Porphyria is the name given to a group of rare metabolic disorders that cause a build-up of certain chemicals in the body. Most of the porphyrias are inherited due to a faulty gene. All of the porphyrias interfere with the way the body makes haem.
So, why is haem so important? Haem is a vital component in the body. It is needed to make haemoglobin and important proteins.
For those with one of the porphyrias, there is a problem with one of the enzymes (special proteins) needed to produce haem. During the production of haem, some porphyrin and porphyrin precursors can be overproduced. In large quantities these can act as toxins to the body, causing significant problems. The way they build up differs depending on the type of porphyria.
There are two general categories of porphyria: the acute porphyrias which mainly affect the nervous system (also called acute hepatic porphyrias – AHP), and the cutaneous porphyrias, which mainly affect the skin. Two types of porphyria have both acute and skin symptoms (What is porphyria?).
Signs and symptoms of the porphyrias vary, depending on the specific type and severity. Although porphyria can’t be cured, in some of the porphyrias, a number of lifestyle changes can help to minimise the chance of triggering symptoms (Living with porphyria). Treatment for symptoms depends on the type of porphyria.
Acute intermittent porphyria is one of the acute porphyrias.
It is an inherited condition. So, it is passed on from generation to generation in what is called an autosomal dominant pattern. This means that it may be passed on from parents to their children. There is a 50% chance that an affected parent will pass the affected gene to each of their children. Both boys and girls stand an equal chance of being affected. The 50% chance of being affected is the same even if the affected person has never had any symptoms of porphyria. Thus, the condition often appears to have skipped a generation. (Please see our Testing and Inheritance page and handy testing leaflet for more information.)
AIP is one of four porphyrias that may present with acute attacks. These attacks are uncommon and are often difficult to diagnose. In AIP only acute attacks occur – the skin is never affected.
The condition cannot be cured, however, symptoms and their severity will vary from patient to patient. Some people will be asymptomatic (without any symptoms) throughout their lives. Most people have only one or a few acute attacks; whereas a minority suffer repeated attacks, sometimes over several years. Attacks occur in about one in five patients, more often in females than males. The most common age for an attack is from the late teens to the early forties and attacks are extremely rare in children before puberty.
Although acute attacks can be very severe, nowadays they are rarely fatal and most people make a full recovery. However, everyone with AIP is at risk of acute attacks, therefore it is vital to take a few simple precautions to reduce the risk of attacks.
For more information on AIP, please see the acute porphyrias FAQs.
Variegate porphyria is an INHERITED condition. It is passed on from generation to generation in what is called an autosomal dominant pattern. This means that it may be passed on from parents to their children; there is a 50% chance that an affected parent will pass the affected gene to each of their children. Both boys and girls stand an equal chance of being affected. The 50% chance of being affected is the same even if the affected person has never had any symptoms of porphyria. Thus, the disease often appears to have skipped a generation. (Please see our Testing and Inheritance page and handy testing leaflet for more information.)
Attacks are uncommon and often difficult to diagnose. In addition to acute symptoms, in VP the skin may also be affected. VP may cause areas of skin exposed to sunlight to become fragile, leading to blistering — skin should therefore be protected. In VP, the skin changes and acute attacks may occur at different times.
The condition cannot be cured, however, symptoms and their severity will vary from patient to patient. Most people with VP will never have any problems. Around 3 in 5 of those that do will have skin sensitivity only, while 1 in 5 will have acute attacks only and the remaining 1 in 5 have both acute attacks and skin problems. Everyone with VP should avoid triggers for acute attacks (see third column for more detail).
VP is quite rare in the UK, but is particularly common in South African individuals of Dutch descent.
Although acute attacks can be very severe, nowadays they are rarely fatal and most people make a full recovery. However, everyone with VP is at risk of acute attacks, therefore it is vital to take a few simple precautions to reduce the risk of attacks.
What skin problems can occur in VP?
Porphyrins can build up in the skin at certain times, causing sensitivity in areas exposed to sunlight, particularly the backs of the hands, face and legs, the scalp and the tops of feet (due to wearing sandals). Small blisters can appear. When they break, they leave narrow brown hollows (often called ‘ice pick lesions’.) They gradually fill up and disappear. Occasionally, VP can cause larger blisters that may be mistaken for porphyria cutanea tarda (a skin porphyria). VP can also cause small white dots (milia) which don’t go away.
Skin fragility is common, and scrapes and cuts take time to heal. Wash wounds carefully and protect with a dressing to prevent infection. Hands can be protected with gloves when scrapes are likely. If you have skin problems, you should look after your skin carefully.
Avoid direct sunlight as much as possible, even sunlight that passes through window glass in your home or car.
Clothing: Protect your skin by wearing dark-coloured densely woven clothing with long sleeves, light cotton gloves and a wide-brimmed hat. Not everyone will find this necessary or acceptable; adjust your clothing as it suits you. Many companies provide sun protective clothing (see back page for examples).
Sunscreens: Ordinary sunscreens are not very effective. The ones that help the most are the thick, opaque preparations with high protection factors (often containing titanium dioxide) that block visible light. Dundee cream is designed for skin porphyrias. Your GP needs to prescribe it for you. Your GP/pharmacist will need to contact Dundee Pharmaceuticals (see back page).
In the UK, the SPF (sun protection factor) tells you how effective the sunscreen is for UVB, and the star rating provides a measure of the UVA protection. High star rating sun creams provide limited protection.
Hereditary coproporphyria is also an inherited condition. People with HCP are prone to acute attacks, and can have skin problems during an acute attack.
ALAD deficiency porphyria, also called plumboporphyria, is an extremely rare condition and in the few cases described is similar to AIP. Please see the above notes on AIP and the acute porphyria FAQs.
Cutaneous (skin) porphyrias
PCT is the most common of the skin porphyrias affecting about one in 25,000 people in the UK (still quite rare), and is the only porphyria which is not always inherited. Very rarely, PCT is inherited. However, most people with PCT did not inherit the disorder and will not pass it on to their children. Here, PCT is secondary to another condition. It can be triggered later in life by heavy drinking, iron tablets, oestrogens, certain drugs or by liver infections.
Most people with PCT acquire / develop it (known as sporadic or Type I PCT), because an excess of iron in the liver, or the systems using iron, slow down the relevant enzyme (uroporphyrinogen decarboxylase – or UROD) and cause a build up of porphyrins.
This is often triggered by alcohol (moderately heavy drinking), though some people are sensitive to iron supplements, artificial oestrogens (found in the pill, HRT and prostate cancer treatment) or other drugs. Viral infections such as hepatitis C and HIV can also trigger it and in 20% of UK patients, it is caused by hereditary haemochromatosis, another genetic condition.
In a small percentage of patients, PCT may be partially due to an inherited mutation in the UROD gene, also called familial (or Type II) PCT. Not all family members who inherit a UROD mutation will develop the condition, as PCT requires the same triggering factors to be present as well.
EPP is a less common form of porphyria and classified in the UK as an ultra rare disease. It is an inherited disorder that is passed on from parents to their children. However, the inheritance of EPP is rather complex. It is currently believed that a severely faulty gene (the ferrochelatase or FECH gene), paired with a less severely affected variant of the gene can cause EPP. When paired in combination with other variants the EPP gene gives no problems, meaning inheritance can seemingly skip generations until it appears again. Please see the testing and inheritance page for more information.
Although EPP patients initially present by reporting intense burning pain and irritation in the skin, EPP is actually a metabolic disorder in the haem pathway. The haem pathway serves many essential processes in the body including building haemoglobin which is important to the transportation of oxygen around the body. When exposed to specific wavelengths of light, EPP patients suffer a severe phototoxic reaction resulting in the breakdown of the haem pathway, it is the breakdown of this essential process that triggers intensely painful reactions that present as intense burning pains in the skin.
EPP normally manifests in early childhood, however many patients endure being undiagnosed into their 30s and beyond. An affected baby will often get fractious if taken outside, or put near bright lights, or by a window during daylight. The pain makes some scream. Even when brought indoors, the baby can still be fractious while the skin recovers.
Due to the ultra-rare nature of the condition, many GPs will not encounter a single EPP patient throughout their career. Combined with the complex nature of the relationship between symptoms and their actual trigger, this frequently results in being incorrectly treated and tested for dermatological or allergic reactions rather than referral to a specialist photobiology unit, where this rare metabolic condition can be diagnosed via some surprisingly simple tests.
What causes EPP?
In EPP, there is a shortage of a particular enzyme (ferrochelatase), which normally helps to convert protoporphyrin into haem by adding iron to it. This deficiency leads protoporphyrin levels to build up in the blood. As blood passes through the skin, the protoporphyrin absorbs energy from specific wavelengths of light which sets off a chemical reaction that can damage the surrounding tissues and causes intense burning sensations and in some cases sensations similar to itching feelings.
Despite the pain reaction manifesting as an intense burning pain close to the surface of the skin, EPP should not be confused with sunburn. The light that protoporphyrin absorbs is different from that which causes sunburn. Sunburn is usually caused by the shorter wavelengths of ultraviolet light UVB & UVA. In EPP, the phototoxic reaction is triggered by longer ultraviolet wavelengths predominantly, but not exclusively around the 408nm wavelength which sits at the extreme of the UVA spectrum, and just into the visible light spectrum. This means that commercially available sunscreens that protect against UVA and UVB are of no value in the prevention of EPP reactions.
What are the symptoms of EPP?
EPP is rather different from the other cutaneous porphyrias, as it doesn’t usually cause blistering. When exposed to light, the EPP reaction results in the skin becoming very painful. The intense pain is usually described as intense burning, with many patients often describing ‘itching’ symptoms too. A large proportion of EPP patients also experience swelling in the affected areas. Unlike the intense nature of the pain, the degree of swelling can vary from person to person.
Exposure to bright sunlight, for as little as a few minutes in the worst affected patients, causes burning pain in exposed skin. Pain may be so severe and persistent that it prevents sleep for several nights. The time of exposure to sunlight, before the pain starts, varies from one person to another, as does the time taken to recover once out of the light.
It is important to remember that light does not always need to be direct – light reflected off water, sand or snow, or passing through window glass may also cause symptoms.
Some people get reddening of the skin, but many have nothing visibly wrong. This in turn makes diagnosis more complex and certainly makes it difficult for EPP patients to convey the nature of their condition. Over time, the skin can thicken on the knuckles and there can be scarring on the face.
In addition to the intense pain, most EPP patients also experience extreme tiredness and fatigue as a result of the reaction. This may come as no surprise once the metabolic nature of the condition, and the role of the haem pathway in the supply of oxygenated red blood cells, is understood.
What can be done to relieve the pain?
Most patients will automatically take whatever actions possible to withdraw themselves from exposure to light immediately a reaction is triggered. As babies, toddlers and younger children are less able to control their environment, this need should be considered of extreme importance.
With over the counter painkillers and other analgesics having little or no effect in reducing the pain, patients often attempt to relieve the pain by placing the skin under cold running water or via the application of cold towels or flannels. Others state that the pain can be temporarily relieved by placing affected areas under running hot water. Both approaches only offer slight and temporary relief. The safety considerations of using hot water should be foremost. The BPA therefore cannot recommend the use of this approach.
Some patients have suggested that fanned air helps diminish the pain to a degree. Again this is but a marginal benefit and it is unfortunately only the passage of time that will reduce the pain to levels where the person can cope with anything more than lying in a darkened room.
The room will ideally be one that is gently ventilated and where all heat sources (radiators, sunlit windows) are eliminated. Even close proximity to body heat from other people can be unbearable until the reaction has subsided considerably.
What about treatment?
Unfortunately, there is no specific treatment for EPP that is presently available and funded under healthcare provision in England, Scotland and Wales.
Until an approved treatment is made available in the UK, it is mostly it is a matter of: avoiding being out in the sun, under bright artificial light or close to a window (tinted film can be attached to windows, very useful in cars); covering up with a hat and light-dense clothing when outside; a small number of patients describe some benefit from Dundee Cream which acts as a physical barrier to light. However, as Dundee Cream is highly visible when applied, and its formulation is frequently garment unfriendly, many patients find it rather impractical and that any benefit in terms of slowing inevitable EPP reactions is outweighed by its negatives. Please see our skin safety page for further information on sunscreens, light protective clothing and window films.
Beta-carotene: Some people respond to high doses of beta-carotene, which is available on prescription. The capsules are taken by mouth and may turn the skin slightly orange. Self treatment is not recommended as foods and some supplements may contain chemicals dangerous in the high doses needed. This medicine is considered to be safe, but may cause tummy upsets in some people. Studies showed some health benefits, eg fewer strokes, but also increased risk of lung cancer in smokers.
Phototherapy: phototherapy involves exposure to artificial ultraviolet light, usually for a few times a week for a few weeks in the spring to allow the skin to thicken slightly and develop a tan. This acts as a natural sunblock and may improve tolerance to sunlight. Please see your porphyria specialist/dermatologist for more information on this treatment.
Clinuvel SCENESSE®: In December 2014, the European Commission approved a first in class treatment (Afamelanotide, commercial title SCENESSE®) for the prevention of phototoxicity in adult EPP patients. The process for approval of Afamelanotide as a treatment that is available under the NHS in England and its Scottish and Welsh equivalents is underway with further news on progress and decisions expected in late 2017 and into 2018.
Afamelanotide increases the levels of melanin in the skin and therefore shields against UV radiation (UVR) and the visible light in sunlight that triggers acute phototoxic reactions. The drug is delivered by a small subcutaneous dissolving implant. Increased pigmentation of the skin appears after two days and lasts up to two months.
EPP does not cause acute attacks, so there is no need to stick to the “safe” drugs list. However, it is not advisable to drink excessively, as the combination of alcohol with EPP can affect the liver. Annual blood tests are needed to monitor the liver, as a few people (around 5%) develop liver problems.
Consideration should be given to the psychological impact of EPP. Patients are forced to live outside social norms and make considerable compromises in order to remain free of the severely painful reactions. In all but the cloudiest weeks and months these compromises are made on a daily basis.
Due to the lack of sunlight, EPP patients can suffer from a vitamin D deficiency, so this should be monitored.
Please see our other publications page for links to the British Association of Dermatologists leaflet on EPP and a link to Clinuvel’s information.
Despite being clinically similar to EPP in that both conditions cause phototoxicity, XLDPP is caused by activation of a gene which leads to overproduction and accumulation of the phototoxic enzyme protoporphyrin IX (PPIX) in the blood.
In terms of symptoms, please see the EPP section for more details.
CEP is one of the rarest porphyrias. It is a genetic condition that is inherited in a recessive pattern. Usually, each parent is unaffected but carries a defective gene that they can pass to their children. Affected children have two copies of the defective gene, one inherited from each parent.
Patients with certain gene mutations have a late onset of the condition and are able to manage their lives successfully with photoprotection. These patients regard the impact of CEP on their quality of life to be minimal. However, those who have other gene mutations develop symptoms in infancy (sometimes even before birth) and their quality of life is severely impaired.
Gene defects cause the enzyme uroporphyrinogen lll cosynthase (UROS) to function ineffectively. Excessive amounts of porphyrins accumulate, particularly in the bone marrow, plasma, red blood cells, urine, teeth, and bones. The porphyrins are photosensitive and patients suffer with a wide array of chronic symptoms including severe photosensitivity to all visible light, photophobia, photomutilation, blindness, haemolytic anaemia and osteoporosis, among others. Skin blistering, severe scarring and increased hair growth can occur on light exposure and bacteria can quickly infect the damaged skin. Facial features and fingers may be lost or become deformed through phototoxic damage and infection. Ocular problems also can occur including corneal scarring, eye inflammation, and infections. All CEP patients, including those with milder versions, should be regularly monitored for complications and encouraged to protect their skin and eyes at all times from visible light.
Treatments and management
Management of CEP is tricky. Treatment is mainly symptomatic and consists of careful light protection and transfusions for haemolytic anaemia. Numerous complications can occur and a CEP specialist may try numerous different treatment regimes in an effort to reduce porphyrin levels.
Skin protection: The most important aspect of day-to-day management of CEP for most patients is the avoidance of sun/light exposure, as well as ultraviolet light and light emitted by fluorescent sources. The skin should be protected from injury as much as possible. If trauma occurs, antiseptic treatments should be used to prevent bacterial superinfections that can make skin blisters worse and result in scarring and mutilation. Severe infections such as cellulitis and bacteremia can be treated with intravenous antibiotics. Sometimes, long-term oral antibiotic therapy may be necessary to prevent chronic skin infections.
Eyes: can become damaged very easily, so the recommendation is to wear wrap-around sun glasses. Corneal ulcers, scleritis, and blepharitis should be treated with topical antibiotics.
Vitamin D supplementation is required to prevent Vitamin D deficiency and bone density problems such as osteoporosis.
Haemolysis: some patients experience severe haemolysis for which frequent blood transfusions may be necessary. Transfusions every few weeks can decrease porphyrin production, which reduces porphyrin levels and photosensitivity. Oral chelators may also be administered to reduce the resulting iron overload.
Treatments: At this time, the only curative treatment option for CEP is Bone Marrow Transplant (BMT) or Hematopoietic Stem Cell Transplant (HSCT). When successful, this can result in marked reduction in porphyrin levels – to normal levels if fully engrafted. However, the procedure is associated with numerous risks and is usually only performed in severe transfusion-dependent patients. For patients considering this option, the risks need to be carefully weighed against the risks associated with the potential complications of CEP.
Future treatments: Other treatment options are currently in the early stages of being investigated, but as yet no clinical trials have been performed in humans.
- Gene therapy: in a mouse CEP model showed improvements in CEP mice.
- Iron restriction using a high dose of deferiprone: in CEP mice treated with deferiprone for 26 weeks, porphyrins decreased in red blood cells and urine, and skin photosensitivity was reversed. Haemolysis and iron overload improved, as did anaemia.
- Ciclopirox: this antifungal agent lowered levels of porphyrin in red blood cells, urine and in the liver in CEP mice. It also led to reductions in enlarged spleens and natural repair of tissues damaged by CEP.
The above early-stage research suggests that there will be soon be clinical trials in humans into viable future therapy options.
As this is such a rare disorder, data is very scarce regarding clinical traits and the resulting impact on quality of life for its sufferers. The following information might be helpful.
American Porphyria Foundation: https://porphyriafoundation.org/for-patients/types-of-porphyria/cep/
Blouin, JM, Ged, C, Lelanne, M et al. Iron chelation rescues haemolytic anemia and skin photosensitivity in congenital erythropoietic porphyria. Blood (2020) 136 (21): 2457-2468. https://ashpublications.org/blood/article-abstract/136/21/2457/461423/Iron-chelation-rescues-hemolytic-anemia-and-skin?redirectedFrom=fulltext
Erwin AL, Desnick RJ. Congenital erythropoietic porphyria: Recent advances. Mol Genet Metab. 2019 Nov; 128(3):288-297. https://pubmed.ncbi.nlm.nih.gov/30685241/