Erythropoietic protoporphyria

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Erythropoietic protoporphyria
Other namesEPP [1]
Chronic skin lesions of EPP.jpg
Chronic skin lesions of EPP
Specialty Endocrinology, dermatology   OOjs UI icon edit-ltr-progressive.svg
Risk factors pain and irritation

Erythropoietic protoporphyria (or commonly called EPP) is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the red blood cells (erythrocytes), plasma, skin, and liver. [2] The severity varies significantly from individual to individual.

Contents

A clinically similar form of porphyria, known as X-Linked dominant protoporphyria, was identified in 2008. [3]

Presentation

Acute photosensitivity reaction in EPP. Acute photosensitivity reaction in EPP.jpg
Acute photosensitivity reaction in EPP.

EPP usually presents in childhood with the most common mode of presentation as acute photosensitivity of the skin. It affects areas exposed to the sun and tends to be intractable. A few minutes of exposure to the sun induces pruritus, erythema, swelling and pain. [4] Longer periods of exposure may induce second degree burns. After repetitive exposure, patients may present with lichenification, hypopigmentation, hyperpigmentation and scarring of the skin. [5] [6]

EPP usually first presents in childhood, and most often affects the face and the upper surfaces of the arms, hands, and feet and the exposed surfaces of the legs. Most patients, if the EPP is not as severe, manifest symptoms with onset of puberty when the male and female hormone levels elevate during sexual development and maintenance. More severe EPP can manifest in infancy. EPP can be triggered through exposure to sun even though the patient is behind glass. Even the UV emissions from arc welding with the use of full protective mask have been known to trigger EPP. EPP can also manifest between the ages of 3 and 6.[ citation needed ]

Prolonged exposure to the sun can lead to edema of the hands, face, and feet, rarely with blistering and petechiae. Skin thickening can sometimes occur over time.[ citation needed ]

People with EPP are also at increased risk to develop gallstones. [7] One study has noted that EPP patients suffer from vitamin D deficiency. [8]

Liver failure

Protoporphyrin accumulates to toxic levels in the liver in 5–20% of EPP patients, leading to liver failure. The spectrum of hepatobiliary disease associated with EPP is wide. It includes cholelithiasis, mild parenchymal liver disease, progressive hepatocellular disease and end-stage liver disease. [5]

A lack of diagnostic markers for liver failure makes it difficult to predict which patients may experience liver failure, and the mechanism of liver failure is poorly understood. A retrospective European study identified 31 EPP patients receiving a liver transplant between 1983 and 2008, with phototoxic reactions in 25% of patients who were unprotected by surgical light filters. The same study noted a 69% recurrence of the disease in the grafted organ. Five UK liver transplants for EPP have been identified between 1987 and 2009. Frequent liver testing is recommended in EPP patients where no effective therapy has been identified to manage liver failure to date. [9]

Pregnancy

EPP photosensitivity symptoms are reported to lessen in some female patients during pregnancy and menstruation, although this phenomenon is not consistent, and the mechanism is not understood. [10] This brings evidence that the pathology of the disorder may be mediated partially by the sex hormones.

Genetics

Most cases of EPP are results of inborn errors of metabolism [2] but the metabolic defect in some patients may be acquired. [11] Mutation of the gene that encodes for ferrochelatase in the long arm of chromosome 18 is found in majority of the cases. Ferrochelatase (FECH) catalyzes the insertion of ferrous iron into the protoporphyrin IX ring to form heme. EPP exhibits both recessive and dominant patterns of inheritance and a high degree of allelic heterogeneity with incomplete penetrance. Most heterozygotes are asymptomatic. Symptoms do not occur unless FECH activity is less than 30% of normal, but such low levels are not present in a majority of patients. [12]

Pathophysiology

Cells which synthesize heme are predominantly erythroblasts/reticulocytes in the bone marrow (80%) and hepatocytes (20%). Deficiency of FECH results in increased release of protoporphyrin, which binds to albumin in plasma and subsequently undergoes hepatic extraction. Normally, most protoporphyrin in hepatocytes is secreted into bile; the remainder undergoes transformation into heme. Some protoporphyrin in bile is returned to the liver as a consequence of the enterohepatic circulation; the remaining protoporphyrin in the intestine undergoes fecal excretion. Protoporphyrin is insoluble and hence unavailable for renal excretion. In EPP, subnormal biotransformation of protoporphyrin into heme results in accumulation of protoporphyrin in hepatocytes. [13]

Since FECH deficiency is associated with increased concentrations of protoporphyrin in erythrocytes, plasma, skin and liver, retention of protoporphyrin in skin predisposes to acute photosensitivity. As a result of absorption of ultraviolet and visible light (peak sensitivity at 400  nm, with lesser peaks between 500–625 nm [14] ) by protoporphyrin in plasma and erythrocytes when blood circulates through the dermal vessels, free radicals are formed, erythrocytes become unstable and injury to the skin is induced. [5]

A significant increase in the hepatobiliary excretion of protoporphyrin can damage the liver through both cholestatic phenomena and oxidative stress [13] —predisposing to hepatobiliary disease of varying degrees of severity. [15] [16]

Diagnosis

EPP is generally suspected by the presence of acute photosensitivity of the skin and can be confirmed by detection of a plasmatic fluorescence peak at 634 nm. It is also useful to find increased levels of protoporphyrin in feces and the demonstration of an excess of free protoporphyrin in erythrocytes. [17]

Screening for FECH mutation on one allele or aminolevulinic acid synthase 2 gain-of-function mutation in selected family members may be useful, especially in genetic counseling.

Liver biopsy confirms hepatic disease in EPP by the presence of protoporphyrin deposits in the hepatocytes that can be observed as a brown pigment within the biliary canaliculi and the portal macrophages. Macroscopically, the cirrhotic liver can have a black color due to protoporphyrin deposits. Using polarized light the characteristic Maltese cross shape of birefringent crystalline pigment deposits is found. The examination of liver tissue under a Wood’s lamp reveals a red fluorescence due to protoporphyrin. Liver biopsy is not helpful for estimation of prognosis of liver disease. [15]

Treatment

There is no cure for this disorder; however, symptoms can usually be managed by limiting exposure to daytime sun and some types of artificial lighting. Most types of artificial lighting emit light in the problematic wavelengths, with fluorescent lighting being the worst offender. Color temperature can be a good indicator of what light is most detrimental, as the higher the color temperature, the more violet light (380–450 nm) is emitted. Incandescent and LED lighting in the soft white range (2700–3000 K) produce the least problematic light. Additionally, selecting lower wattage bulbs can reduce the overall output of light.

Since the photosensitivity results from light in the visible spectrum, most sunscreens are of little use (with the exception of non-nano zinc oxide which provides uniform protection between 290–400 nm and some protection up to 700 nm [18] ). Sun protective clothing can also be very helpful, although clothing with UPF values are only rated based on their UV protection (up to 400 nm) and not on their protection from the visible spectrum. Some sun protective clothing manufacturers use zinc oxide in their fabrics, such as Coolibar's ZnO Suntect line, which will offer protection from visible light. [19]

Window films which block UV and visible light up to 450 nm can provide relief from symptoms if applied to the patient's automobile and home windows.

Blue blocking screen protectors can help provide relief from symptoms caused by televisions, phones, tablets and computer screens.

EPP is considered one of the least severe of the porphyrias. Unless there is liver failure, it is not a life-threatening disease.

Approved therapies

Afamelanotide, developed by Australian-based Clinuvel Pharmaceuticals, was approved in Europe in December 2014 and in the United States in October 2019 for treatment or prevention of phototoxicity in adults with EPP. [20] [21]

Off-label therapies

Several drugs are used off label by patients with EPP:

Bone marrow transplantation, liver transplantation, acetylcysteine, extracorporeal albumin dialysis, parenteral iron and transfusion of erythrocytes are alternative plans for treatment of EEP.

Over-the-counter drug

Some over-the-counter drugs may help:

Experimental therapies

Bitopertin has been undergoing trials in Australia since 2022 with some success in allowing participants to spend more time in full sunlight without ill effects. [30]

Home remedies

Although erythropoietic protoporphyria symptoms may be temporarily suppressed with cold temperatures, patients have found that this method may extend, or even intensify pain and discomfort. However, home treatments that increase blood flow to the affected areas, such as immersion in warm water with quick drying or warm dry compresses, may increase the rate of pain relief. This has been noted as particularly effective in the hands, forearms, and face, as areas of decreased blood flow may be exposed to the accumulation of protoporphyrins for an extended period. [31]

Epidemiology

Case reports suggest that EPP is prevalent globally. The prevalence has been estimated somewhere between 1 in 75,000 and 1 in 200,000 [32] however it has been noted that the prevalence of EPP may be increasing due to a better understanding of the disease and improved diagnosis. [33] An estimated 5,000–10,000 individuals worldwide have EPP.[ medical citation needed ] EPP is considered the most common form of porphyria in children. [34] The prevalence in Sweden has been published as 1:180,000. [35]

History

Erythropoietic protoporphyria was first described in 1953 by Kosenow and Treibs [36] and completed in 1960 by Magnus et al. at the St John's Institute of Dermatology in London. [37]

See also

Related Research Articles

<span class="mw-page-title-main">Jaundice</span> Abnormal pigmentation symptom for disease of the liver

Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme metabolism, liver dysfunction, or biliary-tract obstruction. The prevalence of jaundice in adults is rare, while jaundice in babies is common, with an estimated 80% affected during their first week of life. The most commonly associated symptoms of jaundice are itchiness, pale feces, and dark urine.

<span class="mw-page-title-main">Bilirubin</span> Red pigment of the bile

Bilirubin (BR) is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the destruction of aged or abnormal red blood cells. In the first step of bilirubin synthesis, the heme molecule is stripped from the hemoglobin molecule. Heme then passes through various processes of porphyrin catabolism, which varies according to the region of the body in which the breakdown occurs. For example, the molecules excreted in the urine differ from those in the feces. The production of biliverdin from heme is the first major step in the catabolic pathway, after which the enzyme biliverdin reductase performs the second step, producing bilirubin from biliverdin.

<span class="mw-page-title-main">Porphyria</span> Metabolic disorders in which porphyrins build up in the body

Porphyria is a group of disorders in which substances called porphyrins build up in the body, adversely affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are rapid in onset and short in duration. Symptoms of an attack include abdominal pain, chest pain, vomiting, confusion, constipation, fever, high blood pressure, and high heart rate. The attacks usually last for days to weeks. Complications may include paralysis, low blood sodium levels, and seizures. Attacks may be triggered by alcohol, smoking, hormonal changes, fasting, stress, or certain medications. If the skin is affected, blisters or itching may occur with sunlight exposure.

<span class="mw-page-title-main">Heme</span> Chemical coordination complex of an iron ion chelated to a porphyrin

Heme, or haem, is a ring-shaped iron-containing molecular component of hemoglobin, which is necessary to bind oxygen in the bloodstream. It is composed of four pyrrole rings with 2 vinyl and 2 propionic acid side chains. Heme is biosynthesized in both the bone marrow and the liver.

<span class="mw-page-title-main">Hereditary coproporphyria</span> Medical condition

Hereditary coproporphyria (HCP) is a disorder of heme biosynthesis, classified as an acute hepatic porphyria. HCP is caused by a deficiency of the enzyme coproporphyrinogen oxidase, coded for by the CPOX gene, and is inherited in an autosomal dominant fashion, although homozygous individuals have been identified. Unlike acute intermittent porphyria, individuals with HCP can present with cutaneous findings similar to those found in porphyria cutanea tarda in addition to the acute attacks of abdominal pain, vomiting and neurological dysfunction characteristic of acute porphyrias. Like other porphyrias, attacks of HCP can be induced by certain drugs, environmental stressors or diet changes. Biochemical and molecular testing can be used to narrow down the diagnosis of a porphyria and identify the specific genetic defect. Overall, porphyrias are rare diseases. The combined incidence for all forms of the disease has been estimated at 1:20,000. The exact incidence of HCP is difficult to determine, due to its reduced penetrance.

<span class="mw-page-title-main">Variegate porphyria</span> Medical condition

Variegate porphyria, also known by several other names, is an autosomal dominant porphyria that can have acute symptoms along with symptoms that affect the skin. The disorder results from low levels of the enzyme responsible for the seventh step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.

<span class="mw-page-title-main">Porphyria cutanea tarda</span> Medical condition

Porphyria cutanea tarda is the most common subtype of porphyria. The disease is named because it is a porphyria that often presents with skin manifestations later in life. The disorder results from low levels of the enzyme responsible for the fifth step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.

<span class="mw-page-title-main">Aminolevulinic acid</span> Endogenous non-proteinogenic amino acid

δ-Aminolevulinic acid, an endogenous non-proteinogenic amino acid, is the first compound in the porphyrin synthesis pathway, the pathway that leads to heme in mammals, as well as chlorophyll in plants.

<span class="mw-page-title-main">Gunther disease</span> Medical condition

Gunther disease is a congenital form of erythropoietic porphyria. The word porphyria originated from the Greek word porphura. Porphura actually means "purple pigment", which, in suggestion, the color that the body fluid changes when a person has Gunther's disease. It is a rare, autosomal recessive metabolic disorder affecting heme, caused by deficiency of the enzyme uroporphyrinogen cosynthetase. It is extremely rare, with a prevalence estimated at 1 in 1,000,000 or less. There have been times that prior to birth of a fetus, Gunther's disease has been shown to lead to anemia. In milder cases patients have not presented any symptoms until they have reached adulthood. In Gunther's disease, porphyrins are accumulated in the teeth and bones and an increased amount are seen in the plasma, bone marrow, feces, red blood cells, and urine.

<span class="mw-page-title-main">Cholestasis</span> Medical condition

Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are:

<span class="mw-page-title-main">Sideroblastic anemia</span> Medical condition

Sideroblastic anemia, or sideroachrestic anemia, is a form of anemia in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells (erythrocytes). In sideroblastic anemia, the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need in order to transport oxygen efficiently. The disorder may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome, which can develop into hematological malignancies.

<span class="mw-page-title-main">Polymorphous light eruption</span> Medical condition

Polymorphous light eruption (PLE) presents with itchy red small bumps on sun-exposed skin, particularly face, neck, forearms and legs. It generally appears 30 minutes to a few hours after sun exposure and may last between one and 14 days. The bumps may become small blisters or plaques and may appear bloody,often healing with minimal scarring.

<span class="mw-page-title-main">Protoporphyrinogen oxidase</span>

Protoporphyrinogen oxidase or protox is an enzyme that in humans is encoded by the PPOX gene.

<span class="mw-page-title-main">Carotenosis</span> Skin discoloration caused by carotenoids

Carotenosis is a benign and reversible medical condition where an excess of dietary carotenoids results in orange discoloration of the outermost skin layer. The discoloration is most easily observed in light-skinned people and may be mistaken for jaundice. Carotenoids are lipid-soluble compounds that include alpha- and beta-carotene, beta-cryptoxanthin, lycopene, lutein, and zeaxanthin. The primary serum carotenoids are beta-carotene, lycopene, and lutein. Serum levels of carotenoids vary between region, ethnicity, and sex in the healthy population. All are absorbed by passive diffusion from the gastrointestinal tract and are then partially metabolized in the intestinal mucosa and liver to vitamin A. From there they are transported in the plasma into the peripheral tissues. Carotenoids are eliminated via sweat, sebum, urine, and gastrointestinal secretions. Carotenoids contribute to normal-appearing human skin color, and are a significant component of physiologic ultraviolet photoprotection.

<span class="mw-page-title-main">Ferrochelatase</span>

Protoporphyrin ferrochelatase (EC 4.98.1.1, formerly EC 4.99.1.1, or ferrochelatase; systematic name protoheme ferro-lyase (protoporphyrin-forming)) is an enzyme encoded by the FECH gene in humans. Ferrochelatase catalyses the eighth and terminal step in the biosynthesis of heme, converting protoporphyrin IX into heme B. It catalyses the reaction:

Erythropoietic porphyria is a type of porphyria associated with erythropoietic cells. In erythropoietic porphyrias, the enzyme deficiency occurs in the red blood cells.

<span class="mw-page-title-main">Solar urticaria</span> Medical condition

Solar urticaria (SU) is a rare condition in which exposure to ultraviolet or UV radiation, or sometimes even visible light, induces a case of urticaria or hives that can appear in both covered and uncovered areas of the skin. It is classified as a type of physical urticaria. The classification of disease types is somewhat controversial. One classification system distinguished various types of SU based on the wavelength of the radiation that causes the breakout; another classification system is based on the type of allergen that initiates a breakout.

<span class="mw-page-title-main">Zinc protoporphyrin</span> Chemical compound

Zinc protoporphyrin (ZPP) refers to coordination complexes of zinc and protoporphyrin IX. It is a red-purple solid that is soluble in water. The complex and related species are found in red blood cells when heme production is inhibited by lead and/or by lack of iron.

<span class="mw-page-title-main">Pseudoporphyria</span> Medical condition

Pseudoporphyria is a bullous photosensitivity that clinically and histologically mimics porphyria cutanea tarda. The difference is that no abnormalities in urine or serum porphyrin is noted on laboratories. Pseudoporphyria has been reported in patients with chronic kidney failure treated with hemodialysis and in those with excessive exposure to ultraviolet A (UV-A) by tanning beds.

<span class="mw-page-title-main">Harderoporphyria</span> Medical condition

Harderoporphyria is a rare disorder of heme biosynthesis, inherited in an autosomal recessive manner caused by specific mutations in the CPOX gene. Mutations in CPOX usually cause hereditary coproporphyria, an acute hepatic porphyria, however the K404E mutation in a homozygous or compound heterozygous state with a null allele cause the more severe harderoporphyria. Harderoporphyria is the first known metabolic disorder where the disease phenotype depended on the type and location of the mutations in a gene associated with multiple disorders.

References

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