Erythropoietic protoporphyria: case reports for clinical and therapeutic hints

Porphyria is a group of rare diseases caused by the altered biosynthesis of heme. Defects in the ferrochelatase (FECH), delta-aminolevulinate synthase 2 (ALAS2) or caseinolytic mitochondrial matrix peptidase chaperone subunit (CLPX) genes are associated with erythropoietic protoporphyria (EPP), a disease usually presenting in children, due to the accumulation of protoporphyrin-IX (PPIX) in erythrocytes, skin and liver [1]. Liver damage, which is the main risk in EPP, is rare in children, who usually complain only of symptoms related to sun exposure (burning, itching, pain), that can have significant impact on patients’ health-related quality of life (QoL) [2]. Treatment relies on the protection from sunlight and on the prevention of liver damage associated with protoporphyrin accumulation. We report a series of children cared for at the Rheumatology Service of IRCCS Burlo Garofolo Hospital in Trieste (Italy) describing clinical, biochemical, genetic features, and the effect of treatment with cimetidine on Erythropoietic Protoporphyria - Quality of Life (EPP-QOL) questionnaire (total score ranging 0 to 36, higher scores indicating better quality of life – Fig. 1) [3].

All patients treated with cimetidine (20 mg/kg/day in two doses) reported an improved tolerance to sunlight after cimetidine, with increased hours spent in outdoor activities. The EPP-QOL questionnaire was administered before and after two months from the beginning of treatment. Total scores of patients expressed as the percentage of the maximum (100%) quality are summarized in Table 1.

In Italy, the prevalence of EPP is estimated of 3.15 cases per million persons, with an incidence of 0.13 cases per million persons / year [1]. EPP is characterized by a wide heterogeneity in age of onset, symptoms severity, and duration, leading to a significant diagnostic delay [4]. Rarely, there may be a complete absence of visible skin lesions (patient 3 and 5). Although skin manifestations are the main reason for investigations, the most important complication in EPP is hepatic failure, due to the accumulation of protoporphyrin in the hepatobiliary structures. Approximately 1–5% of patients develop liver damage and require liver transplantation. However, this does not correct the underlying metabolic deficiency, and the transplanted liver is likely to have protoporphyrin damage [5]. In our cases, no patients developed consistent liver involvement in pediatric age. The diagnosis is based on clinical symptoms and increased levels of circulating protoporphyrin, while urinary porphyrins values ​​are usually normal [6]. In our cases, all patients had normal values of urinary porphyrins with increased erythrocyte levels and two of them increased fecal ones (patient 1 and 4). Genetic analysis is used to confirm the diagnosis of EPP. EPP can be caused by a compound heterozygous or homozygous mutation in FECH gene, but more often, it results from semi-dominant inheritance with compound heterozygous of two mutations, one of which is clearly pathogenic and the other having a minor contribute on the phenotype [7]. The genetic analysis performed on our patients agrees with the literature, although in one case (patient 2) only one heterozygous variant in the FECH gene was identified (c.315-48T > C), but, the possible presence of other variants in intronic regions or in the promoter have been hypothesized and therefore further investigations may be necessary. From this small case series, a correlation between genotype and clinical manifestations cannot be assumed. Nonetheless, Balwani et al. described a significant correlation between erythrocyte protoporphyrin levels and earlier age at onset, decreased sun tolerance, and increased risk of liver dysfunction [8]. Analyzing the characteristics of our patients and previous study on this topic, a direct correlation between blood protoporphyrin values ​​and skin phenotype was seen, regardless of the underlying genetic defect and the inheritance pattern. Although, in the study by Minder et al., liver injury was described as strongly associated with null FECH mutations and in patients with autosomal recessive protoporphyria, recent studies have shown that mutations in the FECH gene alone do not explain the severe liver disease phenotype, since the same mutations are present in asymptomatic family members [9].

Skin diseases in children can have profound effects on their QOL, interfering with family and social relationships. Currently, EPP therapy is based on reduction of sun exposure and the use of high protection factor creams in the spring-summer months. To prevent hepatopathy, it could be useful to promote biliary secretion with ursodeoxycholic acid and to interrupt the enterohepatic circulation reducing the circulating levels of protoporphyrin with cholestyramine. Other treatments gave contradictory results, such as transfusion of erythrocytes to suppress erythropoiesis and, hence, reduce the protoporphyrin level or plasmapheresis and extracorporeal albumin dialysis, for which there is a lack of studies documenting their efficacy.

Moreover, since protoporphyric hepatopathy may be triggered by another cause of liver disease, all of our patients were vaccinated against hepatitis A and B.

To improve sunlight tolerance, some treatment options are currently available, such as alfamelanotide and cimetidine. The safety and efficacy of alfamelanotide in children has not yet been established, while there are some published experiences on the use of cimetidine in children [10‐12] (Table 2). Cimetidine inhibits ALAS, the first enzyme in the heme biosynthetic pathway, resulting in decreasing protoporphyrin levels. In our experience, four out of five patients underwent treatment with oral cimetidine, at a dose of 20 mg/kg/day divided in two daily administrations. Patient 3 did not start the treatment because he did not feel the need to increase sun exposure. PPIX levels were measured in two patients receiving cimetidine after three months of treatment. Curiously, these levels did not change; therefore, cimetidine showed a cutaneous but not a biochemical effect. None of the patients reported adverse effects with regards to clinical safety. They reported an increase in skin color, although this is not due to the drug but to the increased of sun exposure. No patients complained of photosensitivity deterioration.

The EPP-QOL questionnaires showed that the use of cimetidine led to an improvement in their QoL. However, a limitation of this study was the lack of a defined method of measuring the sun exposure time, except for activities of known duration (e.g., football matches or home-school path).

In conclusion, although its rarity, EPP should be excluded in all photosensitive children, especially when discomfort is disproportionate to the extent of the cutaneous lesions. Based on the literature and our clinical experience, a treatment with cimetidine is effective and safe in improving tolerance to sun exposure.