Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder of the haem (heme) pathway causing severe phototoxicity (toxic reactions to light) in skin due to the build up of a phototoxic chemical in the skin.
EPP belongs to a heterogenous group of disorders (porphyrias) that result from a dysfunction of specific enzymes involved in the haem biosynthesis. Haem serves many essential functions in the body one of which is oxygen transport via haemoglobin.
Incidence
Erythropoietic Protoporphyria (EPP) reaction
Erythropoietic protoporphyria is rare, and few studies have been done on its prevalence. Geographic location generally doesn’t seem to bias the incidence of EPP, although one study has suggested that the incidence in Slovenia is 1:58,000. Other studies include incidence that range from 1:75,000 to 1:200,000. Case reports suggest that EPP is prevalent globally.
It is estimated that between 5,000-10,000 individuals worldwide have EPP.
Symptoms
Typically, erythropoietic protoporphyria symptoms begin in childhood and are characterized by episodes of phototoxicity. The main symptoms are pain, which is often described as heat, prickling, itch or extreme sensitivity of skin exposed to light. The pain is often very severe, and swelling and blistering of the skin may result. Skin lesions resolve slowly often leaving waxy or pitted scars. Repeated exposure leads to scarring and waxy thickening of the skin on the backs of the knuckles and nose.
Erythropoietic Protoporphyria (EPP) reaction
As little as a few minutes of sunlight (which may overcast or window transmitted) may be sufficient to evoke symptoms. Symptoms are due to visible light (at wavelength above 400 nanometers, part of the electromagnetic spectrum). In most affected individuals, skin involvement persists throughout life, although some people become less symptomatic with time. Symptoms can be seasonal, starting early in the spring, continuing through summer and diminishing in winter. Some patients report that wind may exacerbate their symptoms.
Erythropoietic protoporphyria patients will sometimes have a mild microcytic anaemia, presumably due to the inability or reduced ability to form haem. This should not be confused with iron deficiency anaemia and patients should not take iron replacement for this as it may actually exacerbate the porphyria. Gall stones, usually pigment stones, are more common at an earlier age in EPP.
Liver failure occurs in 5% of erythropoietic protoporphyria patients; this is thought to be related to the increased work of the liver to clear the excessive intermediate by-products from the defective haem pathway. If liver failure occurs it can be fatal.
This lack of permanent symptoms in erythropoietic protoporphyria leads to frequent misdiagnosis by doctors, much to the frustration of parents and their child.
Causes
Protoporphyrin IX molecule
Erythropoietic protoporphyria is inherited and can be autosomal dominant or recessive. This disorder causes a chemical known as protoporphyrin IX to accumulate in the skin. When the skin is exposed to the sun, these molecules undergo a chemical reaction that results in swelling, severe and intolerable pain and scarring, a condition known as phototoxicity.
The pain is sometimes described as like having hot needles stuck into the skin. The lifelong pain experienced by these patients typically resigns them to become socially isolated, due to the lack of an efficacious treatment and their need to continuously avoid sunlight.
Ferrochelatase deficiency
The specific defective enzyme in erythropoietic protoporphyria is ferrochelatase, the last of eight enzymes in the porphyrin-haem pathway. Consequently there is an inability to chelate iron with protoporphyrin IX to form haem. Intermediates from the pathway accumulate before this final step and cause toxic effects which are involved in the dermal symptoms of EPP.
The gene for the ferrochelatase enzyme, which shares the same name, is located on chromosome 18q21.3. Molecular studies on the gene indicate that more than 60 different mutations exist, most of which are insertions or deletions.
Diagnosis
Diagnosis of erythropoietic protoporphyria is based on the detection of increased levels of free protoporphrin IX in red blood cells. Monitoring of liver function tests and red cell porphyrins are sometimes performed to pick up any early signs of liver failure.
Treatments
Action spectrum of PPIX
Sun avoidance by remaining indoors or wearing sun protective clothing including cotton gloves and a wide brimmed hat is the first line in erythropoietic protoporphyria management. The remaining treatment is focused upon symptomatic relief, although no effective symptomatic treatments have been reported. Patients have reported immersing affected skin in water (both hot and cold) to try and relieve the phototoxicity.
Most commercially available sunscreens are of no value as a treatment, but a large particle size titanium dioxide sunscreen may be of some benefit if used with other forms of sun protection.
Drugs such as β-carotene, cysteine (an amino acid which has been shown to decrease photosensitivity) and cimitedine have been used with various disappointing results and because the disease is inherited, genetic counselling is recommended.
Hematin infusion may temporarily decrease the production of haem and may also result in a decrease of plasma and faecal porphyrins. Also, there is sporadic evidence that autologous blood cell transfusion with washed red blood cells may successfully induce clinical and biochemical remission for erythropoietic protoporphyria patients. Finally, narrow band UVB phototherapy as a treatment option may provide some protection, presumably through epidermal thickening and tanning.
Since sun avoidance is recommended, patients lead lives where they are in the sun for very limited time. This can prevent normal social activities and the intense pain that is experienced interferes with normal daily activities and can prevent adequate sleep.
Liver transplantation in EPP
Liver failure occurs in 2-5% of patients with erythropoietic protoporphyria; this is thought to be related to the increased workload of the liver to clear excessive intermediate by-products from the defective haem pathway. If liver failure occurs it can be fatal.
31 European liver transplants in EPP patients have been reported in medical literature from 1983 and 2008. A 2005 US study followed up 20 patients who had undergone the procedure.
When conducting transplants and other surgery in EPP patients, it has been recommended that yellow filters be fixed to surgical lights to remove light wavelengths below 470nm and prevent phototoxic reactions resulting from exposure.
Psychological and social impact
EPP has been widely recognised as having a serious impact on the quality of patients’ lives due to sun avoidance leading to social exclusion. Depression, anxiety due to fear of reactions and suicidal thoughts have been reported by EPP patients in the literature. A 2010 UK study has also shown that individuals with photosensitive disorders, including EPP, have a greater unemployment rate.
Misdiagnosis and ‘invisible’ reaction symptoms can compound these issues as patients also report accusations of hypochondria when experiencing reactions or avoiding situations which may cause the onset of symptoms.
Prognosis
Symptoms of erythropoietic protoporphyria are usually with patients for life; however a few people have described symptoms reducing over time.
References
- Lecha, M et al., (2009). ‘Erythropoietic protoporphyria’, Orphanet Journal of Rare Diseases. 14(9) available online at http://www.ojrd.com/content/4/1/19
- Marko PB et al., (2007). ‘Erythropoietic protoporphyria patients in Slovenia’, Acta Dermatoven. 16(3):99-104.
- McGuire BM, et al, (2005). Liver transplantation for erythropoietic protoporphyria liver disease. Liver Transpl. 11(12):1590-6.
- Murphy GM, (2003). ‘Diagnosis and Management of the Erythropoitetic Porphyrias’, Dermatologic Therapy. 16:57-64.
- Rufener EA (1987). ‘Erythropoietic protoporphyria: a study of its psychosocial aspects’, British Journal of Dermatology. 116:703-708.
- Schneider-Yin et al., (2000). “New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care”, European Journal of Pediatrics. 125:719-725.
- Stafford R, et al., (2010). ‘The impact of photosensitivity disorders on aspects of lifestyle.’ British Journal of Dermatology. 163(4):817-822.
- Thunell S, Harper P & Brun A, (2000). ‘Porphyrins, Porphyrin Metabolism and Porphyrias, IV, Pathophysiology of Erythropoietic Protoporphyria – Dianosis, Care and Monitoring of the Patient’, Scandinavian Journal of Clinical and Laboratory Investigation. 60:581-604.
- Todd DJ. ‘Clinical Implications of the Molecular Biology of Erythropoietic Protoporphyria’, Journal of European Academy of Dermatology Venereology. 11:207-213.
- Wahlin S, et al, (2008). “Protection from phototoxic injury during surgery and endoscopy in erythropoietic protoporphyria.” Liver Transpl. 14(9):1340-6.
- Wahlin S, et al, (2011). “Liver transplantation for erythropoietic protoporphyria in Europe.” Liver Transpl. epublished May 20.