Erythropoietic protoporphyria

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Classification according to ICD-10
E80.0 Hereditary erythropoietic porphyria
ICD-10 online (WHO version 2019)

The erythropoietic Protoporphyrie ( EPP ) is a rare, hereditary metabolic disorder of heme synthesis and is one of the group of porphyria . The disease manifests itself mainly through a painful (sun) light sensitivity; occasionally from photodermatosis . The first symptoms usually appear between the ages of 1 and 10 and are expressed in avoidance of sunlight and hyperactivity in children. In 20–30% of cases, there may be a slight impairment of liver function. Severe liver damage occurs in 5% of those affected and a liver transplant is necessary.

Pathogenesis

Histological findings (skin)

Biochemistry: The enzyme ferrochelatase is responsible for the last step in the production of the red blood pigment, the heme  b. The heme results from the incorporation of an iron (II) ion into the protoporphyrin ring, its main task is the transport of oxygen in the blood. If, for example, the activity of ferrochelatase is restricted by a mutation , not enough iron ions can be incorporated and the precursor substance, the eponymous protoporphyrin, accumulates in the red blood cells, the blood plasma and the liver. It is assumed that a reduction in ferrochelatase activity to below 30% is necessary for EPP to develop.

Phototoxicity: The ring-shaped protoporphyrin is responsible for the light intolerance. The skin of those affected reacts most sensitively to light in the wavelength range of around 400 nanometers, as protoporphyrin absorbs light of this wavelength particularly well: The main absorption band of protoporphyrin is 400 nm (UV-A radiation / Soret band ), other absorption bands exist between 500 and 625 nm. The protoporphyrin molecules get into an energetically excited state through light absorption, the release of energy creates oxygen radicals that attack and destroy structures in the tissue ( oxidative stress ). Inflammatory reactions and involvement of the immune system are the result (itching and swelling of the skin exposed to sunlight).

Genetics: The inheritance in EPP is autosomal recessive if it is caused by mutations in the FECH gene. In rare cases, EPP can be traced back to mutations in the ALAS2 gene, and the disease is then inherited on the X chromosomal .

Liver involvement: Protoporphyrin is not soluble in water and therefore cannot be removed from the body with the urine. In the liver, the protoporphyrin is converted into a transportable form and then excreted in the stool. If too much protoporphyrin is washed from the blood into the liver, the capacity of the organ can be overloaded and crystalline deposits occur in the liver cells. These deposits damage the cells of the bile ducts and thereby impair the discharge of the bile. Fluorescent gallstones often develop .

In addition, up to 5–10% of those affected develop life-threatening liver complications. In an early stage of liver involvement, the concentration of protoporphyrin in the red blood cells and blood plasma increases demonstrably, and the conversion product coproporphyrin isomer I is increasingly found in the urine. In the advanced stage, jaundice develops due to liver cirrhosis . It is not yet fully understood why only 5–10% of those affected by EPP develop severe liver dysfunction. There is evidence that liver cells have detoxification mechanisms in order to be able to tolerate increased stress. If this ability is missing, the liver is more sensitive to the toxic effects of protoporphyrin. Mutations in certain sections of the ferrochelatase gene seem to favor liver involvement.

Symptoms

Pain after exposure to light / sun
Edema and erythema in acute photosensitive reaction in EPP
The main symptom of EPP usually occurs from the age of 10 and is characterized by burning, tingling or itching when exposed to the sun; this can occur within a few minutes to hours after exposure. Artificial light can also cause pain and phototoxicity. In many of those affected, there are also visible changes in the skin, especially edema , blistering and reddening ; However, these visible skin changes do not occur in all affected persons. Symptoms can persist for hours to days after the initial exposure.
If the person concerned has been exposed to the personal threshold dose of light, other stimuli such as drafts or cold are perceived as unpleasant and painful. If the stay in the sun cannot be broken off, the symptoms increase to an extremely painful, burning sensation of heat. Those affected try to relieve the symptoms by cooling, often objects made of metal or glass are held on the affected skin areas or cooled with (running) cold water. Warmth, including (your own) body heat, is perceived as painful heat.
Permanent changes
After repeated exposure and phototoxicity, chronic skin changes can occur (including lichenification, deviating pigmentation, coarsening of the skin relief (lichenoid infiltrates)). The dorsal surfaces of the hand and face are most affected.
Psychosomatic symptoms
The pain that is triggered can lead to insomnia, irritability and motor restlessness.

Particularities:

  • Since most of those affected do not have any visible symptoms on the skin, the patient is often not believed. The resulting pressure to adapt, despite the pain, often leads to the symptoms being hidden ( dissimulation )
  • Only the areas of the skin exposed to light are affected.
  • Window panes do not provide adequate protection. Most sunscreens are ineffective for the same reason, as they mainly filter UV-B light.
  • In some cases, symptoms partially or completely go away during pregnancy but return after the baby is born. This indicates an influence of hormones on the symptoms of EPP, but the mechanism has not yet been clarified.
  • There are some as yet misunderstood cases of patients who report asymptomatic stays in countries with high solar intensity such as Brazil, Egypt, Cuba, Florida and India while they regularly have problems with the sun in Europe.
  • Loss of the lunula (nails) and photo-onycholysis can occur

frequency

The symptoms of EPP usually appear in the first months or years of life. Based on the spread of genetic predisposition, it is estimated that one in 100,000 people in Germany has EPP. With 80 million people in Germany, this corresponds to 800 cases, the vast majority of which have not yet been recognized.

Rare cases of first manifestations later in life have been described, the cause being changes in the blood stem cells in adulthood. In animal experiments, some substances have been described as triggering EPP.

diagnosis

Due to its rarity and the invisible symptoms in the acute stage, erythropoietic protoporphyria is often not diagnosed for many years (on average 16 years after the onset of symptoms).

All those affected who suffer from a pathogenic reduction in ferrochelatase activity are photosensitive - but not all develop visible skin changes. In children this is noticeable through extreme avoidance behavior, such as running through sunny areas to the closest possible shade, using small temperature differences of materials for cooling, restlessness, insomnia and long screaming.

Pathognomonic for EPP is an increase in the free protoporphyrin level (in contrast to zinc-bound protoporphyrin) in the erythrocytes; the measurement is a reliable diagnosis for EPP. In addition, a plasma fluorescence examination can be used, which is not so important, but can provide confirmation and exclude other porphyria diseases. With an excitation of 410 nm, the EPP has a maximum fluorescence emission at 634 nm. (For Porphyria cutanea tarda 617 nm, for Porphyria variegata 625 nm.)

Differential diagnosis:

  • An increased measurement of zinc-bound protoporphyrin can also occur in the case of lead poisoning, iron deficiency or other prophylactic diseases.
  • Other diseases to be excluded: phototoxic drug reaction, hydroa vacciniforme, solar urticaria, contact dermatitis, angioedema, other types of porphyria.

treatment

Treatment of affected skin areas
Existing symptoms subside within hours to days when you stay in dark, cool rooms. Cooling the affected skin areas with water is not recommended, as the resulting relief is only short-term and the skin dries out and tears easily. Careful warming of the affected skin areas with z. B. warm water was described by some patients as initially very painful, but afterwards helpful. Pain relievers are usually ineffective.
New treatment approaches
There is currently no real cure; new treatment approaches are currently being pursued and are in various early stages of development:
Beta-carotene : Some individual reports indicate a possible effectiveness of high doses of beta-carotene (Mathews et al. 1975 ff). However, after a meta-study, beta-carotene therapy is no longer discussed as a suitable measure (European Porphyria Meeting, Rotterdam, May 2007; meta-study: Minder et al. 2008).
Afamelanotide : Since 2014, treatment with the active ingredient Afamelanotide has been approved for adult EPP patients in the EU, which stimulates skin pigmentation and has an anti-inflammatory effect. Since 2007, more than 350 patients have been treated in several placebo-controlled studies worldwide, and in a long-term observational study in 115 Italian and Swiss EPP patients over eight years, safety, treatment adherence / reasons for discontinuing treatment and quality of life were measured. In the approval-relevant study (Langendonk et al. 2015), the patients were exposed to direct sunlight painlessly for twice as long as the untreated control group.

The most important measure remains the consistent avoidance of sunlight and sometimes artificial light sources and appropriate clothing (gloves, hat, long sleeves, umbrella, etc.). Since the main trigger of the symptoms is the visible light spectrum between violet and blue, yellow (complementary color) colored films have a special protective effect. Sun cream with a high sun protection factor in the UV-A range and micropigments is recommended, but does not adequately cover the triggering wavelengths. Thick, commercially available covering cosmetics are somewhat helpful. We advise against alcohol in large quantities and other substances that are harmful to the liver; advanced liver damage can only be counteracted by transplantation.

Psychosocial Aspects

Difficult employability
Since there are no visible changes to the skin in most of those affected, the presence of real pain is often doubted by the social environment and even by doctors. The pain caused by the sun cannot be compared to any known type of pain, which makes conveying the quality and intensity of the sensations extremely difficult for those affected. The descriptions (“hot needles that pierce the skin” or “ice-cold tingling”) that those affected develop independently of one another for the very special sensations are very similar to one another.
Social constraints
The difficulty of communicating the externally invisible pain (“Don't stand in line ...”) leads, especially in children, to adaptive behavior and repression mechanisms. Although the vast majority of those affected know very early on that the sun is not good for them, they repeatedly expose themselves to potentially dangerous situations. The correct diagnosis of EPP, which is often only made in adulthood, makes things more difficult. Those affected are excluded from many outdoor activities or always dependent on protective clothing that is conspicuous and the understanding of the group members.
Effects on the psyche
The isolation resulting from the restrictions and the need to avoid sunlight are often difficult for those affected. Since the cause of the sun intolerance is recognized very late in many cases, many people concerned fear for years that their suffering could be psychological. But even after a diagnosis, knowledge of a possible impairment of liver functions can be stressful.
Relatives
The situation is not easy, especially for families with one sick child; parents, for example, often have to meet the needs of unaffected children at the same time. The hazard potential of daylight fluctuates and is extremely difficult to estimate for those who are not affected. If the child has been exposed to light for too long and shows the first symptoms, the sensitivity to body heat is usually so high that physical proximity is perceived as painful. Any physical contact, well-intentioned, worsens the symptoms and becomes a burden for the child. In a partnership, EPP can have a stressful effect, as those affected often withdraw or become irritable and restless when symptoms break out.

Related topics

The Photodynamic Therapy (.. V a skin cancer) for the treatment of various cancers based on the same cell-damaging effect that protoporphyrin even with EPP has: where cancer cells are stimulated to form protoporphyrin and save. The areas are then exposed to visible light, which selectively destroys the cancer cells. The reaction is the same in all symptoms as an EPP, the treated complain of similar pain perceptions and intensities.

literature

Review article EPP:

  • E. Hölzle: Photodermatoses and light reactions of the skin. Wissenschaftliche Verlagsgesellschaft, Stuttgart 2003, ISBN 3-8047-1890-6 .
  • O. Braun-Falco , G. Plewig, HH Wolff, W. Burgdorf, M. Landthaler: Dermatology and Venereology. 5th edition. Springer Verlag, Berlin / Heidelberg 2005, ISBN 3-540-40525-9 .
  • DJ Todd: Erythropoietic protoporphyria. In: Br J Dermatol . 131, 1994, pp. 751-766.
  • X. Schneider-Yin, L. Gouya, A. Meier-Weinand, J.-C. Deybach, EI Minder: New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care. In: European Journal of Pediatrics. 159, 2000, pp. 719-725.

Treatment:

  • EI Minder, X. Schneider-Yin, J. Steurer, LM Bachmann: A systematic review of treatment options for dermal photosensitivity in erythropoietic protoporphyria. In: Cellular and molecular biology (Noisy-le-Grand, France). 55 (1), 2008, pp. 84-97.
  • JG Langendonk, M. Balwani, KE Anderson, HL Bonkovsky, AV Anstey, DM Bissell, JD Phillips and others: Afamelanotide for erythropoietic protoporphyria. In: New England Journal of Medicine. 373 (1), 2015, pp. 48-59.
  • G. Biolcati, E. Marchesini, F. Sorge, L. Barbieri, X. Schneider-Yin, EI Minder: Long ‐ term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria. In: British Journal of Dermatology. 172 (6), 2015, pp. 1601-1612.

Psychosocial Aspects

  • EA Rufener: Shadow jumping. Disease adaptation in people with erythropoietic protoporphyria. Dissertation . University of Zurich, 1990, DNB 94464693X .

Study on EPP and quality of life from the UK:

  • SA Holme, AV Anstey, AY Finlay, GH Elder, MN Badmington: Erythropoietic protoporphyria in the UK: clinical features and effect on quality of life. In: British Journal of Dermatology . 155, 2006, pp. 574-581.

"Invisible" skin symptoms with EPP:

  • Anne LY Lecluse, Veronica CM Kuck-Koot, Huib van Weelden, Vigfus Sigurdsson, Ingrid M. Russel, Jorge Frank, Suzanne GMA Pasmans: Erythropoietic protoporphyria without skin symptoms-you do not always see what they feel. In: Eur J Pediatr. 2007. ( doi: 10.1007 / s00431-007-0557-1 )

Liver involvement:

  • S. Navarro, P. del Hoyo, Y. Campos, M. Abitbol, ​​M.-J. Moran-Jimenez, M. Garcia-Bravo, P. Ochoa, M. Grau, X. Montagutelli, J. Frank, R. Garesse, J. Arenas, RE de Salamanca, A. Fontanellas: Increased mitochondrial respiratory chain enzyme activities correlate with minor extent of liver damage in mice suffering from erythropoietic protoporphyria. In: Experimental Dermatology . 14, 2005, pp. 26-33.
  • E. Alexandrakis, R. Porstmann, J. Rüschoff: Erythropoietic protoporphyria - an enzymatic disruption of heme biosynthesis and its effects on liver and skin. In: Gastroenterology up2date. 2, 2006, pp. 7-11.

Ferrochelatase:

  • HA Dailey, TA Dailey, C.-K. Wu, AE Medlock, K.-F. Wang, JP Rose, B.-C. Wang: Ferrochelatase at the Millennium: Structures, Mechanisms and [2Fe-2S] clusters. In: CMLS, Cell. Mol. Life Sci. 57, 2000, pp. 1909-1926.

Web links

Individual evidence

  1. ^ María José Casanova-González: Liver disease and erythropoietic protoporphyria: A concise review . In: World Journal of Gastroenterology . tape 16 , no. 36 , 2010, ISSN  1007-9327 , p. 4526 , doi : 10.3748 / wjg.v16.i36.4526 ( wjgnet.com [accessed October 26, 2018]).
  2. ^ IA Magnus: Photobiological Aspects of Porphyria . In: Proceedings of the Royal Society of Medicine . 61, February 1968, pp. 196-198. doi : 10.1177 / 003591576806100233 .
  3. ↑ PROTOPORPHYRIA, ERYTHROPOIETIC, 1; EPP1.  In: Online Mendelian Inheritance in Man . (English)
  4. ↑ PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED; XLEPP.  In: Online Mendelian Inheritance in Man . (English)
  5. ↑ SA Holme, AV Anstey, AY Finlay, GH Elder, MN Badminton: Erythropoietic protoporphyria in the UK: clinical features and effect on quality of life . In: The British Journal of Dermatology . tape 155 , no. 3 , September 2006, ISSN  0007-0963 , p. 574-581 , doi : 10.1111 / j.1365-2133.2006.07472.x , PMID 16911284 .