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Erythropoietic protoporphyria

This is part of Rare diseases.

Diagnosis: Erythropoietic protoporphyria

Synonyms: Porphyria, erythropoietic protoporphyria, Inherited ferrochelatase deficiency

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Date of publication: 2012-02-27
Version: 3.2

ICD 10 code

E80.0A

The disease

Erythropoietic protoporphyria (EPP) is one of the porphyrias, a group of inherited diseases caused by hereditary deficiencies in particular enzymes (certain types of proteins). The enzyme affected in erythropoietic protoporphyria contributes to the production of heme, the red blood pigment. The term erythropoietic refers to the process by which red blood cells are formed in the bone marrow, while protoporphyrin is a substance involved in the final stage of heme production. The primary symptom of the disease is skin hypersensitivity to light, particularly to sunlight.

The disease was first described in 1961 by British dermatologist Ian Magnus and his associates. During the 1970s it was shown that the accumulation of protoporphyrin in the red blood cells was caused by a deficiency of ferrochelatase, the enzyme which converts protoporphyrin into heme.

Occurrence

There is no definite information to indicate how common the disease is. Internationally, the frequency is given as two to five individuals per million, but these figures have not been confirmed. In Sweden, approximately fifty individuals are known to have the disease and its associated skin symptoms, but the number of carriers who do not develop symptoms is many times higher. Erythropoietic protoporphyria is more common among men than women. It is found in all ethnic groups and in all parts of Sweden.

Cause

The disease is the result of a combination of hereditary and environmental factors. The hereditary factor is a mutation in the gene controlling for (coding for) the production of the enzyme ferrochelatase (FC). This FECH gene is located on the long arm of chromosome 18. The function of the enzyme is to convert protoporphyrin to heme. The environmental factor triggering the onset of symptoms is light of particular wavelengths.

Normally, individuals have two FECH genes, one from each parent. The total amount of ferrochelatase produced in the cell is therefore the result of the activity of two genes. The mutation reduces ferrochelatase activity in all cells by approximately fifty per cent. The remaining activity is usually sufficient for the normal production of heme and to prevent an accumulation of protoporphyrin. However, approximately ten per cent of individuals who inherit a mutated gene from one parent also inherit a low-expression variant of the normal gene (an underactive gene) from the other parent. The gene’s ability to produce ferrochelatase is reduced because one of its normal structural constituents has been replaced (polymorphism IVS3-48T/C). Total enzyme activity is then approximately 30 per cent of normal, and protoporphyrin accumulates in cells. Cells in bone marrow which develop into red blood cells are especially sensitive to low levels of ferrochelatase. The ferrochelatase enzyme normally transforms all protoporphyrin present within the cell into heme, but now protoporphyrin accumulates and is gradually released into the body by immature red blood cells, eventually reaching the skin and the liver.

When red blood cells are exposed to sunlight as they travel through the outer layers of the skin, protoporphyrin leaks out of the cells and accumulates in the innermost layers of the blood vessels. Activated by short wavelength light, protoporphyrin forms free radicals that are harmful to tissue. The resulting inflammation quickly results in severe, long-lasting skin pain, a characteristic symptom of erythropoietic protoporphyria. This effect is also produced by short-wavelength artificial light.

The excess of protoporphyrin is passed by the liver via the bile ducts to the intestines. In some carriers with very low levels of ferrochelatase, the high levels of protoporphyrin discharged cause severe damage to liver cells and bile ducts.

Heredity

If one parent is a healthy carrier of a mutated gene and the other parent has a low-expression variant of the normal gene, there is a 25 per cent risk that their child will receive the mutated gene in combination with the low-expression variant. This means that enzyme activity in immature red blood cells will be impaired, resulting in hypersensitivity to light. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and, like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene. (See figure 1.)

If both parents are healthy carriers of the mutated gene there is a 25 per cent risk that their child will receive two copies of the mutated gene. Enzyme activity is then very low - perhaps only 5 to 15 per cent of normal activity. This causes the most serious form of erythropoietic protoporphyria, associated both with a severe hypersensitivity to sunlight and with a major risk of liver complications later in life. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and, like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene. (See figure 2.)

In Sweden the incidence of erythropoietic protoporphyria is approximately 1 per 200,000 individuals. The low-expression variant of the normal gene resulting in impaired enzyme production is present in only eight per cent of the Swedish population, while the mutated, inactive gene is very rare. The probability of inheriting both the low-expression normal variant and the mutated, inactive gene is therefore small.

 

Figure 1: A child with the disease may have inherited from one parent a gene which either does not produce the enzyme or codes for an inactive enzyme, and from the other parent a low-expression variant of the normal gene.

 

Figure 2. A child with severe symptoms of the disease may have inherited two genes which are either coded to produce an inactive enzyme, or cannot be translated to produce an enzyme. 

Symptoms

Skin symptoms

Skin symptoms usually present during infancy or early childhood but in rare cases may present during the teens or later. The most characteristic symptom is hypersensitivity to sunlight. The reaction is sudden and severe. Within hours or even minutes of being in the sun there is an intense, burning sensation in the skin.

Skin reactions are not always visible and as a result diagnosis may be delayed, especially during infancy when the child is unable to describe the burning sensation. After prolonged sun exposure, swelling and redness may occur. The severity of symptoms fluctuates during the year, depending on the degree of exposure to sun, wind or cold. In the summer there is a high risk of sun exposure, but many people with the disease experience most discomfort during early spring or on clear, crisp autumn days. Winters tend to be less problematic. For many people wind, cold or draughts may cause the same problems as heat and sunlight.

It is not uncommon for a person with the condition to spend hours in the sun without symptoms, only to find that the next day symptoms are triggered after only minutes of exposure to the sun. The reason is that on the first day such large amounts of protoporphyrin have been released that the skin becomes particularly sensitive the following day. Prolonged or repeated expose to the sun may cause chronic skin changes, including thickened, leathery skin particularly over the knuckles. Ulcers at the corners of the mouth and wrinkles around the mouth may also develop.

Gallstones and liver function

Protoporphyrin is transported by the blood to the liver from where it is discharged into the intestines via the bile. In some individuals, more protoporphyrin flows through the gall system than can be held in solution in the bile, in which case excess protoporphyrin crystallises and forms gallstones. In some people this may occur as early as in their teens.

Large amounts of protoporphyrin can damage both liver cells and bile ducts, impairing the liver’s excretory function. This is a very serious complication as the liver is unable to rid itself of excess protoporphyrin. Liver function deteriorates with increasing speed as the rapidly accumulating protoporphyrin becomes more toxic. If the condition is not treated promptly, it can lead to potentially fatal acute liver failure within weeks.

In people with skin symptoms, increasing quantities of protoporphyrin in the stool is a sign that the liver is working normally in excreting the excess. The same applies to another type of porphyrin, coproporphyrin I, most of which is excreted by the liver. When the liver’s excretory function is damaged, porphyrin levels in the stool fall while levels of coproporphyrin I in urine rise. At this stage, the liver can no longer remove the yellow pigment bilirubin from the blood and the rising concentrations cause jaundice, where the whites of the eyes and the skin turn yellowish. (Also known as icterus.) As the condition progresses, normal liver tissue is replaced by connective tissue (liver cirrhosis), and the liver’s ability to produce certain blood proteins is impaired. This process can be monitored by repeated blood tests.

Occasionally, even young people with the disease may present with acute liver failure. This usually occurs after alcohol consumption, as alcohol puts a strain on the enzyme system of the liver. Symptoms of acute liver failure include yellowish skin and whites of the eyes (jaundice), abdominal pain, fatigue and increased tendencies to bleed and bruise. Hypersensitivity to light often increases significantly. Acute liver failure is a serious condition requiring immediate intervention.

Psychological and social consequences

The inability of people with erythropoietic protoporphyria to spend time outdoors because of hypersensitivity to sunlight may prevent them from participating in many social activities. Limitations on everyday life, especially when combined with recurring skin pain, can be trying.

Diagnosis

If individuals present with skin symptoms consistent with erythropoietic protoporphyria, the diagnosis can be confirmed by establishing high protoporphyrin concentrations in red blood cells and blood plasma.

The diagnosis can also be confirmed by DNA analysis. Identification of carriers, pre-natal and embryo diagnoses are all possible if the disease has been identified in a family.

Treatment/interventions

Treatment of acute skin symptoms

When skin pain is acute, a cold bath or a cold cloth held to the skin helps some people. Wet compresses followed by the application of hydrocortisone cream can also be effective, as can antihistamine medication (used in allergy treatment).

Preventive measures

Information and advice on the disease, and on how to handle everyday situations in order to minimise symptoms, has been produced by health care professionals and the patient association The Swedish Porphyria Association. (See under “Organizations for the disabled/patient associations.”) It is also important that people close to the person affected are informed about the disease and its impact on the life of the individual.

Preventive treatment of erythropoietic protoporphyria involves avoiding exposure to ultraviolet and blue wavelength light. Some people with the disease may be particularly sensitive to cold and draughts. As far as possible it is important to avoid sunlight, both direct and indirect, including light passing through glass windows. There is an effective filter available which may be used against light coming through windows. Cotton gloves, a sun hat, or a parasol can also prove useful. Outdoor activities such as walking or jogging should preferably be carried out in early morning or evening. Although a lifestyle adapted to the disease may be demanding, these recommendations should be followed as closely as possible in order to prevent the occurrence of symptoms and the onset of chronic skin changes.

Outdoor activities entailing intensive or prolonged exposure to the sun and many outdoor sports should be avoided.

It is important to know that light sources other than the sun, including tanning beds, operating room lighting, and other types of work lights may also produce symptoms. People with impending liver failure may become more sensitive to light. Mucous membranes are also light-sensitive and should be protected from harmful light during long abdominal operations (including liver transplantation for EPP patients with impending liver failure). Protective measures include a yellow filter on surgical lighting. Shorter surgical procedures, including keyhole surgery, can be performed with normal surgical lighting.

Pre-school, school, workplace and home environments should be adapted so that harm to the skin is avoided. Winds and indoor draughts are common problems. A climate control system or changes to the ventilation system may be necessary, while lighting and the inflow of sunlight may also have to be modified. In many cases the best solution may be to work from home. Outdoor work is normally unsuitable.

Physical exertion is not harmful to people with erythropoietic protoporphyria. During periods when the disease is active the individual should take care to eat properly as the production of protoporphyrin increases while fasting. It is important not to become overweight as dieting is harmful.

Many people are helped by sunscreens and artificial protective pigmentation. Sunscreens and sunblocks protect against some, but not all, damaging light wavelengths. Sunscreen or sunblock with the highest protective factor should be applied in the morning. This treatment may be combined with the use of a sunless tanning product that darkens and protects the skin (dihydroxyacetone). This should be applied in the evening.

The vitamin beta-carotene, taken in tablet form, gives the skin a yellowish tint. In some people this colour protects the skin to the extent that they are able to live practically normal lives, while other people notice only slight improvements, or none at all. As the intestinal absorption of beta-carotene varies from person to person, blood levels should be checked after a few weeks. An important effect of beta-carotene supplements is believed to be the neutralisation of free radicals thought to cause protoporphyrin’s toxicity.

The symptoms of erythropoietic protoporphyria may be the result of the production of free radicals. Attempts have been made to reduce light sensitivity by preventive treatment with antioxidants, substances which protect body tissues from free radicals. One such antioxidant is cysteine, which is normally present in the body. Some people feel that this treatment makes them less sensitive to sunlight. Fruits and vegetables are good food choices as they are high in antioxidants. It is likely that some antioxidants also contribute to making protoporphyrin more water-soluble, thus facilitating its excretion in urine.

Factors increasing the rate of production of new blood cells should be avoided. Alcohol should be avoided as it stimulates red blood cell production and thus the production of toxic protoporphyrins. Alcohol also exacerbates liver damage and impairs the important process of bile production. For this reason people with erythropoietic protoporphyria are advised to abstain from alcohol, particularly in periods when the disease is active. People with the disease should not become blood donors.

The liver should be protected as much as possible from any harmful factors. Vaccinations against hepatitis A and B are recommended.

Treatment for impending liver failure

In people with low levels of ferrochelatase activity the liver may be so damaged that its capacity to excrete excess protoporphyrin is seriously impaired and liver failure results. In these cases, immediate treatment is of critical importance and it may be necessary to consider a liver transplant. Blood transfusions may be needed to reduce the production of red blood cells in the bone marrow and medication may be given to facilitate the production of bile, until a suitable donor organ is available. However, a liver transplant does not cure the underlying cause of the condition, which is the excess production of protoporphyrin in bone marrow, and therefore it is likely that a new liver will eventually also suffer damage. For this reason haematopoietic stem cell transplantation (a bone marrow transplant) may be a viable treatment option when there is a risk of serious liver damage. Haematopoietic stem cell transplantation cures the underlying disease, and the patient’s hypersensitivity to sunlight disappears. Treatment, however, is not without risk as it requires the body’s immune system to close down temporarily. For this reason haematopoietic stem cell transplantation as a treatment for erythropoietic protoporphyria is carried out only where there is severe liver damage.

Liver failure is a very serious condition. People with erythropoietic protoporphyria should therefore have their liver function checked regularly. This involves analyses of blood, urine and stool samples.

Psychological and social consequences

The social lives of people with erythropoietic protoporphyria often suffer as a result of necessary lifestyle restrictions. Although many people with the disease lead relatively problem-free lives, psychological support may still be important.

Practical advice

A filter (Sun Stop Yellow EPP film) which protects against light passing through car windows can be ordered from a Norwegian company. (Ganta Trading, Boks 39, Sentum, 0101 Oslo, Norge. www.ganta.no) The filter costs approximately 500 SEK per square metre and approximately 1000 SEK, to install in a car. (Prices are from 2011 and exclude Swedish MOMS.) A permit to install the filter can be obtained from the Swedish Road Administration. Contact the secretariat at The Swedish Porphyria Association for application forms. (See under heading, “Organizations for the disabled/patient associations etc.”)

This filter is the result of collaboration between researchers at Karolinska University Hospital Huddinge, and Nasjonalt Kompetansesenter för Porfyrisjukdomar (NAPOS) i Bergen, Norway.

The Swedish Porphyria Association can provide information, application forms, and the necessary certificates required by the Swedish Road Administration. (See under the heading “Organizations for the disabled/patient associations etc.”)

National and regional resources in Sweden

Porphyria Centre Sweden, CMMS, L7:05, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 714 45, fax: +46 8 517 714 74, email: porfyricentrum@karolinska.se, www.karolinska.se/porfyri.

Porphyria Centre Sweden has a specialist laboratory for diagnosing the porphyrias, including DNA analyses. The Centre also offers telephone consultations and has a database register of all Swedish patients, organised by family.

In order to prevent misdiagnosis and incorrect treatment, all diagnosed carriers receive a “warning card” from Porphyria Centre Sweden for use in contacts with health care services. The card confirms the diagnosis and carries a warning that special care needs to be taken if the carrier is to be exposed to certain types of light sources.

Resource personnel

Pauline Harper, MD, PhD, Porphyria Centre Sweden, CMMS, L7:05, Karolinska University Hospital, Solna, SE-117 76 Stockholm, Sweden. Tel: +46 8 517 714 47, email: pauline.harper@karolinska.se.

Staffan Wahlin, MD, PhD, Hepatology Section, Digestive Health Centre, Medicine K63, C2 71, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 879 84, email: staffan.wahlin@karolinska.se.

Courses, exchanges of experience, recreation

In collaboration with Porphyria Centre Sweden, Karolinska University Hospital, Solna arranges clinical and patient meetings of The Swedish Porphyria Association (RMP) for information purposes. (See address under, “Organizations for the disabled/patient associations etc.”)

Organizations for the disabled/patient associations

The Swedish Porphyria Association (Riksföreningen mot Porfyrisjukdomar, RMP), Karolinska University Hospital, Huddinge, M 96, 141 86 Stockholm, Sweden. Tel: +46 8 711 56 09, email: porfyrisjukdomar@gmail.com, www.porfyri.se.

Rare Diseases Sweden, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 764 49 99, email: info@sallsyntadiagnoser.se, www.sallsyntadiagnoser.se. Rare Diseases Sweden is a national association working for people with rare diseases and various disabilities.

Courses, exchanges of experience for personnel

The Swedish Porphyria Association (RMP) publishes care programmes for all forms of porphyria.

Research and development (R&D)

Porphyria Centre Sweden is involved in continuous development and research into increasing the reliability of diagnoses. One of the ways this is to be achieved is through an international project where all European porphyria centres collaborate in the European Porphyria Network (EPNET) to improve the quality of life of porphyria patients.

For about a decade, researchers in Sweden and abroad have been investigating the genetic background of erythropoietic protoporphyria in Sweden and elsewhere. Knowledge of which mutations cause the disease is almost complete and carrier diagnosis is now one hundred per cent reliable. Tools providing prognostic information about carriers have also become available.

Within the framework of European collaboration, work is ongoing to catalogue the prevalence and symptoms of the various forms of porphyria.

Information material

An information leaflet on erythropoietic protoporphyria (article number 2011-12-13), that summarises the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2006-126-1206). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

The Swedish Porphyria Association (RMP) publishes information for patients and health care professionals. The brochures below can be ordered from RMP’s office, see under "Organizations for the disabled/patient associations".

In Swedish only:
The Swedish Porphyria Association (RMP). Kort information om porfyrisjukdomarna och om hur patientföreningen arbetar.

S. Thunell. Frågor och svar vid EPP. An information booklet.

In Norwegian only:
Nasjonalt kompetansesenter för porfyrisjukdomar (NAPOS) has published new information: Erytropoetisk protoporfyri (new edition, 2011), www.helse-bergen.no/omoss/avdelinger/napos/Sider/erytropoietisk-protoporfyri-epp.aspx.

Literature

Anstey AV, Hift RJ. Liver disease in erythropoietic protoporphyria: insights and implications for management. Gut 2007; 56: 1009-1018.

Holme SA, Anstey AV, Finlay AY, Elder GH, Badminton MN. Erythropoietic protoporphyria in the UK: clinical features and effects on quality of life. Br J Dermatol 2006; 155: 574-581.

Bruch-Gerharz D, Bolsen K, Gerharz CD, Goerz G. Erythropoietic protoporphyria and terminal hepatic failure. Acta Derm Venerol 1996; 76: 453-456.

Doss MO, Frank M. Hepatobiliary implications and complications in protoporphyria, a 20 year study. Clin Biochem 1989; 22: 223-229.

Floderus Y, Harper P, Henrichson A, Thunell S. Porfyri - minering i metabolismen. Läkartidningen 1998; 95: 2932-2935.

Gouya L, Deybach JC, Lamoril J, DaSilva V, Beaumont C, Grandchamp B et al. Modulation of the phenotype in dominant erythropoietic protophorphyria by a low level expression of the normal ferrochelatase allele. Am J Hum Genet 1996; 58: 292-299.

Harper P, Thunell S, Ericzon BG, Hultcrantz R, Ros AM. Risk för leversvikt vid erytropoetisk protoporfyri. Var uppmärksam på kolestatisk utveckling! Läkartidningen 1998; 95: 3051-3056.

Magnus IA, Jarrett A, Prankerd TA, Rimington C. Erythropoietic protoporphyria. A new porphyria syndrome with solar urticaria due to protoporphyrinaemia. Lancet 1961; 2: 448-451.

Rand EB, Bunin N, Cochran W, Ruchelli E, Olthoff KM, Bloomer JR. Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria. Pediatrics 2006; 118: 1896-1899.

Rufener E. Erythropoietic protoporphyria: a study of its psychosocial aspects. Br J Dermatol 1987; 116: 703-708.

Thunell S, Harper P, Brun A. Porphyrins, porphyrin metabolism and porphyrias. IV. Pathophysiology of erythyropoietic protoporphyria—diagnosis, care and monitoring of the patient. Scand J Clin Lab Invest 2000; 60: 581-604.

Wahlin S, Aschan J, Bjornstedt M, Bromeé U, Harper P. Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis. J Hepatol 2007; 46: 174-179.

Wahlin S, Floderus Y, Stål P, Harper P. Erythropoietic protoporphyria in Sweden: demographic, clinical, biochemical and genetic characteristics. J Intern Med 2011; 269: 278-288.

Wahlin S, Srikanthan N, Hamre B, Harper P, Brun A. Protection from phototoxic injury during surgery and endoscopy in erythropoietic protoporphyria. Liver Transpl 2008; 14: 1340-1346.

Wiman A, Floderus Y, Harper P. Novel mutations and phenotypic effect of the splice site modulator IVS3-48C in nine Swedish families with erythropoietic protoporphyria. J Human Gen 2003; 48: 70-76.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim
Search: erythropoietic protoporphyria

Orphanet, European database.
www.orpha.net
Search: erythropoietic protoporphyria

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Stig Thunell, Karolinska University Hospital, Solna in Stockholm, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2012-02-27
Version: 3.2
Publication date of the Swedish version: 2011-12-29

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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