This information on erythropoietic protoporphyria (EPP) and X-linked erythropoietic protoporphyria (XLEPP) is based on best available evidence and the consensus of a group of porphyria specialists in the International Porphyria Network (Ipnet).
Contents
1. Introduction
2. Genetics
3. Epidemiology
4. Pathogenesis
5. Clinical Presentation
6. Laboratory Diagnosis
7. Additional investigations
8. Management
9. Complications
10. References
1. Introduction
EPP and XLEPP are rare inherited diseases in which exposure to sunlight and some sources of artificial light leads to painful phototoxic reactions in the exposed skin. This reaction to light usually starts in early childhood but can in rare cases manifest later in life. EPP is the most prevalent form of porphyria in children.
The phototoxic reaction in EPP/XLEPP is a consequence of high levels of metal free protoporphyrin in the blood. When exposed to light and especially blue light in the visible light range, metal free protoporphyrin is activated to form oxygen radicals, which in turn cause a phototoxic reaction. Skin that is exposed to sunlight, commonly the face or back of hands, reacts often within minutes with a prodrome of tingling, burning or itchy sensations. With continued exposure to sunlight, these initial symptoms can progress to severe pain, erythema and oedema of the skin. Symptoms depend on the intensity of the sunlight and the duration of exposure. The severity is variable, but most patients tolerate less than 30 minutes of sunlight before symptoms develop.
Phototoxic reactions often occur outdoors, but visible light also passes through glass. In addition, bright artificial indoor light sources can cause phototoxic reactions, which means that EPP patients can have painful reactions inside buildings or in transportation vehicles. While the intensity of the visible light is highest on sunny days, light on overcast days and light reflected from reflective surfaces such as snow or water can cause severe phototoxic reactions. The pain following exposure to light can be unbearable, responds poorly to analgesics, and can last for several days after light exposure has ceased. In addition, many patients report a priming phenomenon, which is where exposure following a minor reaction can lead to a rapid onset severe reaction to minimal exposure the following day. Strict sun protection measures are needed to prevent reactions, resulting in poor quality of life secondary to a marked restriction in daily activities, limited career options and curtailment of all outdoor activities and hobbies, including sports. Due to the severely painful reactions, EPP patients from an early age learn to avoid sunlight as a form of conditioned behaviour.
2. Genetics
EPP is a result of deficiency in ferrochelatase activity (the final enzyme in the haem biosynthesis pathway) and is inherited in an autosomal recessive fashion. Most EPP patients have an inactivating mutation of the FECH-gene (located on chromosome 18q21.2-q21.3) in combination with a common intronic variant (FECH c.315-48T>C, formerly named FECH IVS3-48C). This polymorphism creates an alternate splice site and results in production of both normal and abnormally spliced mRNA. The latter is rapidly degraded which results in a 20-40% reduction of the activity from this allele. The polymorphism occurs in approximately 10% of the Caucasian population, and its prevalence varies between countries. It is present in 47% of the population in Japan and in 1% in West Africa. A small percentage (<4% in most series) of EPP patients have (partially) inactivating mutations on both alleles and do not have the polymorphism. Very rarely EPP can manifest in adulthood due to an acquired mutation or loss of the FECH gene, usually in association with myelodysplasia.
XLEPP results from a gain-of-function mutation in the erythroid-specific aminolevulinic acid synthase-2 (ALAS2) gene, which leads to overproduction of protoporphyrin. XLEPP is characterised by a marked increase in both metal free protoporphyrin and zinc chelated protoporphyrin in erythrocytes. In rare cases, mutations in the gene for CLPX have the same effect as gain-of-function mutations in ALAS2.
3. Epidemiology
EPP affects males and females equally and most cases are reported from Northern Europe and Japan. The prevalence of EPP in Europe is estimated between 1:75,000 to 1:200,000. Ethnicity and sex do not have an obvious effect on the prevalence, which is primarily dictated by the carrier frequency of the hypomorphic allele as described above. Variations in FECH mutations between populations are thought to contribute, in some cases due to a founder effect.
However, the true prevalence of EPP is likely to be underestimated due to missed diagnosis and a lack of access to specialist services in many countries. Even where dedicated porphyria centres exist, delayed diagnosis of more than 10 years is common.
The rarer form, XLEPP, occurs equally in males and females and accounts for less than 5% of the protoporphyria patient population.
4. Pathogenesis
As noted above, the severe phototoxic reaction is a consequence of excess metal free protoporphyrin which is mainly produced in the bone marrow (hence the term erythropoietic), although there may be a small contribution from hepatocytes.
Metal free protoporphyrin is a chromophore in human skin which absorbs mainly visible light and to a lesser degree longer wavelength ultraviolet A (UVA) radiation. This results in an excited state molecule which transfers energy to molecular oxygen giving rise to free oxygen radicals, particularly singlet oxygen. These reactive oxygen species cause damage to molecules in the immediate vicinity, particularly cell membrane proteins, resulting in cell lysis, complement activation and mast cell degranulation. These mediators initiate an inflammatory response, which further contributes to the phototoxic damage.
In general, there is no indication that the enzyme defects associated with EPP and XLEPP result in significant deficiencies of haem dependent proteins. However, haemoglobin can be moderately decreased in some patients (see below).
5. Clinical Presentation
Pain is always related to exposure to light, especially sunlight, which when prolonged can cause a severe phototoxic reaction. Patients often report a prodrome of tingling or itch within a few minutes of exposure, particularly in strong sunlight. If exposure continues, this progresses to severe debilitating pain which can last for several days, preventing sleep and participation in usual work, leisure or educational activities. Associated erythema and oedema to exposed sites often occur, most commonly to the face and hands. Blisters, scarring and petechiae occur less frequently. Some patients show no outward signs of EPP/XLPP during attacks, despite severe pain. Others have only minor skin changes, and physical examination is frequently normal by the time the patient is seen by a doctor. Patients with EPP/XLEPP may have lichenification (thickening of the skin) on areas of skin subject to repeated light exposure.
Significant liver injury will occur in a small number of patients. The risk of developing gallstones is increased, often in younger patients. Long-term vitamin D insufficiency or deficiency in this patient population due to the sunlight restriction increases the risk of osteopenia and osteoporosis substantially.
6. Laboratory Diagnosis
Skin biopsies are not useful for diagnosing EPP/XLEPP.
Biochemical diagnosis is achieved by measuring erythrocyte protoporphyrin levels, which includes measurement of zinc chelated protoporphyrin and metal free protoporphyrin. The finding of predominantly metal free protoporphyrin (>95%) indicates a diagnosis of EPP and the presence of both metal free and zinc protoporphyrin (>10%) suggests a diagnosis of XLEPP.
NB: Analysis of urinary porphyrins is not suitable for the diagnosis of EPP and XLEPP and leads to a false-negative result.
Genetic counselling for family members is available using DNA testing to detect mutations in the FECH and ALAS2 genes. As with other inherited conditions, in a small number of cases mutations cannot be found on one or both alleles. If required for counselling, ferrochelatase activity in fibroblasts or lymphoblastoid cells can be measured, although enzyme studies are only available in a small number of specialist porphyria centres.
Prenatal diagnosis is possible and if desired can be discussed with a clinical geneticist but is only indicated under exceptional circumstances.
7. Additional investigations
7.1 Blood monitoring
In addition to erythrocyte protoporphyrin, liver enzymes and bilirubin, full blood count, iron and vitamin D status should be tested at diagnosis, and all should be monitored at least annually. Worsening of photosensitivity warrants more frequent monitoring and might indicate the onset of liver disease. The frequency of blood monitoring may vary between porphyria centres.
7.2 Radiological investigations
Liver ultrasound scans are not required as part of regular follow up but should be requested as part of the investigation of abnormal liver function tests. Liver elastography (e.g. Fibroscan) may help monitor for development of liver fibrosis but is not routinely available and requires further evaluation.
Bone mineral densitometry (DEXA) scans may be considered at diagnosis, with follow-up scans based on this result and in accordance with national guidance.
8. Management
8.1 General measures
Lifelong photoprotection is essential in both EPP and XLEPP. Many patients learn to understand their own level of sunlight tolerance and take measures to avoid a phototoxic reaction by avoiding light exposure wherever possible. However, as EPP and XLEPP are diseases with mostly invisible symptoms, patients often do not get believed and may need support in implementing the measures needed.
Clothing:
Newly diagnosed patients and parents of affected children should be advised of the importance of protective clothing in achieving good photoprotection (e.g. appropriate hats, long sleeves, gloves and trousers). Formal advice on the condition and the need for photoprotection should also be provided to educational establishments (e.g. schools, universities) and employers.
Sunscreens:
As EPP and XLEPP are triggered by visible light, standard UV sunscreens are not effective and physical i.e. reflectant sunscreens based on titanium dioxide or zinc oxide can be tried but have limited effectiveness.
Other measures:
During surgery or endoscopy, protective filters are generally not required except for long surgeries in cholestatic patients, such as liver transplantation. However caution should be taken during exposure to newer high intensity light sources.
Vitamin D Supplements:
Due to photoprotection, EPP patients are very likely to become vitamin D insufficient or deficient. Dietary sources are highly unlikely to provide sufficient vitamin D and daily supplementation of 800-1000 IU is therefore recommended throughout the year. Serum vitamin D status should be monitored and if deficiency is identified, replacement doses should be prescribed according to national guidelines.
Liver health:
Alcohol intake should be kept to a minimum as high consumption may increase the risk for developing EPP-associated liver damage.
Hepatitis A/B vaccinations are recommended.
Other vaccinations should be given as advised by your countries National Immunisation Programme.
From early childhood, patients with EPP and XLEPP experience repeated episodes of long-lasting, intense pain that cannot be effectively treated, which induces an ingrained anxiety about exposure to light and situations in which they can`t control their environment. In addition, avoiding light exposure is not compatible with many activities of daily living, and throughout their lives EPP and XLEPP patients face impaired educational and occupational opportunities. Patient with EPP/XEPP at risk of social isolation, depression, and low quality of life and should be offered counselling according to their needs.
8.2 Treatments aimed at reducing photosensitivity
The following information applies to both, patients with EPP and XLEPP.
8.2.1 Afamelanotide
Afamelanotide (SCENESSE©, Clinuvel (UK) Ltd, Leatherhead, UK) is currently the only approved treatment for the prevention of phototoxic reactions in adult EPP patients and, in some countries, is used off-label for treating adolescents >16 years. Although it is currently approved in the EU, USA, and Australia, it is not reimbursed in all countries and availability of the treatment should be clarified with the respective national porphyria specialist centre. Afamelanotide is a super-potent alpha melanocyte stimulating hormone (α-MSH) analogue, which increases melanogenesis, and has anti-oxidant and anti-inflammatory activity in human skin. It is not curative but protects the patient from the adverse effects of sunlight, preventing or reducing the painful reactions. It is administered every two-months, as a biodegradable slow-release subcutaneous implant formulation.
8.2.2 UVB Phototherapy
In some countries patients are offered a course of narrow band UVB phototherapy in early spring, managed through their local Dermatology Department under guidance from a Porphyria Centre. The objective is to increase exposure of the skin to UVB radiation to promote âskin-hardeningâ through stimulating melanogenesis and thickening of the epidermis. This increases sun tolerance in spring and summer months for many patients. Treatment entails repeated short exposures to UVB two to three times per week over a period of 5-10 weeks. This treatment is time consuming and therefore not suitable for everyone, and it is not universally beneficial.
8.2.3. Treatments under investigation
Additional treatments are under development and may become available to patients in the future.
Dersimelagon:
Dersimelagon is an orally available melanocortin 1 receptor (MC1R) analogue with a similar mode of action to afamelanotide. It is currently being investigated in clinical trials for the treatment of EPP.
Bitopertin:
Bitopertin is an oral inhibitor of glycine transporter type 1 (GlyT1). GlyT1 affects mediators at an early stage of the haem biosynthesis pathway and may decrease protoporphyrin production. Its potential role as the first treatment to modify the pathogenesis of EPP is currently being investigated in clinical trials.
9. Complications
Liver disease:
Very rarely patients with EPP/XLEPP can develop an acute cholestatic hepatitis. This complication can be provoked by liver damage due to excess alcohol use, drug-induced hepatotoxicity, occasionally by intravenous iron or other causes of liver disease such as a viral hepatitis. This rare condition should be regarded as a medical emergency and is an indication for immediate referral to an expert centre, or to a specialist liver unit with access to a specialist porphyria service.
Various treatments to reduce protoporphyrin may be introduced, including red cell exchange, plasmapheresis and where possible bone marrow transplantation can be considered.
Iron deficiency anaemia:
EPP: Detailed studies of a large cohorts of patients have shown that patients with EPP have lower mean haemoglobin and ferritin levels. However, as the underlying reason for EPP is a deficiency in FECH enzyme which uses iron to produce heme, care needs to be taken when interpreting these results, as iron supplementation is unlikely to result in improvement, and may even cause worsening of symptoms. However, as with the general population EPP patients, particularly females, are at risk of iron deficiency anaemia which may require treatment. EPP patients with symptomatic anaemia should be treated with low doses of oral iron preferably during the winter months with frequent monitoring of their liver transaminases and blood protoporphyrin.
XLEPP: In XLEPP, gain-of-function mutations in ALAS2 cause an overproduction of protoporphyrin. As the activity of FECH is not affected, supplemented exogenous iron can be inserted into protoporphyrin which is converted to heme. Iron supplementation therefore appears to be beneficial in XLEPP, although there is currently no published evidence of long-term experience.
10. References
Anstey AV, Hift RJ. Liver disease in erythropoietic protoporphyria: insights and implications for management. Gut. 2007;56(7):1009-1018.
Balwani M, Bonkovsky HL, Levy C, et al. Endeavor Investigators. Dersimelagon in Erythropoietic Protoporphyrias. N Engl J Med. 2023;388(15):1376-1385.
Barman-Aksoezen J, Schneider-Yin X, Minder EI. Iron in erythropoietic protoporphyrias: Dr. Jekyll or Mr. Hyde? J Rare Dis Res Treat. (2017) 2(4): 1-5.
Biewenga M, Matawlie RHS, Friesema ECH et al. Osteoporosis in patients with erythropoietic protoporphyria. Br J Dermatol. 2017 Dec;177(6):1693-1698.
Elder G, Harper P, Badminton M, Sandberg S, Deybach JC. The incidence of inherited porphyrias in Europe. J Inherit Metab Dis. 2013;36:849-857.
Elder GH, Gouya L, Whatley SD, Puy H, Badminton MN, Deybach JC.The molecular genetics of erythropoietic protoporphyria. Cell Mol Biol (Noisy-le-grand). 2009;55(2):118-26.
Halloy F, Iyer PS, Ghidini A, et al. Repurposing of glycine transport inhibitors for the treatment of erythropoietic protoporphyria. Cell Chemical Biology 2021; 28(8): 1221-1234.
Minder AE, Kluijver LG, Barman-Aksözen J, Minder EI, Langendonk JG. Erythropoietic protoporphyrias: Pathogenesis, diagnosis and management. Liver Int. 2024 Jul 16. doi: 10.1111/liv.16027. Online ahead of print.
Wahlin S, Aschan J, Bjornstedt M, Broome U, Harper P. Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis. J Hepatol 2007;46:174-179.
Wahlin S, Srikanthan N, Hamre B, Harper P, Brun A. Protection from phototoxic injury during surgery and endoscopy in erythropoietic protoporphyria. Liver Transpl. 2008 Sep;14(9):1340-6.
Wensink D, Langendonk JG, Overbey JR et al. Erythropoietic protoporphyria: time to prodrome, the warning signal to exit sun exposure without pain-a patient-reported outcome fficacy measure. Genet Med. 2021 Sep;23(9):1616-1623
Wensink D, Wagenmakers MA, Barman-Aksözen J et al. Association of afamelanotide with improved outcomes in patients with erythropoietic protoporphyria in clinical practice. JAMA Dermatol. 2020;156(5): 570-575.
V4 July 2024 Ipnet Cutaneous Porphyria Working Group
Based on âCare pathway Erythropoietic protoporphyria (EPP): Practitioner version.â Erasmus MC Medical Centre, Rotterdam, Netherlands