Cutaneous Porphyrias (Porphyria Cutanea Tarda, Protoporphyrias and Congenital Erythropoietic Porphyria)

A group of haem biosynthesis disorders in which accumulation of photoactive porphyrins in the skin produces chronic bullous photosensitivity (porphyria cutanea tarda, hepatoerythropoietic porphyria and congenital erythropoietic porphyria) or acute painful non-bullous phototoxicity (protoporphyrias); genes UROD, FECH, ALAS2, CLPX, UROS and GATA1.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

This article groups three entities: porphyria cutanea tarda (PCT, with types I, II and III and hepatoerythropoietic porphyria as a biallelic allelic form), erythropoietic protoporphyria and related protoporphyrias (EPP1 due to FECH, X-linked protoporphyria due to ALAS2 and EPP2 due to CLPX) and congenital erythropoietic porphyria (due to UROS and, rarely, GATA1). Acute hepatic porphyrias, including hereditary coproporphyria and variegate porphyria, which may also cause blisters, are part of the differential diagnosis; HFE-associated haemochromatosis is a susceptibility factor for PCT.

0.1. Identification of entities

Identification references follow Orphanet and GeneReviews [8–14]. ICD-10 codes are E80.1 for PCT, E80.2 for HEP and E80.0 for erythropoietic porphyrias (EPP, XLP and CEP) [8, 11, 12, 14]. ClinGen classifies the association of UROD with “UROD-related hereditary porphyria”, with semidominant inheritance, as definitive (2022) [15].

0.2. Essential clinical data

None of the sources consulted identifies a European Reference Network (ERN) expressly including cutaneous porphyrias; the MetabERN page does not name them among its subgroups. The operating European clinical reference network is the International Porphyria Network (Ipnet, successor to the European Porphyria Network), which endorses specialist centres [32].

1. Introduction

1.1. Historical overview

Porphyrias are haem biosynthesis disorders in which deficiency or, more rarely, excessive activity of one of the pathway's enzymes leads to accumulation of porphyrins or their precursors. Of the three most frequent porphyrias, PCT causes chronic bullous photosensitivity, acute intermittent porphyria causes neurovisceral attacks and erythropoietic protoporphyria causes acute non-bullous photosensitivity; all porphyrias are hereditary except PCT, which results mainly from an acquired enzyme deficiency in the liver [18]. Congenital erythropoietic porphyria was the first to be described as an entity, by Günther in 1911, and retained the eponym Günther disease [31]. The clinical presentation of protoporphyria was described by Magnus and colleagues in 1961; its complex inheritance was recognised in 1984 and its genetic basis was not clarified until 2002 [6].

In PCT, the milestone separating hereditary and acquired forms was the 1976 study by Kushner, Barbuto and Lee, which demonstrated reduced hepatic uroporphyrinogen decarboxylase (UROD) activity in patients (mean 0.43 U/mg protein, versus 1.61 in controls) and also reduced erythrocyte activity in members of three families, with an autosomal dominant pattern; the authors proposed that disease resulted from the combination of a hereditary UROD defect with an acquired factor, usually siderosis associated with alcoholic liver disease [33]. The importance of environmental factors was illustrated by the PCT outbreak in Turkey following consumption of seed wheat treated with the fungicide hexachlorobenzene [18].

In protoporphyria, apparently vertical transmission across two generations led to its initial classification as autosomal dominant with incomplete penetrance [4]. In 2002, Gouya and colleagues identified, through haplotype segregation, the intronic FECH polymorphism IVS3-48T/C (now c.315-48T>C), which favours an aberrant splice acceptor site and reduces normal allele expression, explaining penetrance and reclassifying the disease as recessive in most families [34]. In 2008, Whatley and colleagues described eight families with C-terminal deletions in ALAS2 that increase enzyme activity, defining X-linked protoporphyria; until then, all known ALAS2 variants caused X-linked sideroblastic anaemia through loss of function [35]. In 2017, a CLPX variant that stabilises ALAS was associated with dominant protoporphyria in a family [36]. In CEP, Phillips and colleagues described the first human porphyria caused by a transcription factor variant, GATA1 p.Arg216Trp, in 2007 [37].

1.2. Classification and nomenclature

Porphyrias are classified by the tissue in which intermediates first accumulate, as hepatic or erythropoietic, or by clinical presentation, as acute (neurovisceral) or cutaneous [18]. The following table summarises the entities in this article and related entities.

AD: autosomal dominant; AR: autosomal recessive. Sources: [1, 6, 18].

PCT is divided into three types. Type I, sporadic or acquired, accounts for approximately 80% of cases and has no UROD variant; type II, familial, results from heterozygosity for a UROD variant, with low-penetrance autosomal dominant transmission and therefore generally no family history; type III designates families with several affected individuals without a UROD variant, in which haemochromatosis or shared environmental factors contribute [2]. The Brazilian reference book describes the same division by erythrocyte UROD activity: normal in type I, reduced in type II and preserved in familial type III [38]. The designation “UROD-related PCT” arises from the dyadic gene–phenotype approach, and in 2013 GeneReviews separated PCT type II from HEP into distinct chapters [1].

For CEP, the terms erythropoietic porphyria, congenital porphyria, congenital haematoporphyria and erythropoietic uroporphyria are obsolete [7]; for EPP, erythrohepatic protoporphyria, haem synthetase deficiency and ferrochelatase deficiency [4]. GeneReviews advises against the expression “X-linked dominant erythropoietic protoporphyria” because heterozygous females range from asymptomatic to as severely affected as males [5], although Orphanet retains inheritance recorded as “X-linked dominant” [13]. Current OMIM nomenclature adopted by the European review distinguishes EPP1 (FECH, #177000), XLEPP (ALAS2, #300752) and EPP2 (CLPX, #618015) [6]; Ipnet adds a fourth cause, acquired protoporphyria due to bone marrow disease [29].

1.3. Definition of the entities within scope

Porphyria cutanea tarda is a hepatic porphyria with bullous photodermatosis [8], caused by inhibition of hepatic UROD to less than approximately 20% of normal activity, regardless of type [2]. Hepatoerythropoietic porphyria is the homozygous or compound heterozygous form of familial PCT, with UROD activity of 15–20% in all tissues, childhood onset and more severe lesions [3, 18]. Erythropoietic protoporphyria (EPP1) is deficiency of ferrochelatase, the last enzyme in the pathway, with accumulation of metal-free protoporphyrin IX (PPIX) in erythroblasts, erythrocytes, plasma and the biliary system [20]. X-linked protoporphyria results from gain of function of ALAS2, the first erythroid enzyme, and accumulates both free protoporphyrin and zinc protoporphyrin [5]. EPP2 results from partial CLPX inactivation, which makes ALAS2 more stable [6]. Congenital erythropoietic porphyria is severe UROS deficiency, with accumulation of isomer I porphyrins and a mutilating, non-photoalgic photodermatosis [7, 14].

2. Molecular Genetics and Pathophysiology

2.1. The haem pathway and porphyrin photobiology

Haem is an iron–protoporphyrin complex produced chiefly in bone marrow, for haemoglobin, and in the liver, mainly for cytochromes P450 (CYP). The pathway has eight enzymes: the first and last three are mitochondrial and the middle four cytosolic. The initial step is catalysed by ALA synthase (5-aminolaevulinic acid synthase), with a constitutive form (ALAS1), rate-limiting in the liver, repressed by haem and induced by CYP-inducing drugs, and an erythroid form (ALAS2), encoded on the X chromosome and induced by haem and iron [18].

Cutaneous damage in porphyrias results from porphyrin excitation by light with a wavelength near 400 nm, in the Soret band (400–410 nm), at the lower boundary of the visible spectrum, and to a lesser extent by long-wave UVA; the absorbed energy generates singlet oxygen and free radicals that damage cells [7, 18]. Because this light passes through glass and is emitted by artificial sources, photosensitivity persists indoors and in cars, and conventional sunscreens, designed for ultraviolet light, provide little protection [4, 19]. The solubility of each porphyrin depends on the number of carboxyl groups and determines its excretion route: uroporphyrin, with eight carboxyl groups, is excreted in urine; coproporphyrin, with four, in urine and bile; protoporphyrin, with two, is water-insoluble and excreted exclusively through bile and faeces. Porphyrinogens are colourless and non-fluorescent, whereas oxidised porphyrins are reddish and emit red fluorescence [18]. This principle explains the clinical contrast: water-soluble porphyrins (PCT, HEP, CEP) are deposited in the dermis and cause subepidermal blisters and fragility, whereas protoporphyrin, lipophilic and bound to endothelium, causes immediate phototoxic pain without blisters and, through biliary excretion, hepatobiliary damage [4, 19].

2.2. Porphyria cutanea tarda and hepatoerythropoietic porphyria: UROD

The UROD gene is located at 1p34.1, has 10 exons and spans more than 3 kb, and encodes a ubiquitously expressed cytoplasmic enzyme that sequentially removes the four carboxyl groups from the acetate groups of uroporphyrinogen III (uro-, hepta-, hexa- and pentacarboxylporphyrinogen to coproporphyrinogen III) [2, 15]. When activity falls, porphyrinogens with 8, 7, 6 and 5 carboxyl groups accumulate; accumulated pentacarboxylporphyrinogen is converted by coproporphyrinogen oxidase to dehydroisocoproporphyrinogen and then to isocoproporphyrins, which appear in faeces and are the specific marker of UROD inhibition [2, 38].

In PCT, the amount of UROD protein remains at the genetically determined level, but hepatic activity falls below approximately 20% through the action of an inhibitor. In a murine model, this inhibitor was characterised as uroporphomethene, derived from partial oxidation of uroporphyrinogen in an iron- and CYP1A2-dependent process; other groups dispute the identity of uroporphomethene [2]. In PCT type II, heterozygosity for a loss-of-function variant reduces UROD activity to approximately 50% in all tissues, but manifestations occur only when susceptibility factors bring hepatic activity below 20%; oxidised porphyrins, mainly uroporphyrin and heptacarboxylporphyrin, pass from liver to plasma, urine and skin [1]. More than 100 UROD variants have been described in PCT type II [18]. There are no known genotype–phenotype correlations, and biallelic null variants are lethal, so in HEP at least one variant preserves catalytic activity [1, 3]. Ipnet estimates clinical penetrance of PCT type II at approximately 10–20% within families [19].

Iron is necessary: hepatic siderosis is present in up to 90% of biopsies and iron depletion induces remission [2]. HFE variants increase intestinal iron absorption and are overrepresented even without marked overload; in a study of 108 patients, 19% were p.Cys282Tyr homozygotes, and p.Cys282Tyr/p.His63Asp compound heterozygosity is also enriched; however, neither HFE homozygosity nor β-thalassaemia major causes PCT without other factors [2, 39]. Hepcidin is reduced in hepatitis C and alcohol consumption, and hepatic HAMP mRNA is reduced in PCT without end-stage kidney disease; in another study of 30 patients, however, serum hepcidin was elevated and correlated with ferritin and interleukin 6, demonstrating complex regulation [2].

Susceptibility factors, three or more of which accumulate in most patients, are alcohol consumption, hepatitis C virus infection (HCV; prevalence in PCT between 21% and 92% according to country), human immunodeficiency virus infection (HIV), oral oestrogens and oestrogen receptor modulators such as tamoxifen, smoking (CYP1A2 induction by polycyclic aromatic hydrocarbons), polyhalogenated hydrocarbons (polychlorinated biphenyls, hexachlorobenzene), end-stage chronic kidney disease with iron overload and poorly dialysable porphyrins, HFE and UROD variants, and low concentrations of ascorbic acid and carotenoids [1, 2, 18, 19]. Iron deficiency is protective [1]. In the Gisbert meta-analysis (50 studies, 2167 patients), hepatitis C prevalence was 47% by serology and 50% by polymerase chain reaction (PCR), 57% in the sporadic form versus 26% in the familial form, with substantial geographical variation [40].

In HEP, UROD homozygosity or compound heterozygosity reduces activity to 15–20% of normal in all tissues; accumulation is most marked in hepatocytes and developing erythrocytes, which accumulate uroporphyrin and zinc protoporphyrin, the marker distinguishing it from PCT [3]. Most described variants are missense and most porphyrins originate in the liver [19]. Large UROD deletions have been described in HEP, including deletion of the entire gene in one patient [3]. In Norway, two founder variants, NM_000374.5:c.578G>C p.(Arg193Pro) and NM_000374.5:c.636+1G>C, account for 74% of pathogenic UROD variants [3, 41].

2.3. Congenital erythropoietic porphyria: UROS and GATA1

The UROS gene is located at 10q26.2 (the Brazilian book gives 10q25.2, a cytoband differing from GeneReviews and ClinGen), spans approximately 34 kb and has 10 exons, of which 1 and 2A are non-coding; it has a constitutive promoter (exon 1) and an erythroid promoter (exon 2A, with GATA1 and CP2 binding sites) producing the same protein [7, 30, 38]. UROS, the fourth enzyme in the pathway, converts hydroxymethylbilane to uroporphyrinogen III, the branching point for haem and vitamin B12 [42]. When absent, hydroxymethylbilane spontaneously cyclises to uroporphyrinogen I, which UROD converts to coproporphyrinogen I; as coproporphyrinogen oxidase is stereospecific for isomer III, isomer I porphyrinogens accumulate in erythroid precursors, become oxidised, damage erythrocytes (intramedullary and intravascular haemolysis) and are deposited in skin, bone, spleen and teeth; urinary excretion reaches 100 to 1000 times normal [7, 30]. Residual activity ranges from less than 1% to approximately 10% of normal; activity at or below 1% is compatible with life, whereas murine knockout is lethal [7, 30].

The Human Gene Mutation Database (HGMD; July 2018) listed 51 UROS variants: 59% missense, 12% regulatory and 8% splicing [30]. The most frequent variant is NM_000375.3:c.217T>C p.(Cys73Arg), present in approximately 30% of alleles in a series of 40 patients and in approximately one-third of patients; it is neither a founder nor located at a CpG dinucleotide, and reduces activity and stability to less than 1% [7, 30]. The review by Erwin and Desnick states “c.217C>T”, an incorrect notation because the reference nucleotide is T [41, 43]. Genotype–phenotype correlation depends chiefly on residual activity: p.(Cys73Arg) homozygosity causes non-immune hydrops fetalis or transfusion dependence from birth; variants with greater residual activity in vitro, such as c.244G>T p.(Val82Phe) (35%), c.311C>T p.(Ala104Val) (7.7%) and c.197C>T p.(Ala66Val) (14.5%), produce mild forms even in trans with p.(Cys73Arg); an adolescent with p.(Cys73Arg)/p.(Ala66Val) had cutaneous disease only [7, 30]. Variant c.139T>C p.(Ser47Pro) is associated with a severe phenotype, but in a family with five homozygous children, four were severely affected and one had only very mild cutaneous findings [7]. These variants are described in GeneReviews on transcript NM_000375.2 [7].

Erythroid promoter variants are detected only if sequencing includes intron 1 upstream of exon 2. In historical nomenclature, −70T>C (GATA1 site) and −90C>A (CP2 site) retain approximately 8% activity and −76G>A and −86C>A approximately 43%; −70T>C in trans with p.(Cys73Arg) caused hydrops, and −76G>A with p.(Cys73Arg) mild disease [7, 30]. GeneReviews converts them to c.-203T>C, c.-209G>A, c.-219C>A and c.-223C>A, positions accepted by VariantValidator on NM_000375.3, but correspondence with historical names could not be confirmed because the erythroid promoter uses a different first exon from the MANE transcript [7, 41].

X-linked CEP due to GATA1 (Xp11.23) has been described in three unrelated males with variant NM_002049.4:c.646C>T p.(Arg216Trp), which reduces transcription factor binding to the erythroid UROS promoter (activity approximately 20%) and is associated with a β-thalassaemia phenotype, thrombocytopenia and persistent fetal haemoglobin; one had no variant in UROS or globin genes [7, 37, 44]. ClinVar classifies this variant as likely pathogenic, associated chiefly with thrombocytopenia with dyserythropoiesis [43]. Variant p.Arg216Gln at the same codon causes thalassaemia with thrombocytopenia without CEP, and other GATA1 variants cause X-linked cytopenia, grey platelet syndrome and Diamond–Blackfan-type erythroid aplasia [30, 45]. Two probands with p.(Arg216Trp) simultaneously had a variant in UROS or SEC23B [45]. More than 10% of patients with CEP have no identified variant in UROS or GATA1 [30].

ALAS2 acts as a modifier gene: a female patient with CEP p.(Cys73Arg)/p.(Arg248Gln) and the gain-of-function variant NM_000032.5:c.1757A>T p.(Tyr586Phe) in ALAS2 exon 11 had more severe disease than three siblings with the same UROS genotype [7, 30, 41]. Late-onset forms, after 50 years, are associated with myelodysplastic syndrome with clonal expansion of UROS-deficient erythroblasts; acquired mosaicism was postulated in a 60-year-old man heterozygous for p.(Cys73Arg) without a second variant [18, 30].

2.4. Erythropoietic protoporphyria (EPP1): FECH

The FECH gene is located at 18q21.31 and encodes ferrochelatase, an inner mitochondrial membrane enzyme (423 amino acids, with a mitochondrial localisation peptide of 54 residues) that inserts ferrous iron into protoporphyrin IX [4, 46]. Almost 200 pathogenic variants have been described, mostly null variants (nonsense, small deletions and insertions, splicing) [4, 18]. Most patients inherit a rare loss-of-function variant from one parent and the common hypomorphic allele NM_000140.5:c.315-48T>C (rs2272783; historical name IVS3-48T>C) from the other, creating a cryptic acceptor site in intron 3; aberrant mRNA is degraded by nonsense-mediated decay, the normal transcript from this allele falls to approximately 25% and the combination results in approximately 30% of normal enzyme activity [4, 20, 41]. Homozygosity for c.315-48T>C does not cause EPP, although it is associated with a slight reduction in mean corpuscular volume and haemoglobin in UK Biobank [20, 21]. ClinVar records conflicting classifications for this variant (VCV000000562), reflecting its nature as a hypomorphic allele pathogenic only in trans with a loss-of-function variant; it should not be classified as a variant of uncertain significance (VUS) or as pathogenic in isolation [20, 43].

In Gouya's French cohort (173 families), the “dominant” form, that is, loss of function in trans with the hypomorphic allele, accounted for 95% (95% confidence interval, 95% CI: 91–99%) and the recessive form with two loss-of-function variants 4% (1–8%) [47]. In UK Biobank, 96% of EPP cases resulted from this combination [21]; among the 155 United States probands in Balwani 2013, 134 had a loss-of-function allele plus c.315-48T>C, 3 had two loss-of-function variants and 3 a variant with two hypomorphic alleles [25]. The frequency of allele c.315-48T>C varies with ancestry: 43% in Japanese people, 31% in south-east Asia, 11% in White French people, 2.7% in North Africans and less than 1% in West Africans, explaining variation in EPP prevalence and its rarity in African populations; the allele's origin was estimated at approximately 60,000 years ago [47]. Ipnet gives 47% in Japan [26] and the European review 43% [6]. Allele frequency (0.05 in UK Biobank; 0.11 in French people) should be distinguished from the proportion of carriers, which the United States guideline estimates at approximately 10% of the Caucasian population [20, 21].

Protoporphyrin accumulates mainly in marrow reticulocytes; in circulating erythrocytes it is more than 90% metal-free, concentrated in a small fraction of cells, diffuses into plasma bound to albumin and is taken up by endothelium. Light releases protoporphyrin from erythrocytes without lysis, and photoactivation causes lipid peroxidation, complement activation, mast cell degranulation and immediate capillary endothelial damage, with perivascular deposition of amorphous material in the upper dermis [4, 26]. In the liver, protoporphyrin forms insoluble crystals in hepatocytes and canaliculi, damages mitochondria and reduces bile flow; obstruction increases plasma protoporphyrin, which would normally be excreted in bile, in a cycle that can progress rapidly [4, 20]. Crystals have a birefringent “Maltese cross” appearance under polarised light [27]. In the murine model lacking transporter ABCG2, hepatocellular retention appeared to protect against liver disease, suggesting that toxicity acts mainly on biliary epithelium [27].

Residual activity determines severity. Patients with missense variants have lower median erythrocyte protoporphyrin than carriers of deletions, nonsense variants or canonical splice site alterations (1462 versus 1702 µg/dL; p=0.01) [22]. In a study of 112 patients from 93 families, all 18 with severe hepatic complications had a null allele and none of the 20 missense carriers had such complications [48]. The United States guideline suggests that biallelic rare FECH variants, without the hypomorphic allele, may be associated with greater risk of liver failure [20, 27]; seasonal palmar keratoderma has been described in these families [4, 18]. Iron availability modulates FECH splicing and ALAS2 translation through IRP2 protein, so iron increases protoporphyrin in EPP1 [6, 18].

2.5. X-linked protoporphyria: ALAS2

ALAS2 is located at Xp11.21 and encodes erythroid ALA synthase, with 587 amino acids and a transit peptide of 49; C-terminal amino acids, encoded by exon 11, negatively regulate activity [5]. All XLP variants are located in exon 11 of transcript NM_000032 and are gain-of-function variants (small frameshift deletions, nonsense and missense); ALA formation increases so much that iron insertion by normal ferrochelatase becomes rate-limiting, and free protoporphyrin and, in iron deficiency, zinc protoporphyrin accumulate [5, 6]. The most frequent variant in the United States is NM_000032.5:c.1706_1709del p.(Glu569GlyfsTer24) (13 of 15 probands), classified in ClinVar as pathogenic [25, 43]. Unlike EPP1, iron reduces protoporphyrin in XLP, and iron stores are frequently reduced in males [5, 20]. Males have penetrance close to 100%; in females, severity varies with X-inactivation, from asymptomatic to as severe as in males [5].

The allelic ALAS2 disease is X-linked sideroblastic anaemia (XLSA), due to loss-of-function variants distributed throughout the gene: hypochromic microcytic anaemia with ring sideroblasts and intrinsic iron overload due to hepcidin suppression, with a response to pyridoxine in approximately one-third of patients [18, 28]. Iron therefore has opposing roles in the two diseases: a hazard to remove in XLSA and a deficiency to correct in XLP [28].

2.6. EPP2 and acquired protoporphyrias

CLPX is a mitochondrial ATPase that unfolds ALAS and promotes its degradation. The dominant variant p.Gly298Asp in the ATPase domain, described in a family, makes ALAS more stable and increases ALA and protoporphyrin [36]; in another patient with EPP2, a variant in the iron-responsive element of ALAS2 modified severity [49]. EPP2 has a zinc protoporphyrin fraction of 29–67% and is likely, like XLP, to respond to iron with a reduction in protoporphyrin [6]. Acquired late-onset protoporphyrias occur in myelodysplastic or myeloproliferative syndromes with clones that have lost FECH through 18q deletion or with somatic ALAS2 mosaicism, and may regress with treatment of the neoplasm [4–6]. Approximately 4% of patients with biochemical protoporphyria have no identified variant in FECH or ALAS2 [20, 22].

2.7. Normalised variants and historical nomenclature

Normalisation by VariantValidator (GRCh38, MANE Select mode) and ClinVar classification accessed on 10 October 2026 [41, 43]. GeneReviews uses earlier transcript versions (NM_000140.3, NM_000032.4, NM_000375.2, NM_000374.5 and NM_002049.3) [3–5, 7]; ALAS2 variant c.1642C>T corresponds to p.(Gln548Ter), rather than “Glu548Ter” as sometimes transcribed. Other variants listed by GeneReviews (UROS c.139T>C, c.197C>T, c.244G>T, c.311C>T, c.673G>A; ALAS2 c.1651_1676del) remain in the text using the nomenclature of those sources.

2.8. Allelic diseases and modifiers

3. Clinical Spectrum and Manifestations by System

3.1. Porphyria cutanea tarda

Skin. Manifestations usually begin in the fifth or sixth decade: vesicles, blisters and erosions on the backs of the hands and other exposed areas (forearms, face, scalp, ears, neck, legs and, in women, the dorsum of the feet), with pink to red fluid, crusting, slow healing and secondary infection [1, 18]. Fragility is characteristic: minimal trauma detaches the epidermis. Milia, hyperpigmented and hypopigmented scars, facial hypertrichosis and hyperpigmentation, scarring alopecia and, in chronic forms, sclerodermoid thickening with calcification (pseudoscleroderma), which may also appear in unexposed areas, and onycholysis follow [1, 2, 19]. Patients often do not associate lesions with light [2]. Unlike acute porphyrias there are no pain attacks, and unlike protoporphyrias there is no acute pain in sunlight [1]. In the Barcelona series (152 consecutive patients), fragility and hand blisters were the most frequent manifestations; women had more facial hypertrichosis (84.8%), more areas affected beyond hands and face (33.3%) and more pruritus (27.3%), and 11.8% of patients presented only with facial hypertrichosis and hyperpigmentation [50]. Urine is dark, pinkish or brownish, with bright pink fluorescence under ultraviolet light in severe forms [1].

Liver. PCT is frequently secondary to internal disease and affects liver health and longevity [51]. Aminotransferases and gamma-glutamyltransferase are frequently elevated, and some patients have iron overload [1]. GeneReviews reports cirrhosis in 30–40%, particularly in the presence of hepatitis C or alcohol, without specifying the denominator [1]. The Norwegian national cohort (2000–2016; 612 national registry patients compared with 5.45 million adults) quantified risk: hepatocellular carcinoma (HCC) with an adjusted hazard ratio (aHR) of 19.7 (95% CI 8.8–44.0), biliary tract cancer 6.8 (2.2–21.0) and premature death 1.5 (1.2–1.7), the latter due to malignancies (1.4), liver disease (5.5) and alcohol or drug overdose (9.9); compared with people with chronic alcohol abuse, HCC risk was still 3.1 times higher (1.2–7.7), suggesting that something inherent to PCT contributes to HCC beyond lifestyle factors [16]. The Brazilian book gives HCC in 5–16% of patients, without identifying the population or source [38].

Metabolism. In a Spanish cohort of 81 patients followed for at least 10 years, 41% developed diabetes or impaired fasting glucose, in 82% of cases long after PCT diagnosis (mean 12.7 years); ferritin at diagnosis was higher in these patients (651 versus 405 ng/mL) and persistent hyperferritinaemia more frequent (52% versus 15%) [52].

Nervous system and associations. The Brazilian book lists peripheral neuropathy, deafness, insomnia and personality changes, conjunctivitis, gastrointestinal symptoms and associations with autoimmune diseases (dermatomyositis, systemic sclerosis, lupus) and haematological diseases [38], whereas Saudubray's textbook states that PCT has no neurological effects [18] and Ipnet emphasises the absence of neurovisceral attacks [19]. The Brazilian list gives no denominators and should be read as reported associations rather than intrinsic disease manifestations; rare associations recognised by Ipnet are diabetes, systemic lupus erythematosus, chronic kidney disease and haematological malignancy [19].

Pregnancy. In the Norwegian porphyria registry linked with the birth registry (1967–2006; 398 singleton births to 200 mothers with porphyria versus 2,275,317), hereditary PCT was associated with perinatal death (odds ratio, OR, 3.0; 95% CI 1.2–7.7) and sporadic PCT with small-for-gestational-age newborns (relative risk, RR, 2.0; 1.2–3.4) and, in primiparous women, low birth weight and prematurity [53]. GeneReviews considers pregnancy with active PCT high risk, requiring monitoring by a qualified obstetrician [1].

Spectrum by factors. Hepatitis C is more frequent in the sporadic form (in the Barcelona study it was the only factor distinguishing sporadic from familial disease; OR 0.05) and, in that series, hepatitis C (65.8%) and alcohol abuse (59.9%) were more frequent in males [50]. In southern Europe, disease is predominantly male because of greater exposure to risk factors, and in northern Europe and the USA there is only a slight male predominance [19]. In a Brazilian tertiary hospital (2002–2017; 87 patients), the male:female ratio was 1.8:1, median age at diagnosis 49 years (18–71), family history of PCT 19.5%, and 42.5% had two or more acquired precipitating factors [54]. Ipnet considers onset before 40 years suggestive of the familial form [19]. Subclinical PCT was identified in five of 84 patients with hepatitis C treated with antivirals in Barcelona and normalised after viral cure [55].

3.2. Hepatoerythropoietic porphyria

HEP begins in infancy or early childhood, with similar frequency in both sexes: extreme photosensitivity, blisters that rupture and heal slowly, hypertrichosis, red urine and erythrodontia when circulating porphyrins are very high; repeated exposure leads to sclerodermoid changes and photomutilation, and mild anaemia or haemolysis is not uncommon [3]. The presentation resembles CEP, but there are mild late-onset cases resembling PCT; concomitant viral hepatitis may accentuate porphyrin accumulation [18]. The Brazilian book also describes osteolysis and phalangeal shortening, joint erosions, splenomegaly and, in some patients, seizures, developmental delay and cortical atrophy [38], and the CEP GeneReviews mentions developmental delay in some HEP patients [7]. No increased HCC risk has been identified in HEP [3]. A Brazilian child with HEP, assessed in the USA, developed blisters and ulcers on the face and upper limbs at 10 months, with dark urine, greyish teeth, hepatosplenomegaly and slightly elevated transaminases; erythrocyte protoporphyrin was 83.5% zinc-bound and erythrocyte UROD activity approximately 5% of normal [56].

3.3. Erythropoietic protoporphyria and X-linked protoporphyria

Phototoxicity. Onset is usually in early childhood, at the first prolonged sun exposure; in the prospective Porphyrias Consortium cohort (226 patients, 6 United States centres, 2010–2015), mean age at onset was 4.4 ± 4.4 years [22], and most European patients have symptoms before 5 years [6]. Within minutes of light exposure, a prodrome of tingling, burning or itching appears, followed by intense pain with erythema and oedema on the backs of the hands, face and feet, which may resemble angioedema; pain responds poorly to analgesics, including opioids, and lasts hours to days [4, 20, 57]. Most tolerate less than 30 minutes of sunlight; reactions also occur with light through glass, intense artificial light, cloudy days and reflection off snow or water [26]. The priming phenomenon describes a rapid, severe reaction with minimal exposure on the day after a mild reaction [26]. During the most painful episodes, skin may have no visible changes, which, together with absence of blisters, delays diagnosis by more than a decade [20, 26]. Extreme cases show petechiae, crusting and necrosis; blisters are rare but occurred in 26% of a large series [4, 6]. Chronic changes are leathery thickening, labial pseudorhagades, comma-shaped scars on the nasal dorsum, joint lichenification and loss of lunulae [6]. Conditioned sun-avoidance behaviour, missed school days and occupational choices reduce quality of life; European patients have lower employment despite higher educational attainment [6, 20]. Symptom-related anxiety and depression are described, but adult rates are similar to those in the general population [20].

Liver and biliary tract. The frequency of liver dysfunction depends on definition and selection. In the United States cohort of 226 patients, 27.4% had a history of liver dysfunction; aminotransferases were elevated in 54 of 204 EPP patients (26.5%) and 8 of 22 with XLP (36%), and one patient from each group underwent transplantation [22, 27]. In the unselected Dutch cohort of 114 adults with EPP, only 6.2% had elevated enzymes, 29% steatosis and 9.6% significant fibrosis on transient elastography, values comparable with the general population; protoporphyrin predicted liver stiffness [58]. Older series, reporting approximately 25%, did not exclude other causes [27]. Severe protoporphyric hepatopathy, in the form of acute cholestatic hepatitis with liver failure (“hepatic crisis”) or slowly progressive biliary cirrhosis, occurs in 1–5% of patients and almost always requires transplantation [6, 27]; in the genotype–phenotype correlation study, approximately 2% developed cirrhosis or progressive liver failure [48]. It is preceded by a rise in erythrocyte and plasma protoporphyrin, worsening liver tests and increased photosensitivity, with right upper quadrant and lumbar pain [4]. Decompensation may be accompanied by motor neuropathy resembling that of acute porphyrias, with dysphagia and respiratory failure [4, 6]. Risk factors are high protoporphyrin, viral hepatitis, hepatotoxic drugs, alcohol consumption, male sex in XLP and genotypes with null alleles or two rare variants [27]. Gallstones composed of protoporphyrin occur earlier and affected 23.5% of the United States cohort (22% in EPP and 36% in XLP), 20–25% in the European series, and may present with lumbar pain [6, 22, 27, 29]. A 2-year-old child with EPP due to two FECH variants (c.901_902del and c.801G>A) had erythrocyte protoporphyrin of 2406 µg/dL and bridging fibrosis with crystals on biopsy [59].

Blood and bone. Mild hypochromic microcytic anaemia occurs in 30–60% of patients (47.3% in the United States cohort); haemolysis is absent or mild, and whether erythropoiesis is restricted by iron or haem deficiency is unclear [20, 22]. Up to half of patients have 25-hydroxyvitamin D below 50 nmol/L, and in the Dutch cohort osteopenia (36%) and osteoporosis (23%) exceeded expectations (15% and 1%); vertebral fractures have been described [6, 29].

Differences between EPP1 and XLP. Higher erythrocyte protoporphyrin was associated with earlier onset, lower sun tolerance and liver dysfunction (2016 versus 1510 µg/dL; p=0.003); males with XLP had twice the protoporphyrin of EPP1 patients (3574 versus 1669 µg/dL) [22]. In Whatley's British series, 5 of 31 patients with XLP had liver dysfunction [5]. GeneReviews cites, from the same United States study, abnormal aminotransferases in 37.5% of males and 22.2% of females with XLP versus 13.7% in EPP1, and anaemia in 30% of males and 75% of females with XLP [4, 5]. Heterozygous females have median onset at 11 years [5]. Severity is generally stable throughout life and protoporphyrin varies little, but a progressive rise precedes hepatic complications [4, 18].

Pregnancy. Pregnancy is associated with lower protoporphyrin and, inconsistently, greater sun tolerance; perinatal outcomes are similar to those in the general population [4, 6, 20].

3.4. Congenital erythropoietic porphyria

The spectrum ranges from non-immune hydrops fetalis to an adult-onset form with cutaneous involvement only [7]. In most, the first manifestation is pink to dark-red urine in nappies, followed by severe photosensitivity at birth or in early childhood; in a Canadian case and the literature it cites, median ages at appearance of red urine, skin lesions and haemolytic anaemia were 1, 2 and 8 months, and median diagnosis 7 months [7, 60]. Neonatal phototherapy may trigger severe burns [18].

Skin and appendages. Easily ruptured serous blisters, secondary infection, scarring and bone resorption lead to photomutilation of digits, nose, ears and eyelids; skin thickening, hyperpigmentation and hypopigmentation, facial and extremity hypertrichosis and scarring alopecia occur [7, 38]. Unlike EPP, immediate pain, burning and oedema do not usually occur [7], although Katugampola's series described acute cutaneous and non-cutaneous symptoms immediately after exposure and erythematous facial papules [61]. Erythrodontia, reddish-brown teeth fluorescing under long-wave UV, is pathognomonic [7].

Blood. Haemolysis is almost always present in severe cases: anisopoikilocytosis, basophilic stippling, reticulocytosis, circulating erythroblasts, absent haptoglobin and increased unconjugated bilirubin; anaemia depends on marrow compensation and varies over time, and splenomegaly aggravates anaemia and causes leucopenia and thrombocytopenia with bleeding [7, 30]. Severe cases are transfusion-dependent [18].

Eyes. Corneal ulcers and scars potentially leading to blindness, scleral necrosis, necrotising scleritis, blepharitis, keratoconjunctivitis, ectropion and eyelash loss [7, 31].

Bone. Porphyrin deposition in bone, marrow hyperplasia and vitamin D deficiency cause osteopenia and, in adulthood, osteolysis [7, 38].

Cohorts. In Katugampola's single-observer study (27 living patients aged 7.6 to 65 years from the United Kingdom, France, Switzerland and Germany, plus 2 deceased), disease was multisystemic (cutaneous, ocular, oral and skeletal), there was no consistent genotype–phenotype correlation, and early onset and haematological complications were adverse prognostic factors [61]. There are no neurological manifestations [18]. Life expectancy is often reduced by infections or haematological complications [18]. Women with CEP have had successful pregnancies with healthy children [7].

X-linked CEP. The three males with GATA1 p.(Arg216Trp) had hypochromic microcytic anaemia from birth, thrombocytopenia (approximately 70 × 10⁹/L in the first) and a β-thalassaemia phenotype with fetal haemoglobin of 59.5%, in addition to cutaneous manifestations; haematological phenotypes may be misleading (dyserythropoietic anaemia, thrombocytopenia, hereditary persistence of fetal haemoglobin) [37, 44].

3.5. Comparison of entities

Sources: [1, 3–5, 7, 27].

4. Clinical Recognition and Warning Signs

4.1. When to suspect the disease, by age

Fetal and neonatal period. CEP should be considered with non-immune hydrops fetalis, pinkish or brown amniotic fluid, and in a newborn with red urine staining nappies, haemolytic anaemia, hepatosplenomegaly or blisters at sites of trauma or light exposure, including pulse oximeter and phototherapy light [7, 30, 60]. In a newborn with hyperbilirubinaemia and a family history of CEP, conventional phototherapy should not be used [18, 30]; in a newborn at risk of protoporphyria, phototherapy is reasonable with conservative doses and monitoring because there are no reports of perinatal phototoxicity [20], although Ipnet advises contacting a specialist and exercising caution while investigating the newborn [29]. There is no newborn screening for cutaneous porphyrias in the sources consulted.

Infant and child. Porphyrias with vesiculobullous manifestations in childhood are CEP, HEP and, rarely, EPP; hypertrichosis accompanies CEP and HEP [57]. In a child crying or experiencing hand and facial pain after being in sunlight or near a window, with oedema resembling angioedema and few visible signs, protoporphyria should be suspected; EPP is included in the differential diagnosis of extremity pain in children [4, 57]. Refusing to go outdoors, seeking shade and needing to immerse the hands in cold water are behavioural clues. Diagnosis is frequently very late at this age [18, 20]. Seasonal palmar keratoderma may signal EPP with two loss-of-function variants [4, 57].

Adult. PCT should be suspected in an adult with blisters, erosions and fragility of the backs of the hands and facial hypertrichosis, particularly with alcohol consumption, hepatitis C, HIV, oestrogens, smoking, haemodialysis or elevated ferritin; family history is negative in most [1, 2]. Onset before 40 years suggests the familial form [19]. In older people with recent-onset photosensitivity and elevated protoporphyrin or isomer I porphyrins, myelodysplastic syndrome should be sought [4, 7].

4.2. Warning signs and emergencies

Laboratory diagnosis should be established before treating suspected PCT because lesions and histology do not distinguish PCT from variegate porphyria or hereditary coproporphyria, in which phlebotomy and hydroxychloroquine are ineffective [2, 18].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Principles and initial algorithm

There are no consensus clinical criteria for any of these diseases; diagnosis is biochemical and confirmed by molecular analysis [5, 7]. The starting point is the cutaneous phenotype. With bullous lesions, the first-line test is total plasma or urinary porphyrins, elevated in all patients with active porphyric lesions; with acute non-bullous photosensitivity, the first-line test is erythrocyte porphyrins, that is, erythrocyte protoporphyrin fractionated into metal-free and zinc protoporphyrin [18]. Fluorescence scanning of plasma diluted at neutral pH, with excitation at 400–410 nm, rapidly distinguishes cutaneous porphyrias by emission peak [1, 18]. Fractionation of urinary and faecal porphyrins is unhelpful if total levels are not increased [18]. Urinary precursors (ALA and porphobilinogen) are normal in PCT, CEP and protoporphyrias, distinguishing them from acute porphyrias [18, 30]. All samples should be protected from light [6, 20].

Sources differ in choice of the first test for cutaneous photosensitivity. The United States guideline recommends fractionated erythrocyte protoporphyrin and does not recommend plasma porphyrins first-line because they may be normal in EPP [20]. The European review proposes plasma fluorescence scanning as initial screening for all cutaneous porphyrias, considering that a negative result excludes porphyria as the cause of concurrent cutaneous symptoms [6]. A British pre-analytical study showed, however, that plasma porphyrins in EPP decrease by a mean of 19% after 6 hours refrigerated and protected from light, 36% after 24 hours at room temperature, 67% within 1 hour exposed to light and 33% after one freeze cycle, whereas erythrocyte porphyrins remain stable for 96 hours; the authors recommend requesting erythrocyte protoporphyrin alongside plasma whenever protoporphyria needs exclusion [64]. This approach reconciles the two positions.

5.2. Biochemical profiles

Sources: [1–5, 7, 19, 20, 30, 65]. The European review places the protoporphyria peak at 633–635 nm [6].

5.3. Porphyria cutanea tarda and HEP

PCT is confirmed by increased plasma and urinary porphyrins with predominance of uroporphyrin and heptacarboxylporphyrin (also hexa- and pentacarboxyl), normal porphobilinogen and normal or slightly increased ALA; a spot urine sample normalised to creatinine is sufficient [2, 18]. The urinary pattern may be similar in variegate porphyria, so plasma and faecal profiles should complete the investigation; faecal isocoproporphyrins are pathognomonic of UROD inhibition [2, 19]. Skin biopsy (subepidermal blister, festooning of dermal papillae, hyalinised vessels positive on periodic acid–Schiff (PAS) staining) is unnecessary and does not distinguish bullous porphyrias from one another, and liver biopsy is rarely indicated [1, 2, 19]. In Singal's trial, inclusion criteria were fragility lesions or blisters on exposed areas, plasma porphyrins above 0.9 µg/dL with an emission peak at 618–620 nm, urinary porphyrins above 300 nmol/L (or per 24 hours or gram creatinine) and predominance of highly carboxylated porphyrins [66].

Initial assessment includes liver tests, full blood count, HCV and HIV serology, ferritin and transferrin saturation, HFE genotype, alcohol and tobacco consumption, oestrogens, renal function and, as appropriate, liver imaging and elastography [1, 19]. Type I and type II are distinguished by erythrocyte UROD activity (approximately 50% in F-PCT, normal in PCT type I) or, preferably, genetic testing [2, 15]. Normal erythrocyte activity does not exclude the familial form, and UROD activity does not distinguish F-PCT from HEP [1, 15]. F-PCT diagnosis requires elevated urinary porphyrins with the typical pattern and a heterozygous pathogenic or likely pathogenic UROD variant; a VUS neither establishes nor excludes it [1].

In HEP, the proposed sequence is total porphyrins at a reference laboratory, then predominance of uro- and heptacarboxyl with markedly increased erythrocyte zinc protoporphyrin (distinguishing it from CEP), and finally molecular testing; diagnosis rests on porphyrins and zinc protoporphyrin and/or biallelic UROD variants [3]. Molecular documentation is important [18]. In the Brazilian child with HEP, diagnosis was made by genetic testing in Brazil, with UROD variants c.239C>G p.(Ala80Gly) and c.464C>T p.(Ala155Val) (transcript not specified in the abstract; positions valid on NM_000374.5) [41, 56].

5.4. Protoporphyrias

Total erythrocyte protoporphyrin with fractionation is the recommended test. According to the United States guideline, total protoporphyrin above three times the upper limit of normal (ULN), predominantly metal-free, is consistent with diagnosis; the free fraction is typically above 90% in EPP and approximately 50–85% in XLP; mild elevations, particularly zinc protoporphyrin or less than three times ULN, suggest iron deficiency or lead poisoning [20]. Laboratories measuring only by haematofluorometry, with false-normal values and results mislabelled as “free erythrocyte protoporphyrin”, should be avoided; the United Porphyrias Association maintains a list of recommended laboratories [20]. Many assays called “free erythrocyte protoporphyrin” measure both fractions; only ethanol extraction or high-performance liquid chromatography separates them [4]. Urinary porphyrins are normal and unsuitable (false negative), faecal porphyrins normal or increased, and skin biopsy is not indicated, being reserved for excluding other diagnoses [20, 26]. The ferrochelatase assay is available in few centres and is not used diagnostically [4, 26].

Genetic testing of FECH and ALAS2 is recommended after biochemical diagnosis to distinguish EPP from XLP, but genetic testing without biochemistry is not recommended because approximately 4% of patients have no identified variant and VUS are frequent [20]. The European review emphasises that genetic testing neither definitively confirms nor excludes disease, and that the diagnostic hallmark is elevated protoporphyrin [6]. In XLP, diagnosis requires increased free and zinc protoporphyrin and a hemizygous (males) or heterozygous (females) gain-of-function ALAS2 variant; exon 11 sequencing detects all known variants and deletion/duplication testing is not indicated [5, 28]. Lymphocyte ferrochelatase is normal in XLP [5]. Molecular analysis also identifies genotypes at higher hepatic risk (two rare FECH variants), a class IIb recommendation [27].

Initial assessment also includes full blood count, iron profile with ferritin, liver tests, 25-hydroxyvitamin D and ultrasound if indicated [5, 20]. With elevated aminotransferases, the liver disease guideline recommends hepatitis B and C serology, ferritin and abdominal ultrasound; if inconclusive and persistent, autoantibodies, immunoglobulins, caeruloplasmin, alpha-1-antitrypsin and thyroid-stimulating hormone (TSH); with predominant alkaline phosphatase elevation, right upper quadrant ultrasound and, without dilatation, antimitochondrial antibodies and magnetic resonance cholangiopancreatography if suspicion is high [27]. A urinary coproporphyrin isomer I/III ratio above 40% indicates greater risk of hepatic involvement, and elastography may be considered, without validated cut-offs in this population [27]. Liver biopsy may be indicated (birefringent deposits, fibrosis), but the European review considers it generally unnecessary in mild to moderate disease because of a bleeding risk of up to 10% [6, 27].

5.5. Congenital erythropoietic porphyria

Diagnosis rests on markedly increased uroporphyrin I and coproporphyrin I in urine, erythrocytes or amniotic fluid, with faecal coproporphyrin I; faecal isocoproporphyrins do not increase and ALA and porphobilinogen are normal [7, 30]. Erythrocyte UROS activity, undetectable to approximately 10% of the normal mean, can establish diagnosis and is clinically available in some laboratories [7, 42]. Confirmation is by biallelic UROS variants or, rarely, a hemizygous GATA1 variant; without biochemistry, biallelic VUS or combinations of a pathogenic variant with a VUS do not establish diagnosis, but reduced enzyme activity with very high isomer I levels confirms it and supports VUS pathogenicity [7]. CEP is one of the few situations in which biochemistry is confirmatory rather than merely suggestive [42]. In late forms with myelodysplastic syndrome, erythrocyte UROS activity may be normal [7].

5.6. Genetic testing and its limitations

Table percentages refer to the proportion of known pathogenic variants detected by each method rather than clinical test sensitivity: in PCT, for example, UROD sequencing detects almost all pathogenic variants, but approximately 80% of patients have none [1, 2]. Options are gene sequencing followed by deletion/duplication analysis, a porphyria or haem biosynthesis panel including UROD, UROS, GATA1, FECH, ALAS2, CPOX and PPOX, or exome or genome sequencing if these are negative [1, 4, 7]. Broader panels exclude variegate porphyria, hereditary coproporphyria, CEP and dual porphyria [2]. Leucocyte DNA may not detect parental mosaicism [1]. The report should specify the gene, reference transcript and version (MANE), variant in HGVS nomenclature, zygosity, classification according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) and, for FECH, presence or absence of allele c.315-48T>C and its phase relative to the rare variant, confirmed by parental testing when necessary [4, 20]. VUS are clarified by biochemistry and family segregation [5, 7].

5.7. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing (PGT) are possible in all entities after familial variants are identified [1, 3–5, 7]. In CEP, biochemical diagnosis is also possible through UROS activity in cultured amniocytes or chorionic villi and uroporphyrin I and coproporphyrin I in amniotic fluid, which is red to dark brown; amniocentesis is performed at around 16 weeks and chorionic villus sampling around 12 [7, 31]. In GATA1-related CEP, data are insufficient to validate biochemical diagnosis [7]. In EPP, biochemistry is unsuitable for carrier detection or prenatal diagnosis, and Ipnet allows prenatal diagnosis only in exceptional circumstances [4, 26]. In F-PCT, prenatal diagnosis is possible but does not predict manifestations because of low penetrance [1].

6. Differential Diagnosis

6.1. Comparative table

NSAIDs: non-steroidal anti-inflammatory drugs; XL: X-linked.

6.2. Distinguishing bullous porphyrias

The bullous lesions of PCT, HEP, CEP, variegate porphyria and hereditary coproporphyria are clinically indistinguishable, and histopathology (subepidermal blister, perivascular PAS-positive material, cleavage within the lamina lucida) is shared by all and by pseudoporphyria [1, 18]. Differential diagnosis is biochemical. In variegate porphyria, faecal coproporphyrin III and protoporphyrin are increased in similar proportions and plasma has a characteristic peak at approximately 626 nm, versus 619–622 nm in PCT and HEP; in hereditary coproporphyria, faecal coproporphyrin III increases in isolation [3, 18]. The distinction has direct therapeutic consequences because phlebotomy and low-dose hydroxychloroquine do not treat cutaneous lesions in these acute porphyrias, and because patients with variegate porphyria or hereditary coproporphyria are exposed to drug-triggered acute attacks [18]. Coexistence of variegate porphyria and PCT has been described [18]. Between PCT and HEP, laboratory findings may be indistinguishable in an adult with mild HEP, and only erythrocyte zinc protoporphyrin and molecular testing separate them [2, 3]. CEP is distinguished by isomer I porphyrins in urine and erythrocytes; late-onset forms may require faecal profiling [1, 3].

6.3. Protoporphyrias and the zinc protoporphyrin problem

Erythrocyte protoporphyrin increases in many erythrocyte disorders, and its measurement alone has low specificity [18]. The metal-free fraction represents 85–100% of the total in EPP and 50–85% in XLP, and less than approximately 50% in iron deficiency, anaemia of chronic disease and lead poisoning [18]. Zinc protoporphyrin also increases in haemolytic disorders and biallelic porphyrias, such as harderoporphyria and HEP [4]. Two patients with homozygous variegate porphyria (PPOX variants c.223G>T p.Val75Phe and c.1070A>C p.Asp357Ala, both of uncertain significance) were initially diagnosed as EPP because of photosensitivity and elevated erythrocyte protoporphyrin, but had zinc protoporphyrin predominance, blisters, fragility, scars and a plasma peak at 624 nm; the authors recommend a broad genetic panel and plasma scanning whenever erythrocyte protoporphyrin is predominantly zinc-bound [65].

In males, EPP and XLP are clinically indistinguishable, and the principal phenotypic difference is the greater frequency of liver disease in XLP [5]. An EPP phenotype without a variant in FECH or ALAS2 occurs in approximately 4% in the USA and 6% in the United Kingdom, where 94% of patients have a variant in one of these genes [4, 22]. Polymorphic light eruption, solar urticaria and drug-induced photosensitivity enter the clinical differential diagnosis and are excluded by normal protoporphyrin [4]. Late-onset protoporphyria requires investigation for myelodysplastic syndrome [4, 6].

7. Treatments and Risk Management Strategies

7.1. Porphyria cutanea tarda

Available guidance. In 2022, GeneReviews recorded the absence of clinical practice guidelines for F-PCT [1]. Since then, the Ipnet cutaneous porphyrias working group has published a consensus document for professionals (version 3, July 2024) [19] and the United States Porphyrias Consortium a practice review in the American Society of Hematology (ASH) educational programme [2]. The sources consulted do not identify a formal American Association for the Study of Liver Diseases (AASLD) guideline for PCT. Treatment aims for clinical and biochemical remission, with normalisation of porphyrins; transient cutaneous worsening and darker urine may occur initially [19]. Diagnosis should be confirmed before starting phlebotomy or antimalarials, which are ineffective in other bullous porphyrias [2].

General measures. Complete alcohol abstinence may itself induce remission; smoking cessation and discontinuation of oestrogens during treatment are recommended (discontinuation alone may lead to remission); after remission, hormone replacement therapy may be resumed, preferably transdermally [1, 18, 19]. Iron should not be taken unless deficiency is documented [19]. Photoprotection uses clothing and gloves because UV-filter sunscreens do not protect against visible light; physical filters containing titanium dioxide or zinc oxide may help [2, 19]. Until porphyrins decrease, direct sun and trauma should be avoided [2]. New blisters may be punctured with a sterile needle, preserving the roof without deroofing; topical corticosteroids may relieve lesions, with a risk of infection and atrophy [2, 19]. Vitamin D 800–1000 IU/day with monitoring and vaccination against hepatitis A and B are recommended [2, 19]. A low-iron diet is not essential, but limiting red meat and liver is reasonable, particularly with HFE variants; tea with meals reduces iron absorption, and adequate ascorbic acid intake is desirable without being primary therapy [1].

Phlebotomy. This is first-line treatment in most centres [1, 2]. One unit of approximately 450 mL is removed; regimens and targets differ between sources (following table). Haemoglobin, usually above 10–11 g/dL, is a safety limit rather than a therapeutic target [1]. Plasma porphyrins fall from an initial 10–25 µg/dL to below the upper limit of normal (approximately 1 µg/dL); new lesions stop with normalisation, but phlebotomy continues to the ferritin target, and chronic lesions and scars resolve slowly or persist [1]. According to the United States approach, phlebotomy ends when the target is reached, typically after 6–8 sessions, even if lesions and porphyrins remain abnormal, because they continue improving over months [2]; Saudubray's textbook states that 5–6 units at 2-week intervals suffice without marked overload [18]. Ipnet gives clinical remission at 6–9 months and biochemical remission at approximately 12 [19]. Adverse effects are transient dizziness and hypotension, and barriers are cost and access [2]. Contraindications are haemoglobin below 10 g/dL or haematocrit below 33% and poor venous access [66]. After remission, maintenance phlebotomies are generally unnecessary and ferritin may rise without relapse, except in HFE p.Cys282Tyr homozygous or p.Cys282Tyr/p.His63Asp haemochromatosis, where haemochromatosis guidelines apply and, according to Saudubray's textbook, ferritin is maintained below approximately 100 ng/mL, as perhaps also in patients with multiple relapses [1, 18, 19].

Low-dose hydroxychloroquine and chloroquine. The regimen is oral hydroxychloroquine 100 mg twice weekly or chloroquine 125 mg twice weekly, never more frequently because antimalarial or antirheumatic doses cause acute hepatocellular damage and exacerbate photosensitivity [2, 18, 19]. Use in PCT is off-label: the United States Plaquenil® (hydroxychloroquine) label authorises only malaria, rheumatoid arthritis and lupus [15]. Antimalarials accumulate in hepatocyte lysosomes and release large quantities of porphyrins; transient hepatocellular damage is mild at low doses [2]. Hydroxychloroquine is preferred over chloroquine for safety [2], and chloroquine is not recommended with elevated ferritin [1]. They are suitable when phlebotomy is contraindicated, not tolerated or inaccessible and in the absence of marked iron overload; they do not deplete hepatic iron [1, 2]. Treatment continues until at least one month after plasma porphyrin normalisation [66] or until biochemical remission has been established for several months [19]. Prior ophthalmological assessment is recommended, and retinal risk is minimal with this regimen for less than a year [2]; Singal's trial included eye examinations before treatment, at 3 and 6 months and at completion [66]. They are contraindicated in advanced liver and kidney disease [19]. Singal's trial also listed pregnancy, breastfeeding, psoriasis, retinopathy, glucose-6-phosphate dehydrogenase deficiency, hepatotoxic drugs, bilirubin >3 mg/dL, alanine aminotransferase (ALT) >200 U/L, international normalised ratio (INR) >1.4, creatinine >3 mg/dL, ferritin >600 ng/mL or ferritin above normal with HFE homozygosity or compound heterozygosity as contraindications, because patients with haemochromatosis respond poorly to chloroquine [66]. Combining an antimalarial with phlebotomy may help when full phlebotomy is not tolerated [1]. Relapse appears more frequent after hydroxychloroquine, based on limited retrospective data [2, 63].

Ferritin units ng/mL and µg/L are equivalent.

Hepatitis C and HIV. With direct-acting antivirals, the United States approach treats hepatitis C without additional PCT treatment unless eradication fails or there is marked iron overload; HIV infection should be optimised beforehand [2]. In trial NCT03118674, 15 patients with PCT and chronic hepatitis C (13 males, all genotype 1) received ledipasvir/sofosbuvir (Harvoni®) at recommended doses and durations, without phlebotomy or hydroxychloroquine; of 13 followed, 12 achieved hepatitis C cure and all of these had sustained clinical PCT remission [67, 68]. Before direct-acting antivirals, iron reduction made interferon more effective; this rationale no longer applies, but reduced iron still decreases hepatitis C severity and progression [1].

End-stage chronic kidney disease. Phlebotomy is limited by anaemia and hydroxychloroquine probably ineffective because mobilised porphyrins are poorly dialysed; cautious phlebotomy supported by recombinant erythropoietin may lead to complete remission, and iron chelation is an alternative, more expensive and less efficient [1, 2, 19]. Chelators described are deferasirox, deferiprone and desferrioxamine [1]. In a Portuguese patient on haemodialysis with hepatitis C, hydroxychloroquine was contraindicated and phlebotomies poorly tolerated; desferrioxamine produced good clinical outcomes but caused iron deficiency with transfusion dependence, and each reintroduction of iron caused recurrence until ferric carboxymaltose was tolerated without relapse or further transfusions [69].

Brazilian experience. In the Brazilian tertiary hospital, 72.4% of patients received antimalarial monotherapy, 22.9% antimalarial plus phlebotomy and 4.6% phlebotomy alone; time to normalisation of 24-hour urinary porphyrins was 38 months with combination treatment and 15 months with antimalarial alone (p=0.004), in a retrospective single-centre study without treatment randomisation [54].

Pregnancy. In women with F-PCT and iron overload, unusual during childbearing years, iron should be reduced before a planned pregnancy [1]. Hydroxychloroquine has no expected adverse fetal effects, and low-dose chloroquine used in rheumatic disease has not been associated with adverse fetal outcomes in reports, although high doses have embryonic effects in animals; United States labels require avoidance during pregnancy or breastfeeding unless benefit outweighs risk. Among chelators, data are reassuring for desferrioxamine, more limited for deferasirox and very limited for deferiprone [1].

Agents to avoid. Iron supplements, alcohol, tobacco, oral oestrogens, hepatotoxins such as hexachlorobenzene and sun exposure during the symptomatic phase [1].

7.2. Hepatoerythropoietic porphyria

There are no guidelines for HEP nor any treatment restoring UROD [3]. Treatment centres on strict sun avoidance, including long-wave UVA passing through glass, with clothing and opaque topical sunscreens, as in CEP [3, 18]. Superimposed infections should be treated promptly; PCT susceptibility factors and hepatic CYP450 inducers are avoided; vaccination against hepatitis A and B is given [3]. Low-dose chloroquine and oral charcoal, which binds porphyrins in the intestine, have been used with variable success; phlebotomy and chloroquine, effective in F-PCT, are generally ineffective in HEP [3]. In the Brazilian child, colestyramine and phlebotomies did not unequivocally improve biochemistry, and cimetidine was temporally associated with a fall in urinary porphyrins, a single-case observation [56]. There are no HEP-targeted clinical trials [3].

7.3. Protoporphyrias (EPP1, XLP and EPP2)

Guidelines. Current references are the Porphyrias Consortium consensus guideline for EPP and XLP diagnosis and management [20], the same consortium's guideline for protoporphyria-related liver dysfunction, with 29 recommendations graded using the American College of Cardiology and American Heart Association system [27], the Ipnet consensus document for professionals (version 4, July 2024, based on the Erasmus MC care pathway) [26] and the expert review from Zurich and Rotterdam [6]. The EPP (2017) and XLP (2019) GeneReviews are outdated regarding drugs [4, 5].

Photoprotection and non-pharmacological measures. Sun avoidance and opaque clothing are recommended for all; car window films and yellow window films are useful (checking road traffic legislation); broad-spectrum or tinted sunscreens containing zinc oxide or titanium dioxide, blocking some long-wave UVA (350–399 nm), are reasonable, whereas untinted and non-broad-spectrum sunscreens are unhelpful [20, 29]. Grey or smoked filters provide only partial protection [4]. Indoor lighting with little blue light may be considered, and caution is needed with recent high-intensity light sources [20, 26]. School and workplace adjustments, teacher and child education, psychological support and patient groups form part of care [20, 26]. Without access to afamelanotide, limited natural exposure or low-dose narrow-band UVB “hardening” phototherapy, increased slowly, may be considered, with uncertain efficacy [20]; Ipnet proposes it in early spring, 2–3 times weekly for 5–10 weeks under a porphyria centre's guidance, recognising that benefit is not universal [26].

Treatment of the acute phototoxic reaction. No study has evaluated treatment of acute phototoxicity. Cold compresses or cooling devices may be considered, although some patients report worsening with cold or heat; there is no evidence of benefit from opioids, oral or topical corticosteroids, antihistamines, paracetamol or non-steroidal anti-inflammatory drugs [20]. Ipnet allows that antihistamines and topical hydrocortisone may help mild reactions, without trials demonstrating this [29].

Afamelanotide (Scenesse®). Afamelanotide (Nle4-D-Phe7-α-MSH) is a long-acting synthetic analogue of α-melanocyte-stimulating hormone binding melanocortin 1 receptor (MC1R), increasing eumelanin, which absorbs light and has antioxidant activity, and exerting anti-inflammatory effects [6, 18, 20]. It is the only approved treatment for protoporphyrias and does not address the underlying mechanism [70]. The presentation is a 16 mg bioabsorbable subcutaneous implant (approximately 1.7 cm × 1.5 mm), inserted above the anterior superior iliac crest by a professional trained in the marketing authorisation holder's programme, every 2 months; in the European Union it is administered before and during periods of increased sun exposure, with total duration at the specialist's discretion, and prescribed only at recognised porphyria centres; the patient is monitored for 30 minutes after insertion [23, 24]. Half-life is approximately 30 minutes, more than 90% of the drug is released by day 5, levels fall below quantification by day 10 and the implant is resorbed in 50–60 days [24]. The United States guideline recommends it to prevent EPP phototoxic symptoms, with full skin examination by a dermatologist every 6 months [20]. The most frequent adverse effects in trials (125 patients receiving drug versus 119 vehicle, through month 6) were site reaction (21% versus 10%), nausea (19% versus 14%), oropharyngeal pain (7% versus 5%), cough and fatigue (6% versus 3%), hyperpigmentation (4% versus 0%), dizziness (4% versus 3%) and melanocytic naevi (4% versus 2%) [23]; pooled European data from 425 patients showed headache in 20% [24]. Warnings are severe hypersensitivity with anaphylaxis, requiring implant removal and no retreatment, and generalised hyperpigmentation with darkening of naevi and freckles, warranting full skin examination twice yearly; photoprotection should continue [23]. The European summary adds caution with a personal or family history of melanoma or other skin malignancies, increased site bruising with anticoagulants, acetylsalicylic acid or anti-inflammatory drugs, safety not assessed beyond 2 years, moderate influence on driving during the following 72 hours (somnolence, fatigue, dizziness, nausea) and a mandatory European patient registry [24]. During pregnancy there are no human data and the drug is not recommended; the EU requires effective contraception during treatment and for the following 3 months and prohibits use during breastfeeding [20, 24]. In the USA, access is limited by cost and the small number of administration sites [20].

Drugs without demonstrated efficacy. Because of lack of efficacy (class III), the United States guideline does not recommend β-carotene, cysteine, cimetidine, isoniazid, warfarin, quinacrine, oral zinc, N-acetylcysteine, vitamin C, omega-3 fatty acids, oral adenosine monophosphate, canthaxanthin, terfenadine, inosine, dithiothreitol with glycerol, pyridoxine or hydroxyethylrutosides [20]. A systematic review of approximately 25 studies did not establish efficacy of β-carotene, N-acetylcysteine or vitamin C [5]. Historical β-carotene regimens targeted serum carotene of 10–15 µmol/L with 2 to 10 capsules of 30 mg daily, started 6–8 weeks before summer [4]; the Brazilian book gives 60–180 mg/day [38]. Few patients find it useful [29]. Oral cimetidine 800 mg twice daily did not alter erythrocyte protoporphyrin in a crossover trial of 26 patients (+10.19% versus +5.24%; p=0.59) [71]. Isoniazid, reducing ALAS2 through pyridoxine depletion, was beneficial in the murine model but not in a patient pilot study, and higher doses were not tested because of hepatotoxic risk [18]. Oral Polypodium leucotomos extract (480 mg/day) as an adjunct in 8 patients improved quality of life at day 60 but not day 120 in an exploratory study [72].

Iron. Iron is the point of greatest divergence between sources because it has opposing effects in the different protoporphyrias.

Reports of iron in EPP1 include both improvement and increased photosensitivity and liver enzymes [4, 27], and the European review observed liver enzyme rises weeks after standard-dose iron [6]. In XLP, replacement in an iron-deficient patient reduced protoporphyrin and corrected anaemia, and a pilot study with oral iron reduced protoporphyrin [5].

Vitamin D, bone, alcohol, vaccines and contraception. The United States guideline recommends vitamin D screening and supplementation according to population standards [20]; European sources recommend vitamin D 800–1000 IU/day year-round in all patients because many remain deficient even during afamelanotide, and dual-energy X-ray absorptiometry (DEXA) at diagnosis or at least once in adulthood [6, 26]. Excessive alcohol should be avoided (a reasonable limit of one drink daily for women and two for men, with abstinence if aminotransferases are elevated), and all should be vaccinated against hepatitis A and B [27]. Without hepatic involvement, low-oestrogen oral contraceptives are reasonable (class IIa), and with liver dysfunction doses above 35 µg ethinylestradiol should be avoided [27].

Protoporphyria-related liver disease. Levy's guideline organises management into prevention, assessment, mild to moderate disease and advanced disease; treatment recommendations are summarised in the following table.

Evidence for these recommendations comes from cases and small series: chenodeoxycholic acid (15 mg/kg/day) reduced protoporphyrin in 5 patients; a 74-year-old woman in Child–Pugh C moved to Child–Pugh A with ursodeoxycholic acid titrated from 18 to 5 mg/kg/day over 6 months; colestyramine 12 g/day increased faecal protoporphyrin and improved tests and photosensitivity in one case, and 18 g twice daily normalised alkaline phosphatase and bilirubin in another; intravenous vitamin E 500 IU/day normalised tests in a cirrhotic patient [27]. GeneReviews includes activated charcoal among adsorbents interrupting protoporphyrin enterohepatic circulation [4]. Haemin contains approximately 8 mg elemental iron per 100 mg and causes overload with repeated doses [27]. The European review adds removal of hepatotoxins, oestrogens and iron in EPP1, treatment of hyperthyroidism, dose-dependent enzyme reduction during afamelanotide in observational studies and, in some centres, low-volume phlebotomies in EPP1 with strict monitoring because of the risk of stimulating synthesis; in severe forms it allows plasma exchange, erythrocyte exchange with or without haemodialysis, transfusions, haemin, hydroxycarbamide and chelators as bridges [6]. Acute cholestatic hepatitis is an emergency requiring management at a specialist centre [26].

Liver and haematopoietic stem cell transplantation. Liver transplantation is not curative because protoporphyrin originates in erythroid cells. Patient survival at 1, 5 and 10 years is 77–85%, 66–69% and 47–66%, comparable with other indications; biliary complications occur in 45–80% and graft recurrence in 65–80% of United States, Australian and European series (43% in the first year) [27]. In the USA and United Kingdom, the MELD (Model for End-stage Liver Disease) score at transplantation was comparable with other causes, without a standardised exception [27]. Without filters, up to 25% of patients suffered severe skin and serosal burns, including intestinal burns with perforation and sepsis, and filters blocking light below 470 nm are strongly recommended [27]. Allogeneic HSCT eliminates photosensitivity and prevents liver damage but has high morbidity and mortality, and who benefits is unknown; sequential liver and marrow transplantation prevents graft recurrence [5, 18, 27]. A 2-year-old child with XLP and stage IV fibrosis stabilised with HSCT without liver transplantation [5]; another, aged 2 years, with EPP due to two FECH variants and bridging fibrosis, improved in protoporphyrin and enzymes after HSCT but died of severe infections, acute respiratory distress syndrome and multiorgan failure [59]. Few patients will choose HSCT without severe liver disease [6].

Perioperative care and procedures. Lighting modification is unnecessary for endoscopy and short operations; prolonged surgery, such as liver transplantation, uses filters limiting transmission at 340–470 nm (for example, a yellow acrylate filter), and no anaesthetic or drug is specifically contraindicated [20]. Ipnet considers filters unnecessary except in long operations in cholestatic patients [26], and the European review adds preoperative erythrocyte exchange in severe cases [6]. Lasers and light therapies are safe outside 350–650 nm, with prior testing on a small area [20]; blue dental lasers may burn the gums [29]. Drugs precipitating acute porphyrias do not aggravate EPP, and the only restrictions are iron and hepatotoxic agents [18, 29].

Acquired protoporphyria. Late-onset protoporphyria in myelodysplastic syndrome may improve with treatment of the malignancy, as in a case treated with azacitidine [6, 18].

7.4. Congenital erythropoietic porphyria

Principles. There is no FDA (Food and Drug Administration)-approved treatment or specific treatment for CEP photosensitivity [7]. Management is multidisciplinary and follows Katugampola's algorithm, derived from 29 patients in four countries: rigorous skin and eye photoprotection for all, initial multidisciplinary assessment and review at prognosis-adjusted intervals [18, 62]. Initial assessment includes full blood count with reticulocytes and bilirubin, iron profile, calcium and vitamin D, bone densitometry, liver function (particularly in transfused patients) and dermatology, ophthalmology, dentistry and genetics consultations [7].

Skin. The only effective measure is blister prevention through light avoidance, including long-wave UVA through glass and fluorescent light: long sleeves, gloves and broad-brimmed hats; window films in cars, homes, schools and workplaces; replacement of LED and fluorescent lamps with reddish incandescent lamps or filtering screens; reflective zinc oxide or titanium dioxide sunscreens, which help but do not replace avoidance [7, 30, 31]. Because immediate pain is limited, patients may not perceive cumulative damage [18]. Trauma is avoided, and wounds are treated with antiseptics, dilute bleach baths, topical hypochlorous acid and topical, oral or intravenous antibiotics (sometimes suppressive) to prevent osteomyelitis and bone resorption [7, 30]. Surgery corrects severe mutilation (microstomia, ectropion, nasal reconstruction), laser hair removal treats facial hypertrichosis, and hand physiotherapy and occupational therapy form part of care [7, 31]. β-carotene and narrow-band UVB phototherapy provided no benefit [7, 30]. Afamelanotide has not been investigated in CEP; in one case it improved sun tolerance without effects on scarred areas [30].

Eyes, bone and teeth. Wraparound sunglasses, topical antibiotics for ulcers, scleritis and blepharitis, artificial tears and lubricants for ectropion, and corrective eyelid surgery; regular ophthalmology [7, 31]. Vitamin D supplementation and bisphosphonates for osteoporosis [7, 30]. Regular oral hygiene [31].

Haemolysis and suppression of erythropoiesis. Chronic transfusions every 2–4 weeks suppress erythropoiesis and reduce porphyrins and photosensitivity; GeneReviews gives a target haematocrit above 35%, and Erwin and Desnick's review reports efficacy with haematocrit above 32% in one section and maintenance above 35% in another [7, 30]. Transfusions cause iron overload requiring parenteral or oral chelation [7]. Hydroxyurea in severe cases and splenectomy, which may improve haemolysis and cytopenia, are other options [18, 30]. In Katugampola's series, oral charcoal, splenectomy and chronic hypertransfusion provided no benefit or had complications and a negative impact on quality of life [62]. Oral charcoal may increase faecal porphyrin loss in mild cases according to one source but has no demonstrated clear clinical benefit according to another; hydroxychloroquine, plasma exchange and haematin have no clear benefit [7, 18, 30].

Induction of iron deficiency. In a woman with CEP, iron deficiency due to gastrointestinal bleeding markedly improved disease, and off-label deferasirox successfully maintained it; marrow cultures confirmed ALAS2 reduction [73]. In cellular and murine models, deferiprone reduced ALAS2 and porphyrin production and, in mice, reversed photosensitivity and corrected anaemia at the highest dose [74]. In Colombes, in a 49-year-old woman homozygous for UROS p.Gly58Arg, phlebotomies initiated at 100 mL twice monthly and increased by 50 mL every 4–6 weeks to 300 mL (to avoid strong stimulation of erythropoiesis) depleted iron at 8 months (ferritin 10.4 µg/L) and reduced urinary and plasma porphyrins by 79% and 85%, with haptoglobin normalisation and marked photosensitivity improvement; a 3-month interruption caused relapse, and maintenance at 200 mL monthly sustained response at 18 months with haemoglobin above 10 g/dL [75]. The authors propose this strategy for patients with haemolysis without chronic transfusion requirements or without access to HSCT, potentially with a chelator initially [75]. Evidence comes from cases, and Ipnet considers it investigational for selected patients [31, 42].

Haematopoietic stem cell transplantation. HSCT is the only cure and normalises porphyrins with complete engraftment, but has significant morbidity and mortality and does not correct scars [30, 31]. It is recommended in transfusion-dependent patients, preferably in childhood, and Katugampola's algorithm proposes considering it for progressive symptomatic haemolytic anaemia and/or thrombocytopenia and poor-prognosis genotypes [18, 62]. In Katugampola's series, 5 of 6 transplanted children remained symptomatically cured up to 11.5 years later [62]. In the Necker experience (1994–2016; 6 patients, 3 transplanted twice following first graft failure), 4 were well 6–25 years later with near-normal porphyrins, 1 died of graft-versus-host disease and 1 of unexplained acute liver failure one year later with complete chimerism; almost all had elevated transaminases from the neonatal period and biopsies showed fibrosis and hepatic porphyrins more than 60 times normal, prompting the authors to recommend liver assessment before and after HSCT [76]. In a Pakistani series of 4 patients with matched sibling donors and myeloablative conditioning (busulfan 16 mg/kg and cyclophosphamide 160–200 mg/kg), all were alive, transfusion-independent and without photosensitivity at a median follow-up of 240 days [77]. The first patients transplanted in childhood are in their third decade, with limited long-term data; urinary and erythrocyte porphyrins monitor the graft [7]. The first HSCT in CEP, in 1991 in a 10-year-old girl, ended in death from cytomegalovirus infection [78]. The youngest reported case is a Canadian newborn homozygous for p.(Cys73Arg), with hydrops fetalis and growth restriction, diagnosed by genetic panel before 72 hours of life and transplanted at 3 months from an unrelated donor (busulfan, fludarabine and alemtuzumab); she developed thrombotic microangiopathy treated with eculizumab and recurrent pericardial effusion requiring pericardiectomy, and at 2 years had no skin lesions or hepatosplenomegaly, with normal blood count, markedly reduced but above-normal urinary porphyrins and erythrodontia [60]. The French multicentre registry of paediatric HSCT in CEP, from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), has been published [79]. The case in section 10 documents the first HSCT in an adult with congenital CEP [78].

Investigational therapies. Ciclopirox, a marketed antifungal, binds to an allosteric UROS site, stabilises missense variants without affecting catalysis and attenuated disease in the murine model [80]. Oral ciclopirox solution ATL-001 is in an open-label phase 1–2 N-of-1 trial in up to 6 adults (NCT07024316, started in January 2026, recruiting), with the primary outcome in photosensitivity lesions every 12 weeks through 48 weeks [81]; Ipnet reports completion of initial safety studies [31]. Proteasome inhibition produced partial metabolic correction in mice without haematological improvement and with neurotoxicity, and lentiviral gene therapy and corrected induced pluripotent stem (iPS) cells remain preclinical [18, 30].

Agents to avoid and surgery. Sun and UV; with liver dysfunction, cholestatic drugs such as oestrogens; during surgery and delivery, operating theatre light filters [7]. “Porphyrinogenic” drugs of acute porphyrias do not aggravate CEP [31]. Newborns with CEP and hyperbilirubinaemia should not receive phototherapy [30].

7.5. Comparative regulatory status

The sources consulted do not include afamelanotide authorisation or reimbursement data from the National Authority of Medicines and Health Products (INFARMED) in Portugal or the Brazilian Health Regulatory Agency (ANVISA) or National Commission for the Incorporation of Technologies (CONITEC) in Brazil.

7.6. Clinical trials

Afamelanotide and dersimelagon trials used different outcomes (pain-free sunlight hours versus minutes until prodrome) in different patients, seasons and durations, so results do not permit indirect drug comparisons. Absolute differences are modest in minutes per day, and the first phase 3 dersimelagon trial was negative for the primary outcome, improving only patient global impression of change; the positive INSPIRE result is known only from press releases and the press [85, 94]. For bitopertin, the FDA accepted the surrogate marker effect but considered it uncertain whether an approximately 40% reduction with 60 mg predicts clinical benefit, particularly because trials showed no association between protoporphyrin change and sun exposure; in AURORA, pain-free sunlight hours (secondary) did not order by dose (133.9; 175.1 and 153.1 h for placebo, 20 and 60 mg) [88, 97]. AURORA authors acknowledge the small sample, short follow-up and absence of multiplicity adjustment [96]. In PCT, Singal's trial had high exclusion for non-adherence in the phlebotomy arm (12 of 22) and did not demonstrate formal non-inferiority [66]. Afamelanotide observational studies show treatment persistence: in a single-centre post-authorisation safety study of 117 patients, 98% continued, outdoor time increased by 6.1 h weekly and quality of life by 14% [100]; in Rome and Zurich, 115 patients received 1023 implants over up to 8 years and quality of life rose from 31% to 74% of the maximum [101]; in Austria, among 20 patients treated in 2023, light tolerance increased from a median of 15 to 250 minutes [102]. These studies have no control group.

7.7. Developments over the past twelve months

The search did not find APOLLO results or a European decision on adolescent afamelanotide by 10 October 2026; this does not demonstrate their non-existence. The bitopertin study in protoporphyric hepatopathy (NCT07123363) was withdrawn without participants, and the expanded access programme (NCT07603401, ≥12 years) and HELIOS extension (NCT05883748) continue [103]. The long-term dersimelagon extension (NCT05005975; 286 patients) is expected to end in December 2027 [106]. Bitopertin was developed for schizophrenia, with negative phase 3 trials in that indication [107]; it inhibits erythroblast glycine transporter GlyT1 and reduces ALAS2 substrate, reducing protoporphyrin and liver disease in murine EPP and XLP models [108]. Gene therapy, ALAS2 mRNA silencing by RNA interference and bifunctional peptide ligands of transferrin receptor 1 targeting erythroid progenitors are preclinical [18], as are, as a future possibility, ABCG2 inhibitors [27]. Small trials are registered for oral iron in protoporphyrias (NCT02979249, 16 patients, completed with registry results; NCT05572125, 10 patients) and topical dihydroxyacetone (NCT05780840, 6 patients, status unknown), and, in PCT, deferasirox (NCT00599326, phase 3 pilot with 10 patients; NCT01284946, phase 2 with 45 patients, status unknown) [103]. A 2026 review concludes that dersimelagon and bitopertin have effects versus placebo but require better characterisation of safety and efficacy and comparative data with afamelanotide [70].

7.8. Special populations

Pregnancy and breastfeeding. In EPP, pregnancy does not increase perinatal risk and requires neither additional neonatal monitoring nor changes in photoprotection [20]; afamelanotide is not recommended during pregnancy and is not used during breastfeeding [20, 24]; iron may limit the improvement in photosensitivity observed during pregnancy [29]. In PCT, pregnancy is high risk and iron should be reduced before conception when overload is present [1, 53]. In CEP and protoporphyrias with cholestasis, delivery room and operating theatre lights should have filters [4, 7].

Children and adolescents. No therapy is approved for paediatric use [20]. Ipnet reports off-label afamelanotide use in adolescents over 16 years in some countries [26]. In a 9-year-old Swiss girl with severe EPP, who missed weeks of school after a prolonged phototoxic reaction, off-label afamelanotide, after family discussion, caused only mild nausea and allowed return to school on day 4, with disease-specific quality of life rising from 0 to 55.6 in 5 weeks; free protoporphyrin did not change [104]. In 2025, the marketing authorisation holder reported administration to a 9-year-old paediatric patient in Switzerland and states that, since 2021, paediatric patients have been treated at European centres with reimbursement [109]. The sources consulted do not describe formal transition programmes; adulthood marks the start of the approved afamelanotide indication in both jurisdictions [23, 24].

Older people. Data above 65 years are limited (10 patients in trials), and the European summary does not recommend afamelanotide above 70 years [23, 24].

Chronic kidney disease. In PCT during dialysis, erythropoietin with small-volume phlebotomies or chelation is used [2, 19]; afamelanotide is contraindicated in renal impairment in the EU [24].

7.9. Divergences between United States and European guidelines

Regarding threshold differences, both positions agree on the essential point: substantially elevated and predominantly metal-free protoporphyrin is diagnostic, and an increased zinc fraction points to XLP or another cause. For ultrasound and iron, differences are real and reflect the scarcity of longitudinal studies [27].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by entity

8.2. Particularities by entity

In F-PCT, most patients inherited the variant from an asymptomatic heterozygous parent, and few have an affected parent; the variant may be de novo, in an unknown proportion, and a negative family history is inconclusive without parental testing, whose leucocyte DNA may not reveal mosaicism [1]. Testing at-risk relatives should not change management because of low penetrance, but is reasonable so carriers can avoid susceptibility factors, namely alcohol, oral oestrogens, tobacco and iron [1]. Prenatal diagnosis and PGT are possible but do not predict disease [1].

In HEP, parents are obligate heterozygotes and therefore F-PCT carriers, generally asymptomatic, with a risk of manifesting disease if exposed to susceptibility factors [3]. If only one parent carries the variant, a de novo variant in the proband, parental mosaicism or, with apparent homozygosity, an undetected deletion or uniparental isodisomy should be considered [3]. The proband's uncles and aunts have a 50% probability of heterozygosity [3].

In EPP1, heterozygotes and homozygotes for the hypomorphic allele are asymptomatic and not at risk of disease; children of an affected individual necessarily receive a loss-of-function variant or the hypomorphic allele, and risk depends on the allele transmitted by the other parent [4]. The simple 25/50/25 estimate for siblings applies when parental genotypes are known; pseudodominance may occur in populations where the hypomorphic allele is frequent [4]. Carrier testing requires identified familial variants, and biochemistry is unsuitable for this purpose [4]. Genetic counselling is recommended for couples with a personal or family history of protoporphyria planning children [20].

In XLP, an affected male's father is not a carrier; a mother with more than one affected son is an obligate heterozygote and, if the variant is not detected in her leucocyte DNA, probably has germline mosaicism [5]. In a simplex case without a parental variant, sibling risk is below 1% [5]. Female probands may have inherited the variant from mother or father, or have it de novo [5].

In autosomal recessive CEP, asymptomatic carriers have approximately 50% UROS activity and are not at risk of disease [7, 18]. If only one parent carries the variant, a de novo variant or uniparental isodisomy is considered [7]. In X-linked CEP, maternal aunts are at risk of being carriers [7].

8.3. Cascade testing and early assessment of relatives

Siblings at risk of CEP should be assessed as newborns or infants to avoid phototherapy, institute strict photoprotection and monitor haemolytic anaemia, by molecular testing when variants are known or, otherwise, urinary or erythrocyte isomer I porphyrins [7]. Siblings at risk of EPP1 or XLP should be assessed at the same age for early photoprotection and liver surveillance, by molecular testing or erythrocyte protoporphyrin with metal-free predominance [4, 5]. In HEP, testing at-risk relatives enables counselling on photoprotection and avoidance of risk factors [3]. When molecular diagnosis is unconfirmed, proband DNA banking is recommended [4, 7].

8.4. Prenatal diagnosis, PGT and counselling of minors

Molecular prenatal diagnosis and PGT are possible after identifying familial pathogenic variants in all entities, and in CEP also by biochemical methods (section 5.7) [7, 31]. Counselling is ideally performed before pregnancy and offered to affected young adults, carriers or those at risk of being carriers [1, 5, 7]. The sources consulted do not specifically address predictive testing in asymptomatic minors; in CEP and protoporphyrias, childhood testing is justified by the direct benefit of early photoprotection and surveillance [4, 7], whereas in F-PCT, without childhood manifestations, the result does not change management at that age [1, 3].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The table figures measure different things and should not be added or directly compared. In EPP, the European Porphyria Network prospective study (335 new patients with hereditary porphyria in 11 countries over 3 years) calculated prevalence by multiplying incidence by mean disease duration and found greater between-country heterogeneity in EPP than other porphyrias [110]. The UK Biobank genetic estimate, 1.7 to 3.0 times higher than diagnoses, indicates underdiagnosis [21]. The afamelanotide marketing authorisation holder cites 1:140,000 in Europe [82]. In PCT, the F-PCT estimate of 1:20,000 reported in HEP GeneReviews differs from 8 per million in F-PCT GeneReviews, and the Brazilian 1:10,000 value specifies neither population nor period [1, 3, 38]. In Orphanet, European CEP incidence appears with ambiguous units across secondary sources; the tabulated value follows the Orphanet convention (per 100,000) and corresponds to the class below 1 per million [14, 42].

9.2. Ancestry, sex and founder populations

EPP frequency follows that of allele c.315-48T>C: disease is concentrated in northern Europe and Japan, rare in African people and almost absent in sub-Saharan Africa [6, 26, 47]. The Netherlands has prevalence of approximately 1:75,000, attributed to a founder effect, and Wales 1:200,000 [4]. The proportion of XLP among protoporphyria patients is approximately 10% in North America (9.7% in the Porphyrias Consortium cohort), two to five times higher than in western Europe; in the United Kingdom it is approximately 2% [5, 22, 25]. In the United States cohort, sex distribution was equal (113 females and 113 males) [22]. In PCT, the two UROD founder variants account for 74% of pathogenic variants in Norway [3]; male predominance is slight in northern Europe and the USA and marked in southern Europe [19]. The South African variegate porphyria founder (PPOX p.Arg59Trp, of Dutch ancestry) is relevant in the differential diagnosis of blisters [18]. CEP is pan-ethnic, and affected consanguineous families have been described, for example in Canada and a Pakistani family [30, 60, 75]; the Pakistani HSCT series comes from a lower-middle-income country [77]. In African iron overload, dietary iron associated with traditional beer predisposes to PCT [1].

9.3. Portugal and Brazil

The sources consulted do not include prevalence estimates for Portugal or Brazil. Available data are a Portuguese case of PCT during haemodialysis, treated in Lisbon with desferrioxamine and ferric carboxymaltose [69]; the cohort of 87 PCT patients at a Brazilian tertiary hospital (2002–2017), with male predominance of 1.8:1, median age 49 years, family history in 19.5% and treatment mainly with antimalarials [54]; and a Brazilian child with HEP genetically diagnosed in Brazil [56]. The Brazilian reference book cites national studies, including a 2012 thesis on 60 patients with PCT and HFE variants [38]. The Ipnet-endorsed centre list includes neither Portuguese nor Brazilian centres, and no patient organisation from these countries appears in the Ipnet list [32, 111].

9.4. Other special populations

Patients with hepatitis C and HIV, frequently coinfected, those on haemodialysis and women taking oral oestrogens or hormone therapy are PCT risk groups [2, 19]. The oestrogen association was identified in men treated for prostate cancer [2]. Patients with myelodysplastic syndrome may develop acquired protoporphyria or CEP [4, 7].

9.5. Reference networks and patient organisations

The sources consulted identify no ERN expressly including cutaneous porphyrias. The International Porphyria Network (Ipnet, successor to the European Porphyria Network) endorses specialist centres in Colombes and Bordeaux (France), Chemnitz (Germany), Petach Tikva (Israel), Bergen (Norway), Barcelona (Spain), Stockholm (Sweden), Zurich (Switzerland), Rotterdam (Netherlands), Cardiff and Dundee (United Kingdom), Brussels and Leuven (Belgium), Milan and Modena (Italy) and Shijiazhuang (China) [32]. In the USA, the Porphyrias Consortium forms part of the National Institutes of Health (NIH) Rare Diseases Clinical Research Network [1, 27]. Patient organisations include the American Porphyria Foundation (with its “Find a Porphyria Expert” service), the United Porphyrias Association, maintaining the recommended laboratory list, the British Porphyria Association, the Global Porphyria Advocacy Coalition, the Canadian Association for Porphyria, AFMAP in France, the Asociación Española de Porfiria, the Swiss Society for Porphyria, the Swedish RMP association, the Dutch EPP patient association, the Porphyria Association Denmark and Porphyria South Africa [4, 7, 20, 111].

10. Illustrative Clinical Case

Peterlin and colleagues, from Nantes and Colombes, described in 2024 a man with CEP diagnosed at 3 years, without a family history [78]. Isomer I porphyrin accumulation was massive: erythrocyte porphyrins 41.1 µmol/L (normal <1.9), plasma 2668 nmol/L in the article table (2520 in the text; normal <20) and urinary 8868 nmol/mmol creatinine (normal <30). The UROS genotype was compound heterozygous, in trans, NM_000375.3:c.217T>C p.(Cys73Arg) and c.683C>T p.(Thr228Met) [41, 78]. Haemolytic anaemia did not require transfusions, but cutaneous and ocular disease progressively worsened throughout life: severe photosensitivity, diffuse hypopigmented sclerotic plaques, chronic ear and hand wounds leading to multiple digital amputations and corneal transplants [78].

At 44 years, mild pancytopenia developed with asthenia, without splenomegaly (haemoglobin 8.6 g/dL, platelets 100 × 10⁹/L, neutrophils 1.3 × 10⁹/L); marrow was normocellular, without excess blasts, with dyserythropoiesis in at least 20%, erythroblastosis and haemophagocytosis, and a normal karyotype; the patient became transfusion-dependent [78]. Without a sibling donor, at 46 years he received peripheral blood HSCT from a matched unrelated donor, with myeloablative FB4 conditioning (fludarabine 30 mg/m²/day from D−6 to D−2 and busulfan 3.2 mg/kg/day from D−6 to D−3), antithymocyte globulin 2.5 mg/kg/day on D−2 and D−1, ciclosporin and mycophenolate. Engraftment occurred on D+30, with complete chimerism, without severe infections or liver dysfunction; he developed grade 3 acute intestinal graft-versus-host disease on D+91, treated with corticosteroids, discontinued systemic immunosuppression in month 7 and retained mild chronic ocular graft-versus-host disease controlled with eye drops [78].

Urinary porphyrins fell from 8868 to 308 nmol/mmol creatinine on D+67 and to 54 at 5 years; plasma levels from 2668 to 21 nmol/L at 5 years; erythrocyte levels from 41.1 to 0.65 µmol/L, and uroporphyrin fell from 59.1% to approximately 10% of erythrocyte porphyrins, with protoporphyrin IX becoming dominant. Slightly above-normal values were attributed to non-erythroid synthesis, particularly hepatic, which HSCT does not correct [78]. At 5 years, the patient had no fragility, excoriations, wounds or nasal or auricular chondritis, pain had disappeared, sclerotic lesions had regressed and photosensitivity had disappeared, to the point of swimming in a T-shirt [78]. Figure 1 of the article shows the ear (erosions, crusts and scars) and hand (digital amputations, erosions and hypopigmented scars) before transplantation and healing without active wounds afterwards: Figure 1 from Peterlin et al., 2024 (CC BY licence) [78].

The case illustrates CEP genotype–phenotype correlation: the combination of p.(Cys73Arg), with less than 1% activity, and a more stable missense variant, p.(Thr228Met), produced disease without childhood transfusion dependence but with cumulative mutilation [30, 78]. It also illustrates progression to marrow failure with dyserythropoiesis in adulthood. The authors describe it as the first published HSCT in an adult with congenital CEP and suggest considering HSCT for childhood CEP that is not severe but worsens progressively in adulthood [78]. This approach does not correspond to recommended practice: HSCT is indicated mainly in children with progressive haemolytic anaemia, thrombocytopenia, transfusion dependence or poor-prognosis genotypes, and has significant morbidity and mortality, including the unexplained liver dysfunction reported after transplantation [18, 62, 76]. In this patient, cytopenia with transfusion dependence provided a haematological indication for transplantation.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

PCT. Most patients enter remission with phlebotomy, antimalarials or hepatitis C cure, and most do not relapse, although relapse rate is unknown and relapses may appear more than 2 years after treatment, particularly with resumed alcohol consumption [2, 18, 19]. Relapses respond to another treatment course [18]. PCT is associated with greater HCC risk (aHR 19.7), biliary tract cancer (aHR 6.8) and premature death (aHR 1.5) in the Norwegian national cohort, partly explained by lifestyle factors [16]. Glucose metabolism abnormalities develop in 41% of patients followed for at least 10 years [52].

HEP. It is usually more severe than PCT and does not respond to its treatments; no increased HCC risk has been identified [3, 18].

Protoporphyrias. Severity is generally stable and life expectancy not reduced except in patients with advanced liver disease; protoporphyrias do not increase mortality outside rare cases of liver failure [5, 18, 27]. A progressive protoporphyrin rise precedes hepatic complications [4]. After liver transplantation, 10-year survival is 47–66% and graft recurrence 65–80% [27]. Quality of life and employment are substantially affected [6, 18].

CEP. Life expectancy is often reduced by infections and haematological complications; early onset and haematological complications are adverse prognostic factors [18, 61]. The Brazilian book states that most patients reach adulthood [38]. Successful HSCT virtually eliminates photosensitivity, with follow-up up to 25 years, but not scars, and may be followed by liver dysfunction [7, 31, 76].

11.2. Surveillance

AST: aspartate aminotransferase. In EPP, GeneReviews gave liver tests every 6–12 months [4]; current guidelines recommend them at diagnosis and annually when normal, and every 6 months when liver injury is present [27]. In XLP, GeneReviews groups tests into an annual assessment [5]. Worsening photosensitivity warrants more frequent monitoring because of possible liver disease [26].

12. Summary and Final Considerations

Cutaneous porphyrias share a common mechanism, activation of accumulated porphyrins by visible light in the Soret band, but divide into two phenotypes guiding all clinical reasoning. Water-soluble porphyrins in PCT, HEP and CEP cause fragility, blisters, scarring and hypertrichosis, whereas lipophilic protoporphyrin in EPP1, XLP and EPP2 causes immediate phototoxic pain with few visible lesions and hepatobiliary disease. Diagnosis is biochemical: plasma and urinary porphyrins with fractionation for blisters, and erythrocyte protoporphyrin fractionated into metal-free and zinc protoporphyrin for phototoxic pain, with light-protected samples. Molecular testing confirms, distinguishes EPP1 from XLP, identifies higher hepatic-risk genotypes and enables counselling but does not replace biochemistry, particularly in PCT, where approximately 80% of patients have no UROD variant, and in EPP, where the hypomorphic intronic allele c.315-48T>C is detected only if test design includes it.

PCT is the most frequent and most treatable porphyria. It results from iron-dependent hepatic UROD inhibition, with accumulated susceptibility factors (alcohol, hepatitis C, HIV, oestrogens, smoking, HFE, end-stage kidney disease), and responds to phlebotomy or low-dose hydroxychloroquine, 100 mg twice weekly, used off-label; in hepatitis C, direct-acting antivirals may suffice. United States and European sources differ in ferritin targets and phlebotomy intervals, and long-term surveillance should consider relapse, diabetes and hepatocellular carcinoma, whose increased risk was demonstrated by the Norwegian cohort. HEP, the biallelic UROD form, begins in childhood, is severe and does not respond to these measures.

In protoporphyrias, photoprotection targeting visible light is the foundation, afamelanotide is the only approved drug and only for adults in the USA and EU, without funding in the English NHS, and oral drugs under development are at different stages: dersimelagon had one negative and one positive phase 3 trial, the latter known through press releases, with an FDA decision reported by the press for February 2027, and bitopertin received a complete response letter because protoporphyrin reduction was not accompanied by demonstrated clinical benefit, with APOLLO awaited. Iron has opposing effects in EPP1 and XLP, vitamin D and bone require surveillance, and liver disease, rare but severe, requires annual monitoring and early referral; United States and European guidelines diverge on baseline ultrasound, fractionation thresholds and iron supplementation.

CEP, ultra-rare and mutilating, has HSCT as its only cure, reserved mainly for children with severe haematological disease; alternatives include rigorous photoprotection, transfusions with chelation, induction of iron deficiency by phlebotomy or chelator in selected patients and, under investigation, pharmacological chaperones such as ciclopirox. Genetic counselling varies between entities, from low-penetrance dominant inheritance in F-PCT to recessive inheritance with a common hypomorphic allele in EPP1 and X-linked inheritance in XLP and GATA1-related CEP, and early assessment of siblings at risk of CEP and protoporphyria enables avoidance of neonatal phototherapy and institution of photoprotection from birth.

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