluorescence when exposed to a UVA light source.

Triggering factors

• Alcohol (most common).
• Estrogens.
• Polychlorinated hydrocarbons.
• Dialysis in patients with renal failure.
• Iron.
• Inheritance of specific mutations in HFE underlying classic hemochromatosis.
• Viral infections such as hepatitis C and HIV.
• Homozygosity for HFE mutation C282Y associated with earlier onset of disease in both sporadic and familial PCT, effect more marked in familial PCT.

• Due to a semi-dominantly inherited deficiency of ferrochelatase, the last enzyme in the heme biosynthetic pathway.
• Cutaneous photosensitivity typically manifests early in life (early childhood).
• Acute photosensitivity episodes: intense burning, stinging, and pruritus of sun-exposed skin (nose, cheeks, dorsal hands), followed by erythema, edema, crusts, petechiae, then wax-like scarring.
• Blistering usually does not occur.
• Symptoms develop within minutes of sun exposure, often starting early in springtime, continuing through summer, diminishing in fall/winter.
• Window glass does not protect the patient.
• Only relief is cooling affected skin under cold water.
• In patients without recent sun exposure, only detectable cutaneous findings may be scars on the nose and lips.
• In rare patients with recessively inherited EPP, palmar keratoderma can be seen.

Adult-onset (late-onset) EPP

• Very unusual; atypical age of onset often delays diagnosis.
• All reported individuals have had a history of either a myeloproliferative disorder or myelodysplastic syndrome.
• Hematologic disease thought to possibly give rise to somatic hematopoietic mutations/clones causing abnormal porphyrin metabolism and systemic protoporphyrin accumulation.
• Should be considered in adults with new-onset, otherwise unexplained photosensitivity, especially with underlying hematologic disorder.

Histology

• Vacuolization of epidermal cells in acute lesions.
• Intercellular edema.
• Vacuolization and lysis of endothelial cells within superficial dermal blood vessels.
• In older lesions (waxy scarring areas): eosinophilic PAS-positive deposits around blood vessels — more pronounced than in PCT.
• Resemblance to amorphous protein depositions seen in lipoid proteinosis.
• Ultrastructurally: thickening and degeneration of capillary basement membranes.

Biochemical findings

• Increase in free protoporphyrin levels in erythrocytes, plasma, feces, and other tissues (e.g. liver).
• Historically, microscopic examination of blood smear via UV illumination detected erythrocyte fluorescence — not particularly sensitive or specific.
• Greatest concern: rapid accumulation of protoporphyrin within liver and biliary system, with development of cholestasis, potentially leading to hepatic damage and progressive (even fatal) liver failure; occurs in ~5% of patients.
• Liver function tests may remain normal until late in the disease course.

Genetic basis

• Cutaneous symptoms develop only in individuals who inherit:
• A heterozygous ferrochelatase gene mutation involving one parental allele (allele A), AND
• A specific intronic polymorphism (IVS3–48 T/C) of the other parental allele (allele B).
• This polymorphism in trans constitutes a "hypomorphic" allele, leading to abnormal modulation of splicing.
• Aberrantly spliced mRNA is degraded by nonsense-mediated decay, producing decreased steady-state mRNA level.
• Combined, mutation in allele A plus polymorphism in allele B lead to marked reduction in ferrochelatase activity that is ~15%–25% of normal.
• Molecular mechanisms underlying protoporphyrin-induced hepatic disease and severe liver injury phenotype are not yet well understood.

• Characterized by gain-of-function mutations in ALAS2 on the X chromosome.
• Gene encodes the erythroid tissue-specific isoform of the first enzyme in heme biosynthesis, δ-aminolevulinic acid synthase 2.
• Resultant increase in synthetase activity leads to overproduction of protoporphyrin IX.
• Clinical phenotype indistinguishable from EPP.
• Percentage of patients at risk for potentially fatal liver disease appears higher than in classic EPP.
• Biochemical profiling: higher total protoporphyrin levels in erythrocytes compared to EPP (ferrochelatase deficiency), with ~40% being zinc protoporphyrin.

• Synonym: Günther disease.
• With ~170 cases reported to date, CEP is a very rare, autosomal recessively inherited disorder.
• Results from markedly decreased catalytic activity of uroporphyrinogen III synthase, the fourth enzyme in heme biosynthesis.
• Manifests shortly after birth with severe cutaneous photosensitivity, blistering, erosions, crusts, and ulcerations, followed by extensive scarring and deformation, primarily of the hands.
• On the face: loss of eyebrows and eyelashes, severe mutilation of cartilaginous structures (e.g. the nose).
• Erythrodontia, acro-osteolysis, and skeletal abnormalities (e.g. demineralization) common.
• Variable hematologic involvement ranging from mild hemolytic anemia to intrauterine hydrops fetalis and hepatosplenomegaly.
• Pink, red, or violet staining of diapers can serve as an early clue to the diagnosis.
• Biochemically: increased urinary excretion of uroporphyrin I and coproporphyrin I, plus elevated coproporphyrin I in the stool.

• The homozygous (or compound heterozygous) variant of hereditary PCT.
• Extremely rare disease due to pronounced decrease in uroporphyrinogen decarboxylase activity.
• Usually presents during early childhood, with dark urine in the diapers often the initial clinical finding.
• Severe cutaneous photosensitivity develops subsequently, with blistering, pruritus, hypertrichosis, hyperpigmentation, and sclerodermalike scarring.
• If severe, symptoms closely resemble CEP; however, unlike CEP, HEP is not usually associated with hematologic abnormalities (e.g. severe anemia).
• Urinary levels of uroporphyrin and hepta-carboxylated porphyrins elevated, as are fecal levels of coproporphyrin and isocoproporphyrin.
• Increased levels of zinc-chelated protoporphyrin within erythrocytes also seen.

• Also referred to as pseudoporphyria cutanea tarda, bullous dermatosis of dialysis, or therapy-induced bullous photosensitivity.
• Clinically resembles PCT, but no biochemical abnormalities in porphyrin metabolism are detected.
• Skin fragility, erosions, blisters, and scarring predilect for the dorsal aspect of the hands, the face, and extensor surfaces of the legs.
• Commonly encountered in:
• Patients with stage 4 or 5 chronic kidney disease.
• Patients undergoing renal dialysis (hemodialysis more often than peritoneal dialysis).
• Ingestion of specific drugs.
• Use of tanning beds — vesicles may be seen on the palms in this situation.
• Histologic findings indistinguishable from PCT lesions.
• Patients requiring renal dialysis may develop PCT or pseudoporphyria; even if anuric, diagnosis of PCT can be established via plasma or stool studies.
• Treatment easier for drug-induced pseudoporphyria — major recommendation is discontinuation of exposure to the suspected precipitant.
• Sun protection advised for all patients.

Drug-induced pseudoporphyria (most common causes in bold)

• NSAIDs: Naproxen (propionic acid derivative; NSAID most frequently implicated), Mefenamic acid, Nabumetone, Oxaprozin (propionic acid derivative), Ketoprofen (propionic acid derivative), Diflunisal, Celecoxib.
• Antibiotics: Nalidixic acid, Tetracycline/doxycycline, Ciprofloxacin, Ampicillin/sulbactam combined with cefepime.
• Diuretics: Furosemide, Hydrochlorothiazide/triamterene, Chlorthalidone, Bumetanide, Torsemide.
• Retinoids: Isotretinoin, Acitretin.
• Miscellaneous: Amiodarone, Carisoprodol/aspirin (attributed to the carisoprodol), Chlorophyll, Cyclosporine, Dapsone, Finasteride, 5-Fluorouracil (intravenous), Flutamide, Imatinib, Leflunomide, Metformin, Olanzapine, Oral contraceptive pill (estrogens, progestins), Pyridoxine (vitamin B6), Sunitinib, Voriconazole.
• Note: When caused by NSAIDs, consider prescribing indomethacin, meloxicam, or sulindac.
• In addition to discontinuation of the offending agent, antioxidants such as N-acetylcysteine have had a beneficial effect in some case series.

• PCT must be distinguished from:
• Mild variants of CEP and HEP.
• Variegate porphyria (VP) and hereditary coproporphyria (HCP) — important since these can be associated with life-threatening acute attacks.
• Pseudoporphyria.
• Epidermolysis bullosa acquisita.
• Polymorphous light eruption.
• Phototoxic and bullous drug eruptions.
• These can easily be differentiated from PCT by porphyrin analysis; if no porphyrin abnormalities detected, histologic examination (routine and immunofluorescence) can aid diagnosis.
• EPP differential diagnosis: solar urticaria, phototoxic or photoallergic contact dermatitis and drug reactions, polymorphous light eruption, hydroa vacciniforme, and lipoid proteinosis.
• CEP must be differentiated from: HEP; rare homozygous (or compound heterozygous) variants of VP and HCP; STING-associated vasculopathy with onset in infancy (SAVI) (see Ch. 45.7); mild variants can sometimes mimic PCT.
• HEP most important differentials: CEP and the rare aforementioned homozygous/compound heterozygous variants of VP and HCP.

• A causal therapeutic strategy would consist of either specific enzyme replacement therapy or gene therapy — such modalities are not currently available.
• General measures for all: avoidance of UV light exposure, sun-protective clothing, window films, and regular application of broad-spectrum sunscreens — crucial both prophylactically and therapeutically.
• Because primary porphyria-inducing wavelengths are in the visible 400–410 nm range, standard chemical sunscreens are limited in efficacy.
• Exception: physical blockers titanium dioxide and zinc oxide are effective (see Ch. 132).
• Tinted sunscreens containing iron oxide also protective against visible light.

Non-acute porphyria therapy strategies

Porphyria cutanea tarda:

1. Photoprotection (broad-spectrum sunscreens*, protective clothing, window films).
2. Avoidance of sunlight exposure and trauma.
3. Cease alcohol ingestion; stop estrogen therapy.
4. Phlebotomy: 400–500 ml every 2 weeks over ~3–6 months.
5. Low-dose hydroxychloroquine: 100 mg twice weekly (e.g. Monday and Thursday) over 6–12 months, until porphyrin excretion is within normal range.
6. Measurement of urinary porphyrin excretion to monitor therapeutic outcome.

Erythropoietic protoporphyria/X-linked dominant protoporphyria:

1. Photoprotection.
2. Avoidance of sunlight exposure (common window glass provides no protection).
3. Oral β-carotene: 30–90 mg/day in children; 60–180 mg/day in adults; desirable maximum plasma level 600–800 mcg/dl; administration during spring, summer, fall with hiatus during winter in higher latitudes.
4. Afamelanotide ([Nle4, D-Phe7]-α-MSH; 16 mg every 60 days as a resorbable implant) may increase tolerance to light exposure.
5. Consider cholestyramine or charcoal to reduce enterohepatic recirculation of porphyrins and bile acids to enhance hepatic porphyrin excretion; results vary.

Congenital erythropoietic porphyria:

1. Photoprotection.
2. Strict avoidance of sunlight exposure.
3. Change day–night rhythm.
4. Splenectomy (reduces hemolysis and platelet consumption).
5. Bone marrow or hematopoietic stem cell transplantation.

Hepatoerythropoietic porphyria:

1. Photoprotection.
2. Strict avoidance of sunlight exposure and trauma.
3. Change day–night rhythm.
4. Of note, therapeutic approaches used in PCT (e.g. phlebotomy, antimalarials) are NOT effective.

• *Sunscreens containing the physical blockers zinc oxide, titanium dioxide, and iron oxide are most effective.

Additional treatment detail — PCT

• Eliminate triggering factors: alcohol ingestion, estrogen therapy.
• In patients with iron overload: successful treatment via repeated phlebotomy (venesection) of ~500 ml blood every 2 weeks, as tolerated; some authors recommend weekly venesections of 300 ml blood.
• Maintenance phlebotomy performed at less frequent intervals when required.
• Phlebotomy reduces iron stores, improving heme synthesis by reducing iron-induced inhibition of uroporphyrinogen decarboxylase activity.
• Therapeutic goal: reduce serum ferritin to lower limit of reference range, avoiding anemia.
• Phlebotomy usually leads to resolution of skin fragility and blistering within 2–4 months.
• Normalization of urinary porphyrin concentrations usually takes longer (about 12 months).
• Low-dose hydroxychloroquine: works by accelerating hepatic elimination and urinary excretion of porphyrins; may also inhibit porphyrin synthesis.
• Standard therapy: 100 mg twice weekly; complete remission expected within 6–9 months; scored tablets should be prescribed.
• Higher doses (as used in cutaneous lupus erythematosus) can lead to hepatotoxicity.
• Can be combined with phlebotomy to induce remission more rapidly.
• Genetic background regarding HFE mutations plays a critical role in outcome:
• Heterozygosity for C282Y and compound heterozygosity for HFE mutations did not compromise therapeutic response.
• PCT patients homozygous for C282Y failed to respond to antimalarial therapy and retained high serum iron/ferritin and transferrin saturation.
• Deferasirox: pilot trial — improvement of cutaneous findings in 8 of 10 patients with PCT who completed 6 months of treatment.
• Treatment of underlying HCV infection with direct-acting antivirals also leads to improvement.

Additional treatment detail — EPP

• β-carotene minimizes burning, stinging, and photosensitivity reactions in some patients.
• Has no effect on erythrocyte protoporphyrin levels, but reduces photosensitivity by quenching formation of free radicals during cutaneous photoreaction.
• Doses: 30 to 90 mg/day in children; 60 to 180 mg/day in adults; desired maximum plasma levels 600–800 mcg/dl.
• Afamelanotide, analogue of melanocyte stimulating hormone ([Nle4, D-Phe7]-α-MSH):
• FDA-approved for prevention of EPP phototoxicity in 2019; European regulatory approval in 2016.
• Multicenter, randomized, placebo-controlled trial involving 168 patients with EPP: those treated with afamelanotide (16 mg every 60 days as a resorbable implant) experienced increased tolerance to sun exposure and improved quality of life.
• Narrowband UVB phototherapy, including home phototherapy: shown of benefit in a case series after 15–20 treatments.
• Cholestyramine or charcoal can be considered to reduce enterohepatic recirculation of porphyrins and bile acids.
• Overall, current therapeutic options for EPP are more limited than for PCT.

Additional treatment detail — CEP

• Require surveillance for anemia and skin infections.
• Frequent blood transfusions can suppress erythropoiesis, decreasing porphyrin production and photosensitivity.
• Concomitant administration of deferoxamine or deferasirox can reduce resulting iron overload.
• Bone marrow or hematopoietic stem cell transplantation leads to marked reduction of porphyrin levels and photosensitivity and has been reported to be curative.

Additional treatment detail — HEP and XLDPP

• No specific treatment options currently available.
• Careful patient education regarding sun protection is very important.

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• Consist of: acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and δ-aminolevulinic acid dehydratase (ALA-D) deficiency porphyria.
• Broad range of clinical findings, including persistent colicky abdominal pain, nausea and vomiting, obstipation, tachycardia, hypertension, seizures, paresthesias, para- and tetraplegia, and acute psychosis.
• This nonspecific spectrum of symptoms can mimic many other diseases; porphyrias are often not included in the differential diagnosis, especially if neurologic symptoms prevail.
• Acute attacks can be precipitated by:
• Porphyrinogenic drugs (e.g. antimalarials, tetracyclines, sulfonamides).
• Alcohol.
• Hormonal changes.
• Recurrent or chronic infections.
• Reduced caloric intake due to fasting or diets — may be a result of enhanced expression of the transcriptional coactivator PGC-1α.
• Patients with VP and HCP may have cutaneous findings clinically indistinguishable from PCT; as a result, VP and HCP are also referred to as neurocutaneous porphyrias.
• The European Porphyria Network (EPNET) — consortium of porphyria specialists from several European porphyria centers — sets standards and guidelines for diagnosis and treatment.
• Resources: EPNET (porphyria.eu) and the American Porphyria Foundation (porphyriafoundation.com).

• Worldwide, AIP is the most common type of acute porphyria.
• Autosomal dominantly inherited disorder characterized by deficiency of porphobilinogen deaminase, the third enzyme in heme biosynthesis.
• Patients do NOT have skin manifestations.
• Usually presents after puberty with acute porphyric attacks, precipitated by the various trigger factors above.
• Elevated urinary levels of porphyrin precursors ALA and PBG detected during an acute attack:
• ALA levels: 5 to 20 times normal.
• PBG levels: increased to as high as 20- to 50-fold normal.

• Synonyms: South African porphyria, Mixed porphyria.
• Characterized by autosomal dominantly inherited deficiency of protoporphyrinogen oxidase, the seventh enzyme in heme biosynthesis.
• Cutaneous and neuropsychiatric symptoms can occur separately or simultaneously.
• Skin findings cannot be differentiated from PCT.
• Acute attacks identical to those in AIP.
• During acute attacks, elevated urinary ALA and PBG.
• During remission, urinary ALA and PBG may be within normal range (shaded areas) — therefore, additional biochemical analyses of fecal porphyrins are mandatory to establish the diagnosis.
• Elevated levels of stool protoporphyrin and coproporphyrin detected, with protoporphyrin concentration usually higher than coproporphyrin.
• This abnormal biochemical stool profile can 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.

• Very rare autosomal dominantly inherited disease.
• Characterized by deficiency of coproporphyrinogen oxidase, the sixth enzyme in the porphyrin–heme biosynthetic pathway.
• Clinical symptoms similar to VP.
• In contrast to VP: stool coproporphyrin concentrations usually higher than protoporphyrin.

• Synonyms: Plumboporphyria, Doss porphyria.
• Autosomal recessively inherited porphyria variant, extremely rare.
• Fewer than 10 cases reported worldwide; does not have an important clinical presence.
• Can present during early childhood (as well as adulthood) with acute neurologic symptoms resembling AIP.

• When VP or HCP present with cutaneous manifestations, differential diagnosis identical to PCT (see above).
• If acute neurologic attacks prevail, must exclude a broad range of gastrointestinal, neurologic, and psychiatric diseases, including:
• An "acute abdomen".
• Peripheral neuropathies.
• Viral infections.
• More detailed discussion found in textbooks of internal medicine.

• The more prevalent symptoms are in bold in the original table.
• Gastrointestinal and metabolic: Colicky abdominal pain, Nausea and vomiting, Constipation, Obstipation, Hyponatremia.
• Neurologic: Paresthesias, Motor and sensory peripheral neuropathy (para- and tetraplegia), Seizures, Muscle pain/back pain, Encephalopathy, Paralysis, Anxiety, Acute psychosis, Coma.
• Cardiac and pulmonary: Tachycardia, Hypertension, Respiratory paralysis.

Cutaneous symptoms (VP or HCP)

• Minimize outdoor light exposure via sun-protective clothing and broad-spectrum sunscreens.
• In contrast to PCT, phlebotomy seems to be of no benefit, as are chloroquine and hydroxychloroquine.
• Antimalarials are potential inducers of acute porphyric attacks — their use is not recommended.

Acute porphyric attack

• A potentially life-threatening event associated with a significant mortality rate (up to 5%).
• Requires rapid therapeutic intervention to prevent complications such as paralysis, respiratory failure, and coma.
• Treatment should consist of the following consecutive measures:

1. Precipitating factors (e.g. porphyrinogenic drugs) must be identified and eliminated. If necessary, monitor in an intensive care unit with input from porphyria specialists.
2. Systemic symptoms (abdominal pain, nausea, vomiting) treated symptomatically, e.g. with opioid analgesics and ondansetron or promethazine.
3. Most important therapeutic step: prompt intravenous administration of heme preparations:

• Heme arginate (Normosang® [Orphan Europe/Recordati Rare Diseases]; Europe only) — 3 mg/kg once daily for 4 consecutive days.
• Hemin (Panhematin® [Recordati Rare Diseases]; FDA-approved) — usually 1–4 mg/kg/day (over 10–15 min) for 3–14 days, versus 3–4 mg/kg once daily for 4 days, with more extended treatment for severe cases.
• Heme arginate reduces overproduction of porphyrin precursors via a negative feedback mechanism, repressing the increased activity of ALA synthase, the rate-limiting enzyme in heme biosynthesis.
• Heme preparations have the disadvantage of being unstable, and thrombophlebitis is a fairly common side effect.

1. If necessary, until heme preparations become available, intravenous glucose infusions — historically primary treatment, now only adjunctive/temporary if heme arginate or hematin not immediately available.
2. Once monthly subcutaneous givosiran (Givlaari®), an aminolevulinic acid synthase 1-directed small interfering RNA (siRNA).
3. Measurement of urinary porphyrin excretion during the acute attack (daily, if possible).

• Givosiran (Givlaari® [Alnylam Pharmaceuticals]):
• FDA-approved 2019; European Medicines Agency approval 2020, for treatment of adults with acute (hepatic) porphyria.
• Solution of small interfering RNAs injected subcutaneously once monthly.
• Promotes degradation of aminolevulinic acid synthase 1 (ALAS1) mRNA within liver cells, reducing circulating levels of neurotoxic metabolites.
• Most common side effects: injection site reactions and nausea.
• Both liver function tests and serum creatinine need to be monitored.
• Can lead to severe hyperhomocysteinemia, probably due to inhibition of the heme-dependent enzyme cystathionine-β-synthase, important for homocysteine metabolism, with subsequent protein-N-homocysteinylation.

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• ARUP Laboratories (www.arupconsult.com).
• Mayo Medical Laboratories (www.mayocliniclabs.com) — also perform enzyme assays and genetic analyses.
• University of Texas Medical Branch – Porphyria Center.

• Porphyrin Laboratory, Free University of Brussels.
• Porphyria Research Centre Finland.
• French Porphyria Center Paris.
• French Porphyria Center Bordeaux.
• European Porphyria Specialist Center, Düsseldorf.
• German Competence Center for Porphyrias Karlsruhe.
• Porphyrin Specialist Center Dublin.
• Porphyria Center Milano.
• Dutch Porphyria Center Rotterdam.
• Norwegian Porphyria Center (NAPOS).
• Porphyria Center Stockholm.
• Porphyria Center Barcelona.
• Porphyria Center Madrid.
• Swiss Porphyria Center Zürich.

• Porphyria Center England, London.
• Porphyria Center Wales, Cardiff.

• The porphyrias are a group of disorders caused by defects in the biosynthesis of haem.
• Their relevance to the skin arises from the PHOTOTOXIC properties of the porphyrins, which accumulate in most porphyrias and cause photosensitivity.
• The majority of the porphyrias are INHERITED. Many affect other organs as well as the skin.

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• A PYRROLE is a ring composed of four carbon atoms and one nitrogen atom.
• Four pyrroles linked into a ring create a TETRAPYRROLE — a structure found in chlorophyll, haem and vitamin B12.
• A PORPHYRIN is a special type of tetrapyrrole in which four pyrrole rings are linked by METHINE BRIDGES into a large ring structure.
• HAEM is the molecule created by the insertion of FERROUS iron into the centre of the porphyrin molecule PROTOPORPHYRIN IX.
• Incorporation of iron into the porphyrin molecule enables it to become biologically useful:
• Iron's capacity to bind molecular oxygen and to transfer electrons (moving between 2+ and 3+ oxidation states) makes it useful — but free iron precipitates in the presence of water.
• Binding of iron to the porphyrin SOLUBILISES iron and optimises its electronic structure.
• The porphyrin's central cavity is the right size to fit an iron atom, and its four central nitrogen atoms occupy four of the iron's coordination binding sites, leaving only TWO free.
• A KEY feature of the porphyrin structure: each double bond is adjacent to a single bond, so it is ‘AROMATIC’ with 18 of its electrons DELOCALISED and free to move around the molecule.
• Haem binds to a variety of proteins, and the nature of this interaction reflects the protein's function:
• Electron transport proteins (respiratory cytochromes) — amino acids bind to BOTH remaining coordination sites, so haem transfers electrons through alterations in the iron's oxidation state
• Oxygen-binding proteins (haemoglobin) — an amino acid binds ONE remaining site, leaving the SIXTH site free to bind oxygen
• Summary of haem functions: electron transfer (respiratory cytochromes), reversible oxygen binding (haemoglobin and myoglobin) and oxidation/reduction reactions (cytochrome P450, catalase) — with fine tuning determined by the APOPROTEIN.

• The complex electronic structure results in the 18 delocalised electrons having unusual excitation characteristics — excited by relatively LONG WAVELENGTH light.
• The MAIN ABSORPTION PEAK is at 408 nm — the ‘SORET BAND’. This long wavelength predisposes to phototoxic behaviour.
• These photons have insufficient energy to chemically alter the porphyrin structure, so alternative fates — FLUORESCENCE and PHOSPHORESCENCE — become more likely.
• Following excitation: electrons either return to the ground state by releasing energy as characteristic RED FLUORESCENCE, or the excited SINGLET state transforms (by intersystem crossing) to the longer-lived excited TRIPLET state.
• Transfer of energy from the excited TRIPLET state to neighbouring molecules leads to the PHOTOTOXICITY responsible for the clinical features.

• Haem is synthesised from glycine and succinyl coenzyme A (CoA) via an EIGHT-STEP pathway.
• Six key structural changes:

1. Pyrrole ring — synthesis of porphobilinogen (PBG)
2. Tetrapyrrole — assembly to hydroxymethylbilane
3. ‘D’ ring FLIPPED → isomer III (the alternative I isomer forms in the absence of the cosynthase enzyme)
4. Removal of FOUR carboxylate groups — uroporphyrinogen III → coproporphyrinogen III
5. Removal of TWO carboxylate groups — coproporphyrinogen III → protoporphyrinogen; then oxidised to protoporphyrin IX
6. Insertion of iron (Fe²⁺) → haem

• Enzymes in order: ALA synthase → ALA dehydratase → PBG deaminase → uroporphyrinogen III cosynthase → uroporphyrinogen decarboxylase → coproporphyrinogen oxidase → protoporphyrinogen oxidase → ferrochelatase
• Progressive decarboxylation to remove six of the eight electron-withdrawing carboxylate groups likely increases the flux of electrons onto the molecule's central nitrogens to facilitate coordination with iron.
• Around 80% of haem is synthesised in ERYTHROID cell precursors in the BONE MARROW (for haemoglobin production).
• Excretion routes (determined by water solubility):
• Uroporphyrinogen — ONLY excreted via the KIDNEYS
• Hydrophobic protoporphyrinogen and protoporphyrin — EXCLUSIVELY excreted into the BILE
• Coproporphyrinogen — excreted by BOTH routes
• Physiological concentrations of porphyrins stay LOW because of the high efficiency of haem synthesis.

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• In any porphyria, a PARTIAL enzyme deficiency causes the accumulation of porphyrins.
• Previously classified by predominant site of porphyrin accumulation into erythropoietic (CEP and EPP) and hepatic (all others) groups — this division is NOT of value clinically.
• For the clinician, the KEY division is between porphyrias that cause ACUTE ATTACKS and those that cause SKIN DISEASE.

1. Cutaneous disease ONLY:

• Porphyria cutanea tarda (PCT) — uroporphyrinogen decarboxylase
• Congenital erythropoietic porphyria (CEP) — uroporphyrinogen III cosynthase
• Erythropoietic protoporphyria (EPP) — ferrochelatase

1. Cutaneous disease AND acute attacks:

• Hereditary coproporphyria (HC) — coproporphyrinogen oxidase
• Variegate porphyria (VP) — protoporphyrinogen oxidase

1. Acute attacks ONLY:

• Acute intermittent porphyria (AIP) — porphobilinogen deaminase

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• ALL cutaneous porphyrias EXCEPT EPP present with FRAGILITY and BLISTERING of light-exposed skin — the term ‘BULLOUS PORPHYRIAS’ is often used for this group.
• The mechanism underlying the skin disease in ALL cutaneous porphyrias is a LOCAL PORPHYRIN PHOTOTOXICITY REACTION — hence histopathological appearances are also similar.
• These disorders can only be reliably differentiated by BIOCHEMICAL ANALYSIS.
• They are ALL caused by SORET WAVELENGTH light (408 nm), so the same strategy for photoprotection applies to them all.

• Photons of violet light (peak 408 nm) transform the porphyrin into an EXCITED SINGLET state.
• This may revert to the ground state by emission of characteristic red fluorescence. However, intersystem crossing converts the porphyrin to the EXCITED TRIPLET state — long-lived enough to interact with other molecules, particularly MOLECULAR OXYGEN, converting it to EXCITED SINGLET OXYGEN.
• Singlet oxygen stimulates the production of HYDROXYL RADICALS, which damage tissue directly and indirectly by stimulating COMPLEMENT ACTIVATION, MAST CELL DEGRANULATION and MATRIX METALLOPROTEINASE activity.
• The SITE of the phototoxic reaction in the skin determines the clinical characteristics:
• EPP — lipophilic protoporphyrin localises to MEMBRANES including endothelial cell membranes and REMAINS WITHIN ERYTHROCYTES. The phototoxic reaction involves the upper dermal BLOOD VESSELS causing PAIN.
• PCT — water-soluble uroporphyrin diffuses easily into surrounding tissues; the phototoxic reaction occurs in the upper dermis → lysis of cells in the superficial dermis with formation of membrane-limited VACUOLES that merge to produce a BLISTER UNDER THE BASAL LAMINA.
• VP — copro- and protoporphyrin accumulate, but patients suffer PCT-like upper dermal BLISTERS rather than EPP-like acute pain. Likely because although hydrophobic porphyrins predominate in the PLASMA, HYDROPHILIC porphyrins, particularly UROPORPHYRIN, predominate in the SKIN — probably due to secondary local PHOTOINACTIVATION of uroporphyrinogen decarboxylase (UROD) in the skin by coproporphyrin. In addition, the protoporphyrin in VP is CONJUGATED TO A PEPTIDE which may reduce its phototoxicity.
• There is NO simple correlation between the plasma porphyrin concentration and the severity of cutaneous disease.

• In ALL cutaneous porphyrias: homogeneous material within the vessel walls of the upper dermal and papillary vascular plexus — PAS positive and DIASTASE RESISTANT, containing a protein polysaccharide complex, lipids and tryptophan.
• Immunofluorescence reveals immunoglobulins (mainly IgG) in a similar vascular distribution and IgG at the dermal–epidermal basement membrane zone in involved skin.
• Electron microscopy shows REDUPLICATION of the vascular basal lamina and masses of fine fibrillar material, mainly around blood vessels and often also at the dermal–epidermal junction.
• In EPP the VESSEL WALL changes are more pronounced, whereas BASEMENT MEMBRANE ZONE changes predominate in PCT and VP.
• In bullous porphyrias, bullae are SUBEPIDERMAL with the split occurring in the LAMINA LUCIDA, leaving the dermal papilla protruding into the blister cavity — an appearance called ‘FESTOONING’.
• The findings in bullous porphyrias are INDISTINGUISHABLE from those of PSEUDOPORPHYRIA.
• In EPP, in the acute phase, there is visible endothelial damage in superficial dermal vessels.

• Apart from PCT, and to some extent CEP, where effective specific treatments exist, management is based on preventing VIOLET (Soret wavelength) light penetrating the epidermis.
• The connection between sun exposure and symptoms is OBVIOUS in EPP, but NOT obvious to patients with the bullous porphyrias where fragility and blistering are not related to individual episodes of sun exposure.
• Basic measures: sun avoidance behaviour, sun protective clothing and hats.
• MOST SUNSCREENS, INCLUDING UV-ABSORBENT CHEMICAL ‘TOTAL SUNBLOCKS’, DO NOT PROTECT AGAINST THE VISIBLE VIOLET SORET WAVELENGTH.
• Any sunscreen providing significant visible light protection will be OPAQUE rather than transparent.
• Sunscreens containing REFLECTANT particles — particularly large particle size titanium dioxide (pigmentary grade), zinc oxide and iron oxide — can effectively protect against violet light.
• Cosmetically acceptable sunscreens with reasonable protection up to 430 nm are available (e.g. Dundee sunscreen, Tayside Pharmaceuticals).
• Dihydroxyacetone paint induces formation of a light-absorbing brown pigment in the stratum corneum — used in some patients with EPP.
• Window films can absorb some violet light — useful on car or home windows, particularly in EPP and CEP.
• Recommended clear films: Dermagard film (Bonwyke); CLS200XSR film (Madico). The Madico TA81XSR film is YELLOWER but provides BETTER protection.
• Films applied to car windows must comply with LOCAL LEGISLATION.

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• A potentially FATAL illness frequently triggered by drugs and hormones which are metabolised by CYTOCHROME P450, characterised by an acute NEUROTOXIC reaction in many tissues.
• AIP, HC and VP can all cause acute attacks; HC and VP may also cause cutaneous disease.
• A rare autosomal recessive acute porphyria, ALA dehydratase porphyria, has been reported but does NOT cause skin disease.

• The commonest acute porphyria is AIP, followed by VP. HC is RARE.
• Prevalence of clinically overt acute porphyria in Europe: 1–2 per 100 000 inhabitants, but OVER 90% of individuals possessing AIP or VP gene defects are ASYMPTOMATIC.
• PBG deaminase deficiency, which causes AIP, is present in 0.2% of all blood donors.

• Impaired activity of PBG deaminase is associated with acute attacks. The deficiency can be:
• PRIMARY — as in AIP
• SECONDARY — inhibition of the enzyme by accumulated coproporphyrinogen and protoporphyrinogen, as in HC and VP
• In the liver, haem is mostly incorporated into cytochrome P450 proteins, whose production is induced by many drugs and hormones metabolised by the P450 system.
• When a drug/hormone induces cytochrome P450 and acutely increases the hepatic requirement for haem, the inability of the pathway to respond because of PBG deaminase deficiency is exposed.
• This acute hepatic haem deficiency causes secondary accumulation of ALA and increased ALA synthase activity due to LOSS OF END-PRODUCT NEGATIVE FEEDBACK.
• Postulated mechanisms of neuronal dysfunction: disturbed metabolism of neurotransmitters (reduced activity of haem-containing hepatic tryptophan dioxygenase); direct neurotoxicity of accumulated ALA (which structurally resembles the neurotransmitter γ-aminobutyric acid); acute haem deficiency within neurons.

• Most common precipitants: DRUGS and the MENSTRUAL CYCLE — recurrent attacks often occurring in the late LUTEAL phase.
• Also: alcohol, cannabis, fasting, stress and infection.
• It is NOT possible to predict whether a specific drug will provoke an attack in an individual. Drugs should be prescribed only after reference to an up-to-date drug list.
• Recommended drug lists (Internet): Welsh Medicines Information Centre; European Porphyria Initiative (EPNET, www.porphyria.eu) — these are lists of drugs known to be SAFE in acute porphyria.
• The risk is highest where that drug has previously caused an attack in that patient, and in any patients who have previously had symptoms suggestive of an acute attack.

• Acute attacks are FIVE TIMES more common in FEMALES, and most frequently occur between the ages of 10 and 40 years. RARE BEFORE PUBERTY.
• Severity varies from mild abdominal pain to very severe attacks with BULBAR PALSY and RESPIRATORY PARALYSIS.
• SEVERE, CONSTANT ABDOMINAL PAIN occurs in almost ALL acute attacks — can be in any abdominal quadrant or even in the back, buttocks and thighs; may require large amounts of opiate analgesia.
• There may be GUARDING but there should be NO TRUE PERITONISM.
• Vomiting and constipation (due to partial ILEUS) occur in at least 50% of attacks.
• Pulse rate and blood pressure are often moderately raised; dehydration is common; HYPONATRAEMIA (probably caused by inappropriate secretion of vasopressin) may be severe enough to cause CONVULSIONS.
• The pain, tachycardia, hypertension and partial ileus are ALL caused by an ACUTE AUTONOMIC NEUROPATHY.
• Sensory or sympathetic involvement manifesting as severe dysaesthesia or causalgia is rarer.
• A MOTOR NEUROPATHY occurs in 5–10% of cases, usually heralded by aching pains in the limbs and sometimes by disappearance of the abdominal pain. May cause a severe acute Guillain–Barré-type syndrome.
• Usually occurs when porphyrinogenic drugs have been administered INADVERTENTLY during the developing acute attack.
• RESPIRATORY PARALYSIS is the COMMONEST CAUSE OF DEATH.
• Confusion, abnormal behaviour, agitation and hallucinations occur in up to 50% of attacks.
• Porphyria is NOT related to any chronic psychiatric disease EXCEPT generalised anxiety.

• The diagnostic finding is of INCREASED URINARY PBG EXCRETION.
• Qualitative screening tests have LOW SENSITIVITY — it is essential to also carry out a QUANTITATIVE assay.
• A NORMAL urinary PBG concentration EXCLUDES an acute porphyric attack (except in ALA dehydratase porphyria).
• An INCREASED PBG concentration does NOT necessarily mean that an acute attack is occurring, since urinary PBG falls between attacks but does not always return to normal, particularly in AIP.
• The higher the PBG concentration the more likely an acute attack, but in the presence of an increased urinary PBG, an acute attack can only be diagnosed on CLINICAL grounds.
• Urinary ALA is also increased during an acute attack but to a LESSER extent than PBG and is NOT as useful diagnostically — the only exception being ALA dehydratase porphyria, in which only ALA is increased and urinary PBG is normal.

• Once diagnosed, the patient should be given a list of drugs with information about their safety.
• It is vital for clinicians and patients to be clear about whether they are dealing with a list of SAFE or UNSAFE drugs — there are advantages to using a safe list.
• A list of safe drugs is a GUIDE; no drug can be guaranteed safe in an individual patient. Conversely, drugs which do not appear on a safe list should NOT be withheld in patients who need them to treat a serious or life-threatening illness — seek expert advice from a specialist centre.
• Advise the patient to abstain from ALCOHOL, CANNABIS and prolonged CALORIE-RESTRICTED DIETS, and to wear an EMERGENCY IDENTIFICATION BRACELET (e.g. MedicAlert).
• Screening of relatives is ESSENTIAL to identify those with clinically latent disease at risk of acute attacks.
• Patients with PCT, EPP and CEP can be REASSURED that acute attacks are NOT part of their disease.

• The KEY is EARLY DIAGNOSIS. Avoidance of acute attack-inducing drugs is essential to prevent exacerbation.
• Supportive treatment: analgesia, sedatives and antiemetics (using drugs known to be safe in acute porphyria) and careful fluid balance with rehydration and correction of hyponatraemia.
• Specific treatments: intravenous HAEMATIN or HAEM ARGINATE (Normosang) — these have now replaced CARBOHYDRATE as the treatment of choice.
• They suppress hepatic ALA synthase activity and so reduce ALA and PBG accumulation.
• Haem arginate is MORE EFFECTIVE when given EARLIER during an attack — increasing the importance of early diagnosis.

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• Suspected bullous porphyria: ADULT → urine PLUS either plasma OR faeces
• Suspected bullous porphyria: CHILD → urine, plasma AND faeces (increased complexity of the differential diagnosis)
• Suspected erythropoietic protoporphyria → RED CELLS and either plasma or faeces
• Faecal analysis is also necessary: when urine and plasma results do not differentiate HC from CEP, and in RENAL FAILURE (where urine may be unavailable and plasma analysis unhelpful because renal failure increases plasma porphyrins).

• Laboratory testing of body fluids measures porphyrins, since porphyrinogens are spontaneously oxidised to their respective porphyrins outside the body.
• PBG has a tendency to POLYMERISE, but porphyrins are reasonably stable when protected from LIGHT and OXIDANTS.
• All specimens should be kept at ROOM TEMPERATURE or at 4 °C IN THE DARK, and ideally analysed within 48 h of collection.
• FRESH RANDOM specimens (10–20 mL urine or 5–10 g dry weight faeces) are PREFERABLE to 24 h collections — random specimens yield equally useful results and 24 h collections delay samples reaching the laboratory.
• Very dilute urine (creatinine <4 mmol/L) is UNSUITABLE.

• Old-fashioned QUALITATIVE screening methods (often involving a Wood light) are INSENSITIVE — negative results from such tests are NOT of value.
• Quantitative screening using SPECTROPHOTOMETRIC or FLUORIMETRIC techniques is necessary, yielding total porphyrin concentration.
• Whole blood or red cell porphyrin testing measures BOTH the TOTAL and FREE protoporphyrin concentrations.
• PLASMA is analysed by FLUORIMETRIC SCANNING — a diagnostically POWERFUL and SIMPLE qualitative technique.
• In urine and faeces, an increased porphyrin concentration leads on to HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC) to rapidly identify the accumulated porphyrins.
• HPLC principle: the MORE carboxylate groups a porphyrin possesses, the FASTER it passes through the column. After the column, porphyrins are detected by fluorimetry.
• For PBG measurement in urine, qualitative tests are INSENSITIVE — quantitative measurement (usually a kit) is required. Semiquantitative test kits are useful in emergencies.

• Emission peak at 615–620 nm → uro- or coproporphyrin → suggests PCT, HC, CEP or hepatoerythropoietic porphyria (HEP) (urine analysis differentiates PCT and HEP from the other two)
• Peak at 624–626 nm → a PORPHYRIN–PEPTIDE CONJUGATE — DIAGNOSTIC of VP
• This peak is a SENSITIVE indicator of VP and may persist during periods of clinical remission when faecal excretion becomes normal. It is also positive in MOST cases of LATENT VP (in relatives).
• Peak around 633 nm (can lie between 626 and 634 nm) → protoporphyrin → suggests EPP; EPP is an UNLIKELY diagnosis in the ABSENCE of this peak
• Plasma porphyrin concentrations, particularly uroporphyrin, INCREASE in RENAL FAILURE and can be as high as those found in PCT.

• An INCREASED FREE PROTOPORPHYRIN concentration is the DIAGNOSTIC finding in EPP.
• The TOTAL protoporphyrin concentration includes both free and ZINC-protoporphyrin.
• Zinc-protoporphyrin is ALSO increased in IRON DEFICIENCY, LEAD POISONING and certain ANAEMIAS.
• In a CHILD with plasma, urine and faecal results typical of PCT, RED CELL UROD ACTIVITY needs to be measured to EXCLUDE HEP.

• An increased total porphyrin concentration suggests cutaneous porphyria. The TOTAL URINARY porphyrin concentration is used to MONITOR disease activity in PCT.
• In URINE:
• Increase in UROPORPHYRIN (and other highly carboxylated porphyrins, especially HEPTACARBOXYPORPHYRIN) is typical of PCT — although this does NOT exclude VP. Plasma spectrofluorimetry differentiates these two; faecal analysis is required where unavailable.
• When PCT goes into remission and total urinary porphyrin returns to normal, it may STILL be possible to diagnose PCT from the characteristic urinary HPLC pattern.
• COPROPORPHYRINURIA in the presence of NORMAL faecal porphyrin levels does NOT indicate porphyria — can be caused by certain drugs, lead toxicity and hepatobiliary disease.
• In URINE AND FAECES:
• Increased coproporphyrin suggests VP, but does NOT exclude HC.
• Isomer III to isomer I ratios are INCREASED in EVERY porphyria EXCEPT CEP (where they are DECREASED).
• In CEP, excess TYPE I isomers of uro- and coproporphyrin are present in urine, and type I coproporphyrin in faeces.
• In FAECES:
• With a plasma peak at 615–620 nm, if urine HPLC does not show the PCT pattern, faecal analysis differentiates HC (increased coproporphyrin III) from CEP (increased coproporphyrin I).
• INCREASED FAECAL ISOCOPROPORPHYRIN is CHARACTERISTIC of PCT.
• In renal failure, faecal analysis is VITAL since urine may be unavailable and plasma porphyrins are increased (PCT is the porphyria most commonly associated with renal failure).
• Increased faecal protoporphyrin is SUGGESTIVE but NOT DIAGNOSTIC of EPP — it can also derive from bacterial degradation of haem in the gut and may indicate gastrointestinal haemorrhage when porphyrin concentrations are normal elsewhere.

• In VP and HC, porphyrin levels are NORMAL BEFORE PUBERTY.
• Over the age of 15 years, a PLASMA FLUORIMETRY SCAN is a reasonably sensitive biochemical test for LATENT VP in asymptomatic relatives, picking up most cases.
• A POSITIVE scan is DIAGNOSTIC of latent VP, but a NEGATIVE result is UNINFORMATIVE.
• Faecal analysis to measure the ratio of coproporphyrin isomers will pick up some cases of latent HC after puberty.
• In VP and HC, a NEGATIVE porphyrin screening test in a relative needs to be followed by DNA ANALYSIS before latent disease can be excluded.
• The LACK of any common mutations in porphyria (apart from SOUTH AFRICAN VP) means the causative mutation usually has to be identified for EACH FAMILY.

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• A severe and RARE CHILDHOOD porphyria causing LIFELONG MUTILATING PHOTOSENSITIVITY and HAEMATOLOGICAL DISEASE.
• Synonym: GÜNTHER DISEASE

• Incidence in Europe: 0.007 per year per 10 million population; only about 200 cases have EVER been reported worldwide.
• Rare ADULT-ONSET cases of ACQUIRED CEP have been reported secondary to MYELODYSPLASIA.

• Caused by an AUTOSOMAL RECESSIVE inherited deficiency of the UROPORPHYRINOGEN III COSYNTHASE enzyme, usually due to mutations in the gene encoding that enzyme.
• Less commonly this enzyme deficiency is caused by mutations in the GATA1 gene.
• Since this enzyme is required to form the biologically useful type III isomers, its absence results in non-enzymatic reactions producing large amounts of TYPE I ISOMER porphyrins, which cannot participate in haem formation and massively accumulate in erythroid cells and then gradually leak into the plasma.

• Wide spectrum of presentation — from HYDROPS FETALIS, through severe disease starting in infancy, to mild forms presenting later in life.
• The FIRST SIGN is often the mother noting BROWN DISCOLORATION OF AMNIOTIC FLUID at the onset of labour, or observing PINK or BROWN PORPHYRIN STAINING OF NAPPIES (which FLUORESCE RED-ORANGE under Wood light).
• SEVERE photosensitivity begins in INFANCY, often in the NEONATAL period, with blisters developing in light-exposed skin on minimal light exposure. Phototherapy for neonatal jaundice may trigger lesions.
• Most children are so sensitive to the light that they have problems THROUGHOUT THE YEAR. Exposed (and sometimes non-exposed) skin is fragile.
• Repeated bouts of inflammation with vesicles and bullae, often complicated by secondary infection, cause MUTILATING SCARRING, particularly of the FACE and HANDS.
• Photomutilation associated with erosion of the terminal phalanges, onycholysis, and destructive changes affecting the pinnae and nose.
• A diffuse PSEUDOSCLERODERMATOUS THICKENING of exposed skin often gradually develops, with microstomia and sclerodactyly-like changes.
• HYPERTRICHOSIS in most patients — particularly on the upper arms, temples and malar region.
• Patchy hypo- and hyperpigmentation occur EVEN in MINIMALLY EXPOSED areas.
• Milder LATE-ONSET form, presenting from the third decade onward, presents similarly to PCT — occurring either from mild inherited gene mutations or as an acquired disease secondary to bone marrow MYELODYSPLASIA.

Eyes

• Keratoconjunctivitis, blepharitis, cataracts, corneal ulcers, scars, cicatricial ectropion and scarring alopecia of eyelashes and eyebrows.
• Less common: scleromalacia, pterygium formation, optic atrophy, retinal haemorrhage and scleral necrosis.

Bones and teeth

• When teeth emerge, they are ALMOST ALWAYS STAINED BROWN (and FLUORESCE under Wood light).
• Decreased bone density, osteopenia and OSTEOLYTIC LESIONS secondary to EROSION BY HYPERPLASTIC BONE MARROW — seen on X-ray; associated with vertebral compression and collapse and pathological fractures.
• In the hands: resorption of terminal phalanges with ACRO-OSTEOLYSIS and cortical bone rarefaction.
• Occasionally strict avoidance of the sun may impair VITAMIN D metabolism.

Haematology

• High concentrations of porphyrins in red cells cause HAEMOLYTIC ANAEMIA, severe enough to induce marrow hyperplasia, often with visible expansion of the maxillary bones in the face.
• HYPERSPLENISM is common.
• Haemolysis can be fully compensated or may cause severe anaemia; occasionally so severe that patients become TRANSFUSION DEPENDENT. The severity of the anaemia often FLUCTUATES STRIKINGLY over time.
• Very severe haemolytic anaemia may even cause HYDROPS FETALIS.
• Bone marrow examination reveals NORMOBLASTIC HYPERPLASIA. Under violet illumination most normoblasts have persistent RED FLUORESCENCE LOCALISED TO THEIR NUCLEI, with haem-containing inclusion bodies seen in the nuclei of these fluorescent cells.

• The PHOTOSENSITIVITY differentiates CEP from other scarring, blistering disorders of childhood including EPIDERMOLYSIS BULLOSA DYSTROPHICA.
• Cutaneous changes may resemble HEP (the homozygous form of familial PCT) or HOMOZYGOUS VP.
• Late-onset CEP is clinically INDISTINGUISHABLE from PCT or VP.

• In the past, most patients died by the age of 40 years; improvements in supportive care (particularly antibiotics) have improved the prognosis, although the haematological complications may be FATAL.
• Long-term HYPERTRANSFUSION causes significant problems with IRON OVERLOAD as patients reach adulthood, even when iron chelation has been used.
• Bone marrow transplantation now holds out the promise of CURE.
• KEY MARKERS OF POOR PROGNOSIS: EARLY ONSET of disease (especially in the FIRST YEAR of life) and SIGNIFICANT HAEMATOLOGICAL INVOLVEMENT.

• Massive accumulation in all tissues of TYPE I isomers of porphyrins — mainly UROPORPHYRIN, along with coproporphyrin and smaller amounts of 7-, 6- and 5-carboxylic acid porphyrins.
• Red cells and urine contain large amounts of uro- and coproporphyrin (mainly TYPE I); faeces contain increased coproporphyrin (mainly type I).
• Plasma spectrofluorimetry peak at 615–620 nm.
• The ABSENCE of ISOCOPROPORPHYRINS and the NORMAL level of 5-carboxylic porphyrin excretion in faeces distinguish CEP from HEP.
• Since GATA1 mutations cause uroporphyrinogen III cosynthase deficiency, the biochemical findings are the SAME in GATA1-related cases.

• Photoprotection is CRUCIAL — sun avoidance, sun protective clothing and hats are essential.
• Opaque sunscreens containing pigmentary grade titanium dioxide or zinc oxide, possibly with added iron oxide, may be of limited value.
• Amber window films (e.g. Madico TA81XSR) on home or car windows reduce exposure to Soret wavelength light — more opaque films may be necessary (obviously not allowed on car windows).
• Prompt treatment of secondary infection is important.
• HYPERTRANSFUSION with regular blood transfusions to maintain a polycythaemia inhibits endogenous haemoglobin production and decreases porphyrin formation; may reduce haemolysis and cutaneous symptoms in moderately affected patients.
• However, splenomegaly may INCREASE transfusion requirements and the value of hypertransfusion often DECREASES at PUBERTY.
• Frequently complicated by IRON OVERLOAD, even when desferrioxamine has been used; blood-borne infections can be a complication.
• Intravenous haematin has been tried in late-onset disease.
• Haemolysis worsens the porphyria by causing anaemia and usually necessitates blood transfusion. SPLENECTOMY may reduce haemolysis although the improvement may be TEMPORARY.
• Lights during surgical procedures may cause phototoxic reactions — filters should be used over the operation lights during any unavoidable surgery, preferably a YELLOW filter (e.g. Madico TA81XSR).
• Overall, the results from ALL systemic therapies in CEP are DISAPPOINTING — the mainstay of treatment is STRICT PHOTOPROTECTION and treatment of haemolytic anaemia by hypertransfusion.
• Since 1991, ALLOGENEIC BONE MARROW TRANSPLANTATION (bone marrow or umbilical cord blood stem cells) from an HLA-compatible donor has emerged as the treatment of choice in severe CEP — providing a long-term CURE.
• The difficulties of finding a tissue-matched donor and the dangers of marrow transplantation mean it should be reserved for the most severely affected patients and children with markers of poor prognosis.
• Gene therapy has been successfully used in vitro, but NO in vivo studies have been carried out yet.
• Recently, PHLEBOTOMY has been found to be an UNEXPECTEDLY EFFECTIVE treatment, leading to improvements in haemolysis, porphyrin levels and photosensitivity.

• The usual form of CEP (uroporphyrinogen III cosynthase mutations) is AUTOSOMAL RECESSIVE — parents will be unaware of the risk until an affected child has been born; the risk is in further OFFSPRING rather than subsequent generations.
• For parents of an affected child, the chance of each future offspring being affected is 25%.
• Prenatal diagnosis: uroporphyrin I concentration in AMNIOTIC FLUID is increased as early as 16 WEEKS in utero. If the mutations in the index case have been identified, or the fetus is homozygous for the common C73R mutation, prenatal diagnosis from chorionic villous biopsy is possible.
• GATA1 CEP is an X-LINKED disease affecting MALES.

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• The COMMONEST of ALL the porphyrias. Characterised by fragility and blistering of exposed skin.
• Usually ACQUIRED and often associated with LIVER DISEASE. It does NOT cause acute attacks.

• Results from a deficiency of UROD (uroporphyrinogen decarboxylase), causing accumulation of uroporphyrin and other highly carboxylated porphyrins.
• Prevalence varies but in most countries is around 1 in 10 000.
• TYPE I (sporadic) — 75% of patients — enzyme deficiency is ACQUIRED and RESTRICTED TO HEPATOCYTES, due to inhibition of a normal UROD enzyme.
• TYPE II (familial) — 25% — enzyme deficiency is HEREDITARY, present in ALL tissues, associated with a UROD gene mutation.
• Penetrance of this AUTOSOMAL DOMINANT form is so LOW that a family history is present in LESS THAN 7% of cases.
• At least a 75% reduction in enzyme activity is required for clinical expression, so some enzyme inhibition in the liver ALSO occurs in familial PCT.
• UROD mutations are increasingly considered a RISK FACTOR for developing PCT rather than a completely separate familial form.
• Other genetic susceptibility factors: polymorphisms in the cytochrome P450, glutathione-S-transferase and glyceronephosphate O-acyltransferase genes.
• TYPE III disease is RARE — hereditary enzyme deficiency localised to the liver.
• TOXIC porphyria — halogenated aromatic hydrocarbons inhibit the enzyme; rare, mainly affecting workers making herbicides.
• A major epidemic of toxic porphyria in the 1950s in TURKEY was caused by HEXACHLOROBENZENE added as a FUNGICIDE to SEED WHEAT.
• Mechanism: the UROD enzyme is inactivated by UROPORPHOMETHENE, a competitive inhibitor of UROD formed by the oxidation of uroporphyrinogen. The inhibitor is generated in the LIVER by REACTIVE OXYGEN SPECIES IN THE PRESENCE OF IRON (involving cytochrome P450 1A2).
• The accumulated uroporphyrin diffuses from the plasma into surrounding tissues, causing a phototoxic reaction in the UPPER DERMIS in sun-exposed skin → lysis of cells in the superficial dermis with membrane-limited vacuoles merging to produce a blister cavity UNDER the basal lamina.

• Sporadic PCT usually presents in MIDDLE AGE; the familial form can occur at a YOUNGER age.
• Almost ALL patients notice INCREASED FRAGILITY on light-exposed skin, particularly the backs of the hands and forearms, with minor trauma shearing the skin to leave SHARPLY MARGINATED EROSIONS.
• Most patients suffer from BULLAE which can be OVER 1 cm in diameter and may be PAINFUL. They crust and resolve over a few weeks, leaving atrophic scars, MILIA and often mottled hyper- or hypopigmentation.
• Patients RARELY associate the development of new lesions with sun exposure, but symptoms are generally WORSE IN SUMMER.
• Other common features:
• Patches of SCARRING ALOPECIA following resolution of bullae on the scalp
• HYPERTRICHOSIS, usually on the upper face and forehead (sometimes on the ears or arms, occasionally affecting the whole body)
• HYPERPIGMENTATION in a MELASMA-LIKE pattern on the cheeks and around the eyes (or diffuse on light-exposed skin, or occasionally reticulate)
• Photo-induced ONYCHOLYSIS and accelerated SOLAR ELASTOSIS may also occur.
• MORPHOEA-LIKE PLAQUES may develop, particularly on the head and upper trunk.
• Histologically INDISTINGUISHABLE from true scleroderma; mainly occur in longstanding untreated disease.
• Postulated to arise from induction of collagen synthesis by uroporphyrin I.
• These plaques may CALCIFY and may require excision and grafting if they ULCERATE.
• On the scalp, morphoea-like change may cause a slowly expanding SCARRING ALOPECIA starting in the frontoparietal and occipital areas.
• Even sclerodactyly or the facial changes of systemic sclerosis have been reported.
• Rare presentations: cicatricial conjunctivitis and hair darkening.

• The HOMOZYGOUS form of familial PCT, associated with OVER 90% reduction in UROD activity.
• Usually causes a severe disease clinically similar to CEP — photosensitivity during infancy causing IMMEDIATE PAIN on sun exposure, blisters on sun-exposed skin and mutilating scarring of the face and fingers.
• Prominent HYPERTRICHOSIS, FLUORESCENT TEETH, EYE involvement and SHORTENED DISTAL PHALANGES also occur.
• Haemolysis is MILDER than in CEP, and LIFE EXPECTANCY IS NORMAL.
• HEP can occasionally present with a MILDER disease similar to PCT.
• Since mutated alleles in HEP must retain some residual enzyme activity to be compatible with life, the UROD gene mutations in HEP patients are DIFFERENT from those found in type II PCT.

• Can be clinically indistinguishable from VP, drug-induced pseudoporphyria, renal pseudoporphyria, HC, late-onset Günther disease or mild HEP.
• Biochemical analysis is necessary, and it is particularly important to EXCLUDE VP and HC as they can cause ACUTE ATTACKS.

• PCT is essentially a LIVER DISORDER with SECONDARY EFFECTS IN THE SKIN — investigate thoroughly for predisposing systemic diseases and to assess the severity of any liver disease.
• Biochemistry: urinary porphyrin concentration increased, consisting mainly of uroporphyrin, some heptacarboxylic acid porphyrin, and sometimes also hexa- and pentacarboxylic acid porphyrins.
• Plasma spectrofluorimetry peak at 615–620 nm.
• ISOCOPROPORPHYRIN accumulates in the FAECES.
• URINE ANALYSIS ALONE IS INSUFFICIENT to diagnose PCT, since a few patients with VP have the PCT urine pattern (‘DUAL PORPHYRIA’).
• In renal failure, FAECAL analysis is ESSENTIAL — plasma porphyrins are increased by haemodialysis and urine collection may not be possible.
• The biochemical marker of disease activity and treatment response is QUANTITATIVE URINARY PORPHYRIN EXCRETION measured in a RANDOM urine sample.
• In HEP: findings as in PCT, PLUS a raised red cell ZINC-PROTOPORPHYRIN, and LOWER red cell UROD activity than in type II PCT.

• Bullae are SUBEPIDERMAL with a SPARSE inflammatory infiltrate and ‘FESTOONING’ of dermal papillae into the bullae.
• Deposition of PAS-positive, diastase-resistant FIBRILLAR GLYCOPROTEIN material in and around the upper dermal blood vessel walls, with reduplication of the basement membrane.
• Immunofluorescence reveals IgG, a little IgM, FIBRINOGEN and COMPLEMENT at the epidermal–dermal junction.
• Morphoea-like lesions in PCT are histologically indistinguishable from other forms of morphoea.

• The MAJOR risk factors: subclinical genetic HAEMOCHROMATOSIS, HEPATITIS C infection, ALCOHOL and OESTROGENS. All predispose to inhibition of the UROD enzyme in the liver.
• The SAME risk factors apply to sporadic AND familial PCT (since some hepatic inhibition is also required for clinical expression of familial PCT).
• It is ESSENTIAL to investigate for risk factors in ALL patients diagnosed with PCT.

Haemochromatosis

• Almost ALL patients have increased stainable iron in the liver, and total body iron stores are increased in at least 60%.
• In the USA and northern Europe, around 20% of PCT patients have TRUE hereditary haemochromatosis with homozygosity for the Cys282Tyr mutation.
• Homozygosity for this mutation increases the risk of developing PCT 60-FOLD. The clinical relevance of heterozygosity is unclear.
• In SOUTHERN Europe, haemochromatosis is a LESS important risk factor. The iron overload in PCT patients without haemochromatosis is milder and its cause is obscure.

Hepatitis C infection

• Southern Europe: 70–90% of all PCT patients are infected
• USA: around 60%
• Northern Europe: 7–36%

Alcohol

• Between 30% and 90% of PCT patients consume over 40 g of alcohol daily, and 2% of all alcoholics with cirrhosis develop PCT.

Oestrogens

• Ingested oestrogens (oral contraceptive pill or HRT) are the SOLE risk factor in over 25% of FEMALE patients.
• Stopping the hormone may be sufficient to induce remission if the duration of therapy has been SHORT.
• If it is not possible to stop hormone therapy, TRANSDERMAL drug delivery is a SAFER alternative than the oral route.

Other less common risk factors

• Haemodialysis predisposes to PCT (although PCT is LESS common in renal failure than PSEUDOPORPHYRIA — faecal porphyrin analysis differentiates).
• HIV infection — mainly due to co-infection with hepatitis C virus.
• Also reported: non-insulin-dependent diabetes, SLE, dermatomyositis, hepatitis A and B infection, haematological malignancy, sideroblastic anaemia, thalassaemia and the drug TAMOXIFEN.
• MOST patients possess MORE THAN ONE risk factor, with hepatitis C infection and alcohol strongly linked in men.

• In almost ALL cases, liver biopsy reveals INCREASED STAINABLE IRON, FATTY CHANGE and INTRACELLULAR PORPHYRIN CRYSTALS.
• 50% of patients have more severe changes (lobular necrosis or inflamed fibrotic portal tracts) and CIRRHOSIS occurs in 15%.
• The most severe liver disease tends to occur in patients with alcoholism, hepatitis C infection and iron overload.
• The accumulated porphyrins are CARCINOGENIC to the liver, so PCT confers an ADDITIONAL risk of hepatocellular carcinoma on top of that from hepatitis C.
• In southern Europe, around 3% of PCT patients develop HEPATOCELLULAR CARCINOMA during the decade after presentation (incidence probably lower in countries with lower hepatitis C rates).
• Risk factors for hepatocellular carcinoma: a symptomatic period of MORE THAN 10 YEARS prior to treatment; severe changes on hepatic histology at presentation; hepatitis C infection; MALE sex; age over 50 years at presentation.
• The converse situation — where a primary hepatic tumour SECRETES porphyrins to cause a PCT-like skin disease — is RARE.
• Hepatic function MUST be assessed at presentation in ALL PCT patients; patients at high risk of hepatic malignancy require regular ULTRASOUND scans and serum α-FETOPROTEIN measurement.
• PCT should be managed as a LIVER DISORDER, and the threshold for referral to a HEPATOLOGIST should be LOW.

Photoprotection

• Visible light sunscreens containing pigmentary grade titanium dioxide or zinc oxide, sometimes with added iron oxide; filter films for car and home windows; gloves, hats and clothes — important during the several months before specific therapies take effect.

Elimination of risk factors

• Treatment of hepatitis C infection with ANTIVIRALS results in RAPID remission of PCT.
• Stopping oestrogen therapy, if it has not been used for more than 2 years, can induce remission.
• However, elimination of the underlying cause by abstaining from alcohol does NOT ALWAYS induce remission.
• All patients should be advised to abstain from alcohol or oestrogen therapy to prevent exacerbation.

Specific treatments

• Definitive treatment with VENESECTION or LOW-DOSE ANTIMALARIALS is required in almost all cases.
• VENESECTION depletes iron stores and eliminates hepatic iron overload, restoring normal enzyme activity.
• Around 500 mL of blood removed every 1–2 weeks, aiming to decrease transferrin saturation to 15%, haemoglobin to 11–12 g/dL and plasma ferritin to below 25 μg/L.
• Blistering usually resolves within 2–3 months; skin fragility within 6–9 months; porphyrin concentrations generally normalise within 13 months, at which point treatment should be stopped.
• Hypertrichosis and sclerodermoid lesions respond MORE SLOWLY during the years after treatment has stopped. Excision and grafting may be needed for ulcerated sclerodermoid lesions.
• DESFERRIOXAMINE leads to earlier remission than venesection (rapidly chelates hepatic iron); may be of value in PCT with renal failure, but is expensive and requires a subcutaneous pump at night.
• ERYTHROPOIETIN mobilises hepatic iron into haemoglobin — the treatment of choice for PCT in RENAL FAILURE, where patients are too anaemic for venesection and cannot excrete chloroquine.
• PCT in renal failure can improve if the patient is changed from conventional high-flux haemodialysis to HAEMODIAFILTRATION WITH ULTRAFILTRATE REGENERATION BY RESIN ADSORPTION (Supra-HFR).
• LOW-DOSE ANTIMALARIALS are a very effective treatment — they work by complexing with uroporphyrin and promoting its excretion into the BILE.
• Daily doses of chloroquine cause a potentially DANGEROUS ACUTE HEPATITIS, but chloroquine at the LOW dose of 125 mg or 250 mg taken TWICE A WEEK is SAFE and EFFECTIVE.
• Leads to clinical remission within 6 months and biochemical remission after 6–15 months, at which point treatment is stopped.
• RETINOPATHY does NOT seem to occur with such low doses of chloroquine.
• Hydroxychloroquine (100 mg twice weekly) is also effective.
• LOW-DOSE CHLOROQUINE IS THE TREATMENT OF CHOICE EXCEPT in the following situations, where VENESECTION is preferable:

1. Patients who do NOT respond to chloroquine
2. Patients with a pathologically high serum FERRITIN concentration or homozygous for the Cys282Tyr mutation, who require iron depletion to protect internal organs
3. Patients with significant hepatitis C liver disease, who require iron depletion since hepatic siderosis increases their virally induced liver damage and reduces the effectiveness of interferon

• Chloroquine is usually LESS effective in patients with haemochromatosis.
• However, chloroquine is NOT contraindicated in these situations and may be needed when venesection is not possible — particularly in patients with hepatitis C liver disease where venous access is impaired by previous intravenous drug abuse.
• Remission with low-dose chloroquine generally lasts 17–24 months. With venesection, relapse generally occurs around 2.5 YEARS after the end of treatment.
• Long-term follow-up is necessary for ALL patients to monitor for relapse (by measuring urinary porphyrin excretion) and to manage coexisting liver disease.

• Familial and sporadic PCT can be differentiated by measuring red cell UROD activity.
• Since additional hepatic enzyme inhibition is required for clinical expression in familial PCT, UROD mutations can be considered a RISK FACTOR rather than a different form of PCT.
• It is difficult to justify FAMILY SCREENING in familial PCT in view of the identical management of sporadic and familial PCT, the lack of evidence that identifying latent PCT in relatives alters outcomes and the very low penetrance.
• It is therefore of LITTLE VALUE to measure red cell UROD activity UNLESS one is trying to differentiate HEP from PCT.

• Overall, patients with PCT have INCREASED mortality compared with age-matched controls — partly due to co-morbidities associated with PCT, and partly due to diseases related to associated lifestyle factors such as the high prevalence of smoking.

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• A hereditary porphyria characterised by PAINFUL, LIFELONG PHOTOSENSITIVITY and occasionally LIVER DISEASE.

• Incidence in Europe varies between countries — from 0.03 new cases/million per year in SPAIN to 0.36 in the UK.

• Usually results from deficient activity of FERROCHELATASE, the FINAL enzyme of haem biosynthesis.
• In a minority of cases it is caused by GAIN-OF-FUNCTION mutations in ALAS2 (the FIRST enzyme in the pathway).
• Causes accumulation of protoporphyrin predominantly in cells of the ERYTHROID series → phototoxic reaction as the porphyrin-laden cells pass through the small upper dermal blood vessels and are exposed to Soret wavelength sunlight.
• Photoactivated porphyrin from red cells and plasma causes an acute injury to the ENDOTHELIUM mediated by SINGLET OXYGEN and the HYDROXYL RADICAL.
• Many ferrochelatase gene mutations have been identified and NONE are particularly common.
• A few adult-onset cases associated with haematological malignancy may be associated with chromosomal deletions involving the ferrochelatase gene.

• UNLIKE the other cutaneous porphyrias, EPP causes IMMEDIATE PAIN on exposure to bright sunlight.
• Presents most commonly in the FIRST YEAR, quite often in babies presenting with crying in their prams in sunny weather or crying for no obvious reason at night in the summer. Onset later in childhood does occur but onset in ADULTHOOD is RARE.
• In spring and summer, with sun exposure lasting from a few minutes up to 1–2 h, patients describe discomfort, tingling or itching in exposed skin — particularly the dorsae of the hands and the face.
• If exposure continues, SEVERE BURNING PAIN follows, which can last from an hour to SEVERAL DAYS.
• Children often find PARTIAL RELIEF with COLD WATER and WET CLOTHS — this feature may be DIAGNOSTICALLY USEFUL.
• Usually the ONLY physical sign during an attack is OEDEMA, which may be SUBTLE. Redness is LESS common and may be MORE DIFFICULT TO DETECT in skin of colour.
• The LACK of physical signs often leads to DELAY in diagnosis, with some patients initially being labelled as MALINGERERS.
• ‘PRIMING PHENOMENON’ — sunlight tolerance is REDUCED on the day AFTER significant sun exposure.
• In severe attacks: purpuric lesions and crusted erosions or vesicles may occur, taking a week or two to resolve; pain may be severe enough to require hospital admission.
• Rare presentations: prominent purpura with histological changes resembling a LEUKOCYTOCLASTIC VASCULITIS; acute photo-onycholysis; reddish plaques. SOLAR URTICARIA can occur in addition to the EPP photosensitive reaction in some patients.
• Physical signs may develop during childhood:
• Slight thickening of skin over the metacarpophalangeal and interphalangeal joints
• Superficial VERMICULAR WAXY SCARRING on the NOSE
• Shallow linear, punctate or small circular SCARS on the CHEEKS and FOREHEAD
• RADIAL SCARS AROUND THE LIPS
• Skin over the nose, cheeks and forehead can become roughened and ‘PEBBLY’ in texture
• FIFTEEN PER CENT of patients have NO physical signs at all.
• Mild variants may cause diagnostic confusion because of delayed onset of symptoms, shortened duration of attacks and occasionally absence of pain.
• Diagnostic clues: OEDEMA and predilection of the reaction to the FACE and DORSAL HANDS and FEET.
• Occasional association between EPP and a SEASONAL PALMAR KERATODERMA — more commonly seen in autosomal recessive EPP.
• Children suffer SOCIAL ISOLATION due to difficulty joining friends to play outside — sensitivity to psychosocial issues is important.
• Although EPP is lifelong, CHILDHOOD and ADOLESCENCE are frequently the MOST DIFFICULT times because it is potentially easier for adults to organise their lives to reduce sun exposure. Profound impact on quality of life.
• Symptoms often IMPROVE and porphyrin levels FALL during PREGNANCY.
• Patients may develop a mild hypochromic microcytic or normocytic anaemia, which can be associated with decreased serum iron levels and increased serum iron binding capacity.
• With the EXCEPTION of patients with EPP liver failure, OPERATING THEATRE LIGHTS do NOT cause any problems during or after surgery in EPP patients. Anaesthetists can also be reassured that ACUTE ATTACKS DO NOT OCCUR in EPP.
• In CONTRAST, operating theatre lights CAN cause a devastating and potentially FATAL phototoxic reaction in patients undergoing LIVER TRANSPLANTATION for protoporphyric liver failure.

• The DIAGNOSTIC finding is an INCREASED RED CELL-FREE PROTOPORPHYRIN concentration.
• Protoporphyrin is seen as a peak at 633 nm on plasma fluorimetric scanning.
• 60% of EPP patients have an increased FAECAL protoporphyrin concentration, though NOT very useful diagnostically because of its LACK OF SPECIFICITY.
• URINARY porphyrins are NORMAL except in BILIARY IMPAIRMENT, when coproporphyrinuria develops.
• Umbilical cord protoporphyrin concentration is NOT a useful test to identify EPP in newborns.

• Acute phase: visible endothelial damage in superficial dermal vessels.
• Chronic phase, in exposed skin: repeated episodes of damage to small upper dermal vessels cause deposition of PAS-positive, diastase-resistant HYALINE material in the walls of blood vessels of the upper dermal and papillary vascular plexuses.
• Immunofluorescence shows immunoglobulins (mainly IgG) in a similar distribution.
• Electron microscopy: the hyaline material is a greatly replicated, layered and fragmented BASEMENT MEMBRANE, with fine fibrillar material permeating the capillary connective tissue sheath and extending beyond the vessel walls.

Specific therapy

• AFAMELANOTIDE, the α-melanocyte stimulating hormone (α-MSH) ANALOGUE, is the FIRST EFFECTIVE TREATMENT for EPP, significantly decreasing photosensitivity.
• NO other therapy has EVER been PROVEN to be effective in EPP although many have been proposed.
• Attention to sunlight protection remains the KEY to management until α-MSH analogues become widely available.

Photoprotection

• Sun avoidance behaviour, sun protective clothing and hats; correct sunscreens.
• Dihydroxyacetone paint has been used in some patients.
• Window films that absorb violet light are useful for car or home windows, particularly in severely affected patients.

Acute reactions

• COMPLETE sun avoidance (EVEN THROUGH WINDOWS) leads to earlier resolution.
• Fans and cold water provide some pain relief.
• ANTIHISTAMINES and MOST ANALGESICS are of LITTLE VALUE.
• For severe attacks, hospital admission may be necessary for light avoidance and analgesia (usually OPIATE).

Older specific therapies

• Oral β-CAROTENE — previously the most widely used treatment, usually around 180 mg daily in adults (90 mg daily in children) taken throughout spring and summer.
• Postulated to scavenge free radicals involved in the acute phototoxic reaction.
• Some patients report that it reduces symptoms, others do NOT, and PROOF OF EFFICACY FROM CONTROLLED TRIALS IS LACKING.
• Patients may need to take it for several months before any effect is observed.
• Most common adverse effect: REVERSIBLE SKIN DISCOLORATION.
• Controlled trials of N-ACETYLCYSTEINE and COLESTYRAMINE have been shown to be of NO BENEFIT.
• Short courses of a few weeks of PUVA and NARROW-BAND UVB used in the EARLY SPRING may be valuable, particularly in MILDER cases — probably increasing photoprotection by inducing epidermal thickening and pigmentation.
• UNLIKE PUVA, narrow-band UVB does NOT overlap with the EPP action spectrum and so CANNOT trigger attacks of pain.
• Many other systemic antioxidant/free radical scavenging treatments have been used in an uncontrolled way with conflicting and generally unconvincing results.

Bone health

• OSTEOPOROSIS, often in YOUNG ADULTS, is COMMON in EPP. Photoprotection causes vitamin D deficiency and reduced outdoor physical exercise.
• It is CRUCIAL to supplement vitamin D and carry out REGULAR BONE DENSITY SCANS.

• Generally an AUTOSOMAL DOMINANT disorder with INCOMPLETE PENETRANCE, although rare cases of classic autosomal recessive inheritance of two pathogenic mutations have been reported.
• The disease results from co-inheritance of a gene mutation on ONE ferrochelatase allele with a LOW EXPRESSION VARIANT on the OTHER allele.
• Since the low expression variant is generally considered a common non-pathological polymorphism, inheritance may be described as ‘autosomal dominant with incomplete penetrance’; some geneticists consider the variant pathological and describe the inheritance as ‘autosomal recessive’.
• The low expression variant is present in around 10% of the WHITE population and is associated with reduced ferrochelatase mRNA levels resulting from the polymorphic variant IVS3-48C.
• This low expression variant is COMMON in JAPAN and SOUTH-EAST ASIA and RARE in AFRICA — may explain observed variations between continents.
• Overall, the probability of EACH OFFSPRING of an EPP patient suffering from the disease is UNDER 10%.
• Testing for the IVS3-48C polymorphism in a patient's PARTNER is now available and can indicate more precisely whether there is a significant probability of future offspring being affected.
• For a disorder that is RARELY LIFE-THREATENING, termination of pregnancy and thus antenatal diagnosis are NOT relevant.

• Protoporphyrin is excreted EXCLUSIVELY into the BILE.
• It precipitates to form GALLSTONES in around 12% of patients.
• It is HEPATOTOXIC, particularly to BILE CANALICULI, and SEVERE LIVER DAMAGE occurs in around 1% of patients.
• EPP liver failure requiring transplantation may occur at ALMOST ANY AGE.
• Usually a patient develops JAUNDICE, WORSENING PHOTOSENSITIVITY and often UPPER ABDOMINAL PAIN over weeks or months.
• Investigation shows severe or total CHOLESTASIS and a dramatically HIGH red cell protoporphyrin concentration (due to impaired excretion), which causes the worsening photosensitivity.
• Liver histology: deposition of protoporphyrin in VACUOLES within BILE CANALICULI and HEPATOCYTES, which may be accompanied by CIRRHOSIS (black staining by protoporphyrin deposits).
• Although acute episodes may resolve spontaneously, the porphyrin-induced cholestasis may become increasingly severe and itself further increase the protoporphyrin concentration in a VICIOUS CYCLE — in which case the patient will die unless a liver transplant can be performed.
• Unless FILTER FILMS are used over operating theatre lights, the very high protoporphyrin concentration may result in a severe phototoxic reaction with POSTOPERATIVE BURNS.
• A severe and prolonged NEUROPATHY may also occur after liver transplant.
• Protoporphyric liver disease RECURS IN THE GRAFT in 69% of patients over several years, which can be severe enough to require retransplantation in a minority.
• BONE MARROW TRANSPLANTATION does CURE the EPP, but the dangers mean it is reserved for these rare, life-threatening situations.
• In severe liver disease, LIVER TRANSPLANT FOLLOWED BY HAEMATOPOIETIC STEM CELL TRANSPLANTATION has been carried out.
• It is VITAL to recognise impending protoporphyric liver failure EARLY enough to arrange a liver transplant if needed.
• ALL EPP patients should have LIVER FUNCTION TESTS and RED CELL PROTOPORPHYRIN concentration checked AT LEAST ONCE A YEAR.
• The appearance of COPROPORPHYRIN IN THE URINE has been proposed as an indicator of significant liver disease in EPP.
• WORSENING PHOTOSENSITIVITY may be the ONLY clinical indication of the development of severe liver disease.
• Mild abnormalities of liver function tests are COMMON in EPP — significance unclear; monitor closely and refer to a hepatologist if the abnormality is persistent or deteriorating.
• In such patients, an ANION EXCHANGE RESIN such as CHOLESTYRAMINE may protect the liver against further porphyrin toxicity.
• The major difficulty for dermatologists is the LACK OF ANY MEANS OF IDENTIFYING those EPP patients at risk of liver failure.
• Since several cases have been described in SIBLINGS, patients with a relative who has suffered protoporphyric liver failure should be treated as being at INCREASED RISK.
• Classic RECESSIVE inheritance of EPP may increase the risk of severe hepatic disease.
• IRON DEFICIENCY ANAEMIA may TRIGGER or EXACERBATE hepatic disease by increasing porphyrin accumulation, and subsequent iron replacement may make the situation TEMPORARILY WORSE by acutely stimulating haem biosynthesis.

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• A RARE inherited disease usually characterised by ACUTE ATTACKS, that involves the skin as well in a minority of patients.

• Like VP, this porphyria presents from PUBERTY onwards.
• The skin is NOT affected in MOST patients. However, around 10–20% of patients have cutaneous involvement with fragility and blistering in sun-exposed areas, INDISTINGUISHABLE from that seen in PCT or VP.
• The skin disease may be triggered or exacerbated by intercurrent LIVER DISEASE.
• Rare variants:
• A HOMOZYGOUS form characterised by short stature, acute attacks and skin changes with prominent HYPERTRICHOSIS and PIGMENTATION
• ‘HARDEROPORPHYRIA’ — causes HAEMOLYSIS IN THE NEONATE or BULLAE
• Caused by an AUTOSOMAL DOMINANT inherited deficiency of COPROPORPHYRINOGEN OXIDASE.

• 615–620 nm peak on plasma spectrofluorimetry
• Increased uro- and coproporphyrin concentrations in URINE
• Increased coproporphyrin in FAECES
• PREDOMINANCE OF THE TYPE III ISOMER IN FAECES IS A SENSITIVE INDICATOR OF HC.

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• A rare inherited disease usually characterised by photo-induced skin fragility and blistering that may cause ACUTE ATTACKS.

• In SOUTH AFRICA, VP is COMMON (due to a FOUNDER EFFECT), with a prevalence in whites and Afrikaner-descended non-whites of 1 in 200.
• Incidence in Europe varies between countries — 0.01–0.26 new cases/million/year.
• Elsewhere the prevalence is around 0.5–1 in 100 000.

• Caused by an AUTOSOMAL DOMINANT inherited deficiency of PROTOPORPHYRINOGEN OXIDASE.
• In addition to causing photosensitisation, accumulated coproporphyrinogen and protoporphyrinogen also INHIBIT PBG DEAMINASE — the probable mechanism for acute attacks in VP.
• At least 80% of South African carriers of a pathogenic VP mutation are COMPLETELY ASYMPTOMATIC.
• Why PCT-like blistering rather than EPP-like acute pain: although hydrophobic porphyrins predominate in the plasma, HYDROPHILIC porphyrins, especially UROPORPHYRIN, predominate in the SKIN — thought to result from secondary local PHOTO-INACTIVATION of UROD in the skin by coproporphyrin. In addition, the protoporphyrin in VP is CONJUGATED TO A PEPTIDE which may reduce its phototoxicity.

• Of those patients with symptomatic VP, around 70% have cutaneous involvement, and only around 17% of these patients will EVER suffer an acute attack.
• VP only VERY RARELY presents before puberty; usually the skin disease begins in adolescence or young adulthood.
• Patients describe skin fragility, usually fairly MILD, affecting sun-exposed skin particularly on the backs of the hands.
• Generally INDISTINGUISHABLE from PCT: painful TENSE bullae in sun-exposed skin, scarring, pigmentary abnormalities, sometimes pseudosclerodermatous changes of the hands and fingers, and occasionally photo-onycholysis.
• A significant number of patients do NOT describe worsening in the summer, and those who do describe seasonal variation often have their worst problems in LATE SUMMER and AUTUMN.
• Around 50% of patients with VP describe MILD, TRANSIENT, SUNLIGHT-RELATED ERUPTIONS in the EARLY SUMMER.
• Examination findings: scarring, patches of hypo- and hyperpigmentation at the sites of blisters, milia and mild hypertrichosis particularly AROUND THE EYES — indistinguishable from PCT.
• Intercurrent BILIARY OBSTRUCTION EXACERBATES the cutaneous disease since the accumulated porphyrins are excreted into the bile.
• ACUTE photosensitivity can occur in patients with disturbed liver function.
• Hormonally induced hepatic dysfunction may explain exacerbations of skin disease in females taking ORAL CONTRACEPTIVES and during PREGNANCY.
• VP can sometimes IMPROVE in OLD AGE with clinical and biochemical remission.
• Patients with VP have recently been shown to be at INCREASED LIFETIME RISK OF HEPATOCELLULAR CARCINOMA.

• As in other acute porphyrias, women are THREE TIMES as frequently affected as men and 70% of acute attacks occur between the ages of 20 and 40 years.
• Around 17% of patients with cutaneous VP ever suffer an acute attack, and the number has DECLINED recently due to improved use of prophylactic measures.
• Severity varies from mild abdominal pain to very severe attacks with bulbar palsy and respiratory paralysis.

• A mutation on BOTH protoporphyrinogen oxidase alleles results in an enzyme activity less than 20% of normal, compared with the 50% in other VP patients.
• Fragility, bullae and often hypertrichosis develop in exposed (and sometimes NON-exposed) skin in NEONATES or INFANTS, and the skin disease may be severe.
• Also commonly: delayed development, epilepsy, sensory neuropathy, nystagmus, various hand deformities and growth retardation.
• ACUTE ATTACKS DO NOT OCCUR in these patients.
• Biochemical findings are the SAME as in VP except for the LOWER enzyme activity.

• Easily distinguished from non-photosensitive blistering disorders. Can be clinically VERY SIMILAR to PCT, late-onset CEP, HC and pseudoporphyria — biochemical analysis is required.

• A plasma spectrofluorimetry peak around 626 nm (caused by a PORPHYRIN–PROTEIN COMPLEX) is DIAGNOSTIC of VP in the ABSENCE of a raised free red cell protoporphyrin level, and is present in virtually all symptomatic cases.
• It may PERSIST during periods of clinical remission when faecal excretion becomes normal, and is a MORE SENSITIVE test than measurement of faecal porphyrins.
• A persistently NORMAL faecal protoporphyrin concentration in adulthood in patients with the VP genetic defect has been proposed as a PROGNOSTIC MARKER indicating a greater likelihood of the VP never causing clinical problems and staying clinically LATENT.
• Urine: increased coproporphyrin. Faeces: increased copro- and protoporphyrin.
• In a FEW patients, the urine shows the typical PCT pattern of uroporphyrin with hepta- and sometimes hexa- and pentacarboxylic acid porphyrins — ‘DUAL PORPHYRIA’.
• Thus, URINARY ANALYSIS ALONE can result in the MISDIAGNOSIS of VP as PCT, with POTENTIALLY DISASTROUS CONSEQUENCES.
• During acute attacks, urinary PBG (and ALA) are raised. Urinary PBG usually falls to normal within weeks of the attack resolving but may remain slightly increased outside the context of an acute attack.

• The KEY to successful management of the skin disease is PHOTOPROTECTION with sun avoidance using clothes, hats and gloves.
• Opaque sunscreens containing pigmentary grade titanium dioxide or zinc oxide, sometimes with iron oxide, are protective against Soret wavelength light.
• The skin disease is RARELY severe enough to require filter films for car and home windows.
• As the relationship between sun exposure and skin lesions is NOT OBVIOUS, the role of light should be EXPLAINED to the patient.
• β-carotene and canthaxanthin have been claimed to provide limited protection in some patients; UVB phototherapy may also be of value.
• If liver function tests indicate BILIARY OBSTRUCTION, relief of this will REDUCE cutaneous symptoms.
• The RISK OF ACUTE ATTACKS is the key issue for the safe management of patients and their families.
• Patients should be directed to a list of drugs to avoid, including those that can induce attacks and also those known to induce CHOLESTASIS, as well as CANNABIS.
• Advise to wear an emergency identification bracelet, avoid low-calorie diets and avoid ALL alcohol intake.
• LIVER TRANSPLANTATION has been successfully used to CURE variegate porphyria (and acute intermittent porphyria) in cases where acute attacks are frequent, severe and uncontrollable by medical treatment alone.

• It is important to identify relatives who have LATENT VP because of the risk of ACUTE ATTACKS.
• The plasma 624–626 nm peak is found in the majority of cases of latent VP, but ONLY FROM TEENAGE YEARS ONWARDS.
• A POSITIVE plasma fluorimetry result is DIAGNOSTIC of latent VP, but a NEGATIVE result is UNINFORMATIVE.
• The ONLY completely reliable way to identify those carrying the VP gene defect (if the plasma scan is negative) is to identify the PROTOPORPHYRINOGEN OXIDASE gene mutation in the INDEX CASE and then assess its presence/absence in relatives.
• Labour intensive because, OUTSIDE SOUTH AFRICA, most families have their OWN PRIVATE MUTATION.
• Relatives found to have the gene defect are at a LOW risk (roughly 5–10%) of acute attacks and should take all precautions.
• The risk of a patient passing the mutated gene on to EACH offspring is 50%, and around 20% of those carrying the mutation will EVENTUALLY develop symptoms.

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• A NON-PORPHYRIC dermatosis clinically and histologically INDISTINGUISHABLE from porphyria cutanea tarda.
• PORPHYRIN CONCENTRATIONS ARE ENTIRELY NORMAL.
• One of the clinical presentations of drug-induced photosensitivity; there are also non-drug-related causes.

1. PHOTOSENSITISING DRUGS — the relevant drugs are generally recognised photosensitisers.

• The MOST COMMON causes are NSAIDs, especially NAPROXEN and NABUMETONE.
• Also reported: oxaprozin, ketoprofen, mefenamic acid and diflunisal.
• NSAID-induced pseudoporphyria is COMMON: in one group of patients treated with naproxen for juvenile rheumatoid arthritis, 12% developed pseudoporphyria.
• Other drugs: nalidixic acid, tetracyclines including minocycline, bumetanide, furosemide, isotretinoin, olanzapine, imatinib, dapsone, and self-medication with commercially available CHLOROPHYLL preparations.

1. HAEMODIALYSIS — patients with chronic renal failure undergoing haemodialysis (or less commonly peritoneal dialysis).
2. UVA TANNING BEDS (SUNBEDS) — although some reported cases were of patients also taking photosensitising medications, in some patients UVA sunbed use appears to be the SOLE causative factor.

• Indistinguishable from PCT: vesicles, bullae, fragility, MILIA and SCARRING on exposed skin, particularly the dorsal hands, but also the face, chest and occasionally other sites.
• HOWEVER, HYPERTRICHOSIS, HYPERPIGMENTATION, SCLERODERMOID CHANGES and DYSTROPHIC CALCIFICATION are MUCH LESS COMMONLY SEEN than in PCT.
• In CHILDREN, the facial scarring can resemble that seen in EPP but WITHOUT the painful bouts of photosensitivity.
• UNLIKE the porphyrias, pseudoporphyria has NO manifestations EXCEPT IN THE SKIN.

• Main differentials: PCT and EPP (if there is EPP-type scarring).
• The diagnosis requires the presence of clinical features of PCT in the skin with NORMAL urine, faecal and plasma porphyrin concentrations reported by an EXPERIENCED porphyrin laboratory.
• It is PREFERABLE, though NOT ESSENTIAL, to identify a recognised cause.
• Other diseases to exclude: epidermolysis bullosa acquisita and bullous pemphigoid.
• The situation is MORE COMPLEX in patients with RENAL FAILURE — haemodialysis is associated with increased plasma porphyrin concentrations and urine may be unavailable. Further complicated because PCT can ALSO be induced by chronic renal failure.
• Conclusive differentiation of PCT from pseudoporphyria in the context of renal failure and dialysis is NOT ALWAYS POSSIBLE, but can sometimes be achieved on the basis of the degree of increase in porphyrin concentrations in plasma, faeces and (where available) urine.
• Important to try to differentiate the two because of the implications regarding aetiological factors and treatment options.

• By definition, porphyrin concentrations in urine, plasma, red cells and faeces MUST BE NORMAL.
• The histopathological and immunofluorescent appearances of affected skin are ESSENTIALLY IDENTICAL in pseudoporphyria and PCT.
• Blood vessel thickening and sclerosis of collagen are LESS COMMON in pseudoporphyria, but the two diseases CANNOT be reliably differentiated with skin biopsies alone.

• In drug-induced and sunbed-related pseudoporphyria, the KEY is to REMOVE THE PROVOKING FACTOR by stopping the relevant drug or sunbed usage.
• However, symptoms may CONTINUE for SEVERAL MONTHS after discontinuation of a causative drug, and SCARRING MAY PERSIST.
• Dialysis-related pseudoporphyria generally PERSISTS until RENAL TRANSPLANTATION removes the need for dialysis.
• UV LIGHT, ESPECIALLY UVA, causes the photosensitive reaction in pseudoporphyria — IN CONTRAST TO PCT. Hence, BROAD SPECTRUM UV PROTECTION IS VITAL until the disease resolves.
• As expected, the treatments for PCT such as ANTIMALARIALS and VENESECTION are NOT EFFECTIVE in pseudoporphyria.