EPP manifests clinically by skin symptoms of immediate painful photosensitivity 27. This manifestation starts usually in early infancy or childhood, upon the first sun exposures. Skin stinging, prickling and burning on exposed areas are the initial symptoms experienced by the patient during or shortly after sun exposure. These symptoms may have a variable duration, depending on the intensity and duration of sun exposure. If the exposure has been long enough, erythema and oedema may appear, together with petechiae in some cases. Areas affected are the face and dorsa of the hands, but photosensitivity reactions can also appear on any exposed skin area. Reactions may persist for hours up to several days. The appearance of vesicles or bullous lesions characteristic of other forms of cutaneous porphyria is unusual but may occur (Fig. 2, 3). Nail lesions (photoonycholysis and transversal leuconycholysis) are possible associated manifestations.

Late-onset cases have been reported but are exceptional and related to haematologic malignancies, although cases without this association have been described 8910.

Repeated photosensitivity episodes result in altered skin appearance with permanent changes, such as skin thickening with a waxy or leathery appearance, and areas of hyperkeratosis. These lesions are usually located on the dorsa of the hands and face, as these are skin areas usually exposed (Fig. 4). The lips show linear furrows and pseudo-rhagades that arte also characteristic. In contrast to other forms of cutaneous porphyria, lesions of milia, hypertrichosis or hyperpigmentation do not appear. This last cutaneous sign may only appear in patients with severe hepatic involvement presenting with cholestasis, itching and jaundice 2.

Seasonal palmar keratoderma has been reported in some EPP patients and in addition this may indicate autosomal recessive inheritance of the disease 11.

In EPP, the degree of severity of the hepatic manifestations is variable. Hepatic disease in EPP may include: cholelithiasis with possible obstructive episodes and chronic liver disease evolving to rapid acute hepatic failure 1213.

The incidence of cholelithiasis is frequent in EPP (about 20% of patients). Gallstones with high protoporphyrin content are generated due to the accumulation of insoluble protoporphyrin and increased biliary protoporphyrin concentration 7.

Liver disease develops in association with EPP in 1-4% of cases 56, with usual features of visceral enlargement and portal hypertension. Liver disease in protoporphyria is related to the excess protoporphyrin cleared by the entero-hepatic circulation leading to paracrystalin protoporphyrin deposition in hepatocytes and precipitation in the biliary canaliculiy. The percentage of patients who will develop liver disease is not established, nor specific factors that may influence its development. It is not possible to predict whether or not acute hepatic failure will occur. Studies have revealed that an increase in coproporphyrin urinary excretion, together with a change in isomer predominance from isomer III to isomer I, and increasing levels of protoporphyrinaemia may precede this complication 14.

Progression of protoporphyric hepatic deterioration leads to splenomegaly, splenic sequestration of erythrocytes with haemolysis (which increases erythropoiesis) and protoporphyrin generation ending in fulminant hepatic failure 131415.

Patients who have FECH mutations on both alleles or a gain of function mutation of ALAS2 3 have an increased risk of liver disease though together they account for only a small proportion of those with liver disease.

An unsual neurological syndrome has been described with progressive polyneuropathy, swallowing difficulties and respiratory distress in several patients with end-stage liver disease due to protoprophyria 16. Oral mucosa or eye lesions in EPP patents have recently been reported for the first time by Tsuboi H et al. 17.

Cutaneous lesions result from the presence of protoporphyrin in erythrocytes and plasma in skin vasculature. Histologically, hyaline PAS-positive perivascular material deposits can be found together with extensive presence of fine fibrillar material, and reduplication of blood vessel walls and epidermal basal lamina. Although less prominent, these findings appear also in other cutaneous porphyrias (Fig 5).

Deposition of protoporphyrin in hepatocytes and in thrombi within the biliary canaliculi can be observed in the hepatic tissue. Characteristic pigment depositions are produced and under polarised light birefringent crystalline structures appear with the characteristic Maltese cross shape. Canaliculi may be dilatated and amorphous deposits within the lumen may be present 7.

Partial deficiency of FECH produces accumulation of free protoporphyrin IX. It can be detected in circulating red blood cells, in reticulocytes and in bone marrow erythroblasts. Red blood cells are therefore fluorescent under Wood's light. Protoporphyrin may also be detected in patients' plasma, that may also be fluorescent. Protoporphyrin is often excreted in stool and can be detected, but not in all patients. Urine is usually normal, except in cases with cholestasis and protoporphyrin hepatopathy. In this situation, an excess of urinary coproporphyrin isomer I can be demonstrated. FECH deficiency can be detected in different tissues with levels usually under 50% of normal (between 10 - 30%) to induce clinical manifestations 6.

Recently, families have been described in which EPP is inherited in an X-linked dominant pattern 3. Patients with this disorder have normal FECH activities but higher erythrocyte total protoporphyrin concentrations than other types of EPP of which around 40% is zinc-protoporphyrin. This high proportion of zinc-protoporphyrin suggests that protoporphyrin accumulates because supply of both its metal substrates, Fe²⁺ and Zn²⁺, becomes rate-limiting. Additionally, the increase in erythrocyte zinc-protoporphyrin in combination with a marked increase in free protoporphyrin appears to be a distinguishing feature of this form of EPP 1819.

Microcytic anaemia occurs in 20% to 60% of patients. Erythropoiesis was impaired in most patients with dominant EPP from UK and France 1819. All had a downward shift in haemoglobin (Hb), women were slightly more anaemic than men. Iron stores, assessed by serum ferritin (sFn), were decreased by two-thirds, but normal serum soluble transferrin receptor-1 and iron concentrations suggested that erythropoiesis was not limited by iron supply. FECH deficiency in EPP appears to lead to a steady state in which decreased erythropoiesis is matched by reduced iron absorption and supply. This response may in part be mediated by protoporphyrin 18.

With only rare exceptions, EPP is an inherited disorder. Even after the identification of mutations in the FECH gene in EPP, the precise pattern of inheritance remained uncertain. The difference in FECH activity between clinically overt and latent individuals could not readily be explained by the prevailing view that inheritance was autosomal dominant with low clinical penetrance but was consistent with a three allele system. Recent genetic studies revealed different patterns of inheritance in EPP 2324.

In most patients with EPP, a FECH mutation that markedly decreases or abolishes enzyme activity can be identified on only one allele 23252627282930. The discovery that clinical expression of this type of EPP normally required a hypomorphic FECH IVS3-48C allele trans to the mutation was demonstrated in France 2631 and was independently confirmed by studies from Japan, North America, Sweden, Israel, South Africa, the United Kingdom 283031323334.

The pattern of inheritance of photosensitivity has been well documented by Went and Klasen 4 who investigated 91 families from the Netherlands, most of whom were likely to have had this type of EPP. About half the cases were sporadic. When a family contained more than one patient, affected siblings were more common than parent to child transmission. The number of families with patients in more than one generation increases with the population prevalence, occurring in 15% of French and 51% of Japanese families. In contrast, EPP caused by FECH deficiency has not been reported in black South African families 2633.

FECH mutations on both alleles are an uncommon cause of EPP. To date, twenty-one symptomatic patients from 17 families have been reported. In the UK and France, this type of EPP accounts for about 4% of EPP families. Reported FECH activities, either measured in lymphocytes or estimated from in vitro expression studies, are within the median range of 9%. Molecular analyses show that most of the patients are compound heterozygotes. In marked contrast to the type of EPP described above, missense mutations make up 85% of the total and null mutations are unusual 283031323334.

The pattern of inheritance of photosensitivity in these families is characteristic of an autosomal recessive disorder. There is an increased incidence of consanguinity, only siblings are affected and both parents are clinically normal. This last feature may in part be explained by the chance absence of a hypomorphic allele trans to the mutation 3536,

Acquired somatic FECH mutations have been identified in a small number of patients in whom EPP has developed after the age of 40 years in association with myelodysplasia or myeloproliferative disorder 1037.

Patients in which EPP is inherited in an X-linked dominant pattern have normal FECH activities but higher erythrocyte total protoporphyrin concentrations than other types of EPP of which around 40% is zinc-protoporphyrin. Two frameshift mutations have been identified in 8 families that lead to predicted disruption or deletion of the 19-20 C-terminal amino-acids of ALAS2. Prokaryotic expression studies show that both mutations markedly increase ALAS2 activity. Thus the C-terminal region of ALAS2 appears to inhibit enzyme activity; its removal by mutation leads to gain of function whereas all other previously described mutations in ALAS2 decrease activity and cause hereditary sideroblastic anaemia.

Despite advances in techniques for mutation detection and the discovery of gain in function mutations of ALAS2 as a cause of EPP, in about 5% of EPP families no mutations in neither FECH or ALAS2 genes have been identified. Disease in these families is strongly associated with inheritance of the hypomorphic FECH IVS3-48C allele and decreased FECH activity which suggests that most may have mutations in regions of the FECH gene that are not included in current strategies for mutation detection.

The cutaneous features of EPP, though varying in severity are remarkably uniform. No correlation between indices of severity of photosensitivity, such as age of onset or duration of symptoms, and genotype have yet been reported apart from the suggestion that the relatively common missense mutation, P334L, may cause only mild disease Apart from this instance, no correlation between erythrocyte protoporphyrin concentration and type of FECH mutation has been reported. Seasonal palmar keratoderma has to date been reported only in patients who are compound heterozygotes or homozygotes for FECH mutations 1938.

A mainly literature-based study of 112 patients with a single FECH mutation, of whom 18 had severe liver disease, found that all patients with liver disease had a 'null' mutation (splicing defect, nonsense or frameshift) while none of the 20 patients with a missense mutation had liver disease; this difference was statistically significant 39. Under-representation of missense mutations was also noted in a group of 15 patients with liver disease, all studied in the same laboratory, but comparison with a group without liver disease did not reach statistical significance 435. Together these studies suggest that missense mutations that preserve significant amounts of residual activity may carry a lower risk of liver disease than 'null' mutations, a group that includes those misssense mutations that abolish FECH activity. However, 'null' mutations associated with liver disease are found more frequently in patients without liver disease; an observation that indicates the probable importance of genetic factors outside the FECH locus and acquired factors in the pathogenesis of protoporphyric liver disease 40.

Management of photosensitivity is an essential therapeutic measure. Avoidance of sun exposure, even through window glass (e.g. car driving), is the most practical way of preventing photosensitivity reactions in EPP patients. The use of adequate clothing (hats, glasses, gloves) and sunscreens is also advisable. Due to the fact that protection should cover both long-wave radiation plus visible light, physical sunscreens are more effective.

Management of photosensitivity reactions includes the use of: wet (cold) water compresses applied to the affected areas. Topical corticosteroids may be prescribed but are usually ineffective. Oral treatment, if required, may include non-steroidal anti-inflammatory drugs or oral corticosteroids.

Betacarotene has been used extensively, with the aim of improving light tolerance in EPP patients. Some benefit from its use has been experienced by patients. The following doses of betacarotene are recommended: up to 90-120 mg/day in children and up to 180-300 mg/day in adults. Recent studies, however, have suggested inverse associations between carotenoids and lung cancer mainly in smokers 4344.

Other treatment approaches include the administration of Vitamin C and E, and cysteine (500 mg/twice daily), orally. Antihistamines may also be used as they may limit the phototoxic reaction.

Except for betacarotene, there is a lack of firm evidence proving the effectiveness of all these treatment approaches 45. The duration of treatments directed to improve photosensitivity is related to the ratio risk/benefit obtained by patients individually. UVB/NBUVB phototherapy or PUVA may be used in order to induce tanning and improve the sunlight tolerance. The duration of the treatment is limited by the guidelines of phototherapy and depends also on the patient benefit obtained in reduction of photosensitivity 46.

Afamelanotide (an alpha-melanocyte-stimulating hormone analogue that induces epidermal melanin formation) has recently been shown to have beneficial effects in patients with EPP 47.

EPP patients may present photosensivity reactions during surgical procedures due to exposure to the theater lighting or other surgical light conducting devices in laparoscopy, endoscopy or dental procedures. In these cases, the application of yellow filters blocking the radiation under 460 nm offers the best protection in keeping with a level of normal acceptable visibility 4849.

Regarding the reduction of excess protoporhyrn in patients with EPP, two approaches can be considered:

a) Reduction of erythropoiesis. This may be achieved by exchange transfusion or hypertransfusion. It is not clear if haematin may temporarily supress erythropoiesis by modifying the activity of the rate-limiting first enzyme of the haem synthetic pathway, ALA synthase. However, this approach cannot be considered as a long-term treatment of the disease 505152.

b) Cholestyramine (a bile sequestering agent) may be used to increase the elimination of the excess protoporphyrin through the biliary system. It binds the excess protoprophrin, enhancing its faecal elimination, reducing its plasma and red blood cell concentration, and preventing the protoporphyric hepatopathy. The suggested dose of cholestyramine is 4-16 g daily. Other similar drugs have been considered, such as chenodeoxycholic acid and ursodeoxycholic acid 535455.

However these bile sequestering agents might have no or even adverse effect in a mouse model of EPP with progressive liver disease and should be therefore used with caution (JC Deybach and H Puy, personal communication).

Patients studied had a mild microcytic anaemia and thrombocytopenia, as shown by the downward shift of hematologic parameters, which positively correlated with the amount of erythrocyte PPIX. Interestingly, erythropoiesis did not seem to be limited by iron supply in patients, since serum iron and soluble transferrin (Tf) receptor (sTfR) were normal. Therefore oral iron supply is usually found ineffective in trying to correct the usual mild anaemia in EPP patients and is therefore not recommended. However intravenous iron supply or even blood transfusion should be considered in EPP with a more pronounced anaemia 7.

Liver transplantation is the treatment for end-stage liver disease. It was used for the first time in an EPP patient in 1980 55. Progressive liver disease in EPP patients should be considered a medical emergency and, therefore, liver transplantation has ben indicated in patiens with EPP.

It is evident that liver transplantation does not alter the consequences of FECH deficiency and overproduction of proporhyrin. Therefore, the EPP patients continue to present with the typical symptoms and same risks. Bone marrow transplantation should be considered and, in fact, the ideal treatment should be sequential liver and bone marrow transplantation, which has already been performed with success 5657.

As the experience with liver and bone marrow transplantations in EPP patients increases, rationale for patient selection, indication for transplantation and timing either for bone marrow, liver or sequential transplantations can be established. Knowledge concerning tolerance of the immunosuppressive therapy and long-term complications in EPP patients also needs to be gained. A proposal of guidelines to identify liver disease in EPP patients has been published by Anstey and Rift very recently 58. Special attention should be devoted to EPP patients bearing FECH null mutations with recessive inherited disease, those belonging to families with more than one member with manifested disease or those with X linked protoporphyria.

Liver biopsy should be indicated in patients with null mutations or recessive inherited disease, patients from families with previous cases of EPP liver disease, and in individuals with EPP plus other risk factors for liver disease (such as hepatitis, haemochromatosis, alcoholic or non-alcoholic fatty liver disease, abnormal liver function tests). Special attention should also be given to patients with sudden worsening of photosensitivity, rising blood protoporphyrin levels, increasing urinary coproporphyrinuria isomer I and decreasing faecal protoprophyrin.

EPP patients should be monitored through a periodic non-invasive liver testing protocol that includes liver function tests, viral hepatitis serology, haemochromatosis tests and analysis for serum markers of hepatic fibrosis. Liver scanning for detection of gallstones, and computed tomography (CT) and magnetic resonance imaging (MRI) liver studies should also be included.

EPP patients should be vaccinated against hepatitis. They should avoid alcohol intake.