The porphyrias are rare metabolic disorders that result from a primarily hereditary dysfunction of one of the eight enzymes along the haeme biosynthetic pathway (Fig. 1) [1, 2]. Erythropoietic protoporphyria (EPP; OMIM 177000) is because of a marked catalytic deficiency of ferrochelatase (FECH, E.C. 4.99.1.1), the last enzyme in haeme biosynthesis [3]. Because of its often subtle and unspecific clinical symptoms, the disorder can be overlooked for years. This can result in a major delay between disease onset and diagnosis and in a high degree of suffering in affected individuals [4]. Therefore, it is important to update physicians and health care workers regularly on clinic, aetiopathology, diagnosis, complications and therapy of the disorder. The haeme biosynthetic pathway. X-linked dominant protoporphyria results from increased activity of ALA synthase 2, whereas erythropoietic protoporphyria is because of a catalytic deficiency of ferrochelatase. In EPP, there is no apparent racial or sex predilection. Despite of its rarity, it is the most frequent form of childhood porphyria [1-3]. A major challenge in EPP is that skin symptoms may be discrete and hardly notable although the patients experience a considerable cutaneous discomfort upon ultraviolet (UV) light exposure. Skin sensations include pain, burning, stinging and itching within minutes of sun exposure. These subjective symptoms of acute photosensitivity are accompanied by erythema and swelling. Less frequently, petechiae, purpura and vesicles may occur. Commonly, photosensitivity commences early in infancy or childhood. The symptoms are confined to the sun-exposed areas of the body and worsen in spring and summer. If the diagnosis is delayed, continuous UV light exposure can lead to lichenification, postinflammatory hyperpigmentation and scarring, particularly over the knuckles and on the nose [2-4]. The differential diagnosis includes other photo-aggravated dermatoses and hereditary skin disorders like solar dermatitis, solar urticaria, polymorphous light eruption, lipoid proteinosis, hydroa vacciniforme and lupus erythematosus [2]. The most important differential diagnosis, however, is X-linked dominant protoporphyria (XLDPP; OMIM 300752). This very rare disorder has only recently been recognized as an own entity and is clinically undistinguishable from EPP (Table 1) [3, 5]. In patients with EPP, FECH deficiency leads to an overproduction and massive accumulation of lipophilic protoporphyrin (PP) in the skin, liver and other organs. PP is a metal-free porphyrin that shows a strong absorption peak in the blue wavelength region of the visible spectrum between 400 to 410 nm and acts as a photosensitizer. Although there is no clearly defined single pathway that can explain the photosensitization in EPP, excited PP exerts its phototoxic effects predominantly through the generation of reactive oxygen species (ROS) [2]. ROS can induce lipid peroxidation, oxidation of amino acids and mediator release from mast cells, contributing to the acute photosensitivity and protein cross-linking leading to cell membrane damage and cell death [6-9]. Beside the cutaneous manifestations, the most important complication in EPP is the development of cholestasis with rapid accumulation of PP in hepatobiliary structures resulting in severe liver damage and hepatic failure. Although progressive liver failure rarely occurs, about one-third of patients with EPP show biochemical liver abnormalities [3, 10]. Therefore, we advise our patients to have liver function tests performed bi-annually and an abdominal ultrasound once a year. The diagnosis of EPP is based on the clinical symptoms and verified by a significant increase in free erythrocyte PP of more than five times the normal level of ∼1.2 μmol L−1 [11, 12]. Because PP is a hydrophobic metabolite, it is not renally excreted. Hence, urinary porphyrin values are usually normal [2, 11, 12], and indeed, one of the most frequent mistakes observed in daily practice is that physicians try to confirm or exclude the tentative diagnosis of EPP by analysis of a urine sample rather than a blood sample. On the genetic level, EPP is a complex disorder. Classic EPP is caused by inactivating mutations in the FECH gene on chromosome 18q21.3 [13]. By contrast, activating mutations in the ALAS2 gene on chromosome Xp11.21 give rise to the phenotype observed in XLDPP, which is similar to that seen in EPP [5] (Table 1). It is clear now that the cutaneous symptoms in EPP arise from combined inheritance of a heterozygous FECH mutation on one paternal allele with a functional intronic FECH polymorphism, IVS3-48C, in trans to the mutation [14, 15]. Thus, the skin phenotype in EPP is associated with a semi-dominant inheritance mode. Recent studies revealed that the frequency of the hypomorphic allele IVS3-48C shows a high degree of variability in different ethnic groups, which certainly has an influence on the currently available incidence and prevalence numbers of EPP [16]. In exceptional cases, a recessive inheritance mode with mutations on both alleles of the FECH gene has been described [17]. Additionally, late onset of the disease after the age of 40 years because of sporadic somatic FECH mutations can be seen in a small number of patients with myelodysplasia or myeloproliferative disorders [18]. Over the last years, several countries have recognized the necessity and benefits of initiating national centralized registers for hereditary disorders as, e.g. the national database on porphyrias at the Porphyria Centre Sweden in Stockholm. As with all rare genetic diseases though, epidemiological studies and evaluation of the disease burden within a specific population may prove difficult. With this in mind, we would like to express our utmost respect and compliments for the huge body of work delivered by Wahlin et al. [19] who shed new light on EPP in Sweden in this month's issue of the Journal of Internal Medicine. By means of a cross-sectional epidemiologic study, the authors tackle the challenge to provide an actual overview on the frequency and important characteristics of the disease in their country. The results are presented in a stringent and well-structured fashion and put into context with previous data from other porphyria research groups. Wahlin and colleagues show that the prevalence of EPP in Sweden lies within the previously published range of 1 : 75 000 (the Netherlands) to 1 : 200 000 (Wales), suggesting that the proportion of affected individuals does not significantly differ from that of other European populations [3]. Rightly, though they speculate that the real prevalence may be higher because many patients are not diagnosed in due time. This is reflected by the enormous discrepancy between the common median age of disease onset around 3 years and the late diagnosis around the age of 22 years. But these patients are not only left alone with their burning and painful skin. In addition, they experience incomprehension in their immediate surrounding, e.g. the family, at work or when seeking help from physicians [4]. Consequently, the authors find a significant impact of the disease on quality of life, in perfect accordance with previous studies [20]. An important finding is that there is only a neglectable intra-individual variation in erythrocytic PP levels. Hence, it does not seem necessary to repeat these determinations regularly because there is no apparent correlation between the blood levels of free PP and an associated feature of the disease such as photosensitivity, vitamin D deficiency or hepatic injury. Because fulminant liver disease is a precarious complication, one of the most important challenges in EPP is that we currently do not have a reliable prognostic marker to estimate the risk for the occurrence of hepatic failure in these patients. A better understanding of the molecular mechanisms governing the development of liver injury, however, could lead to the identification of suitable molecular markers. In this context, it is important to emphasize that in protoporphyria an association between specific inheritance patterns and the possible phenotypes seems to evolve, namely (i) acute photosensitivity, independent of the underlying genetic defect and inheritance pattern [21]; (ii) severe liver injury with hepatic failure, apparently strongly associated with FECH null mutations [22, 23] and probably also more frequent in patients with autosomal recessive EPP [17] and X-linked dominant protoporphyria [5, 20]; and (iii) palmar keratoderma, exclusively observed in autosomal recessive EPP [24, 25]. As pointed out by Wahlin et al., the currently available therapeutic options in EPP are largely dissatisfying. Regarding prevention and treatment of cutaneous photosensitivity, the recently published results of a phase II clinical trial on CUV1647 are encouraging [26, 27]. In the meantime, more patients with EPP have been enrolled in two multicenter clinical phase III trials in several European countries and the United States to evaluate the effectiveness of this drug in a larger cohort of patients. CUV1647 stimulates the physiological production of melanin, resulting in increased cutaneous pigmentation, and is also supposed to reduce the amount of ROS that are thought to cause pain, burning and stinging. In the case of hepatic failure, liver transplantation is a therapeutic option. However, most patients experience a recurrence of EPP liver disease, because the excess production of PP by the erythroid tissue remains unchanged [28]. A possible solution for this problem might be sequential liver and bone marrow transplantation. In a single patient, this therapeutic intervention led to amelioration of the severe phenotype, resolving photosensitivity and halting EPP-associated liver graft injury [29]. In conclusion, EPP should be excluded in all photosensitive children, especially when discomfort is disproportionate to the extent of the cutaneous lesions. In rare instances, skin symptoms might even be completely absent in early childhood. Timely diagnosis and the differentiation from other photodermatoses are important because the disease can be associated with a considerable decrease in quality of life and severe hepatic complications. To prevent that patients with EPP are labelled as hysterical, hypochondriac or malingering, the awareness for this metabolic disorder has to be heightened, not only in dermatologists but also in paediatricians and general practitioners who might see these patients on first consultation. When liver disease develops, referral to an experienced internist or gastroenterologist for specific treatment of the hepatic complications is mandatory. No conflicts of interest to declare. Jorge Frank is board member of the European Porphyria Initiative (EPI) and the European Porphyria Network (EPNET) and is, in part, supported by grant no. A04155HS, GIS-Institut des Maladies rares: Network on rare diseases to the European Porphyria Initiative (EPI), a grant from the European Union to the European Porphyria Network (EPNET), Program of Community Action in the Field of Public Health, project no. 2006107, and a grant from the Research Committee of the Heinrich-Heine University Düsseldorf, Germany, project no. 9772425.
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