Introduction

Erythropoietic protoporphyria (EPP) is one of the less common forms of porphyrias. There are only a few families known to us in South Africa carrying this condition. It differs from the other porphyrias in several respects.

• It predominantly affects haem synthesis in red blood cells, rather than other organs such as the liver. The major enzyme defect is in red blood cells, and very high levels of protoporphyrin are seen in the red blood cells and plasma. Hence we concentrate on blood tests for diagnosis.
   
• Unlike the other porphyrias, where the disease is only usually noted in adult life, symptoms of EPP often develop in childhood, and even in infancy.
   
• EPP is not an acute porphyrias. This means that patients with EPP will never suffer the acute attack. Patients with EPP for this reason need not follow drug precautions as all drugs are safe for them. 
   
• The skin disease of EPP differs from that of the other porphyrias and is described in more detail below.

Inheritance of EPP

EPP is inherited as an autosomal dominant condition. This means that the disease is transmitted from generation to generation, with each child (irrespective of sex) having a 50% chance of inheriting the defective gene. However, it is known that even where a defective gene has been inherited, the person may quite commonly not show the disease at all. In other words, one can inherit the disease without showing any sign of it: an example of variable expression.

The story of the inheritance of EPP is in fact very interesting. Recall that each of us inherits two genes for every characteristic: one from mother, one from father. It appears that those people who have inherited a gene for EPP and show the disease only do so because their second gene is a "slow" gene, which does not make as much enzyme as a "fast" gene. We call this a low-expression allele. Hence the patient shows signs of EPP because:

• One gene carries a mutation, and makes either a faulty enzyme or no enzyme at all.
• The second gene is slow, and does not make enough normal enzyme to compensate.

Clinical Manifestations Of EPP

Skin Disease

The skin disease of EPP is very typical and is quite unlike that of other forms of porphyria. The skin becomes exquisitely sensitive to sunlight. After a certain threshold of exposure has been reached, the patient experiences very severe burning, tingling, pain and sometimes numbness in the exposed areas of the skin, something like a very severe sunburn. We call this immediate photosensitivity. Often there is nothing actually to be seen in the skin; occasionally the skin may actually become red and swollen. Children with EPP learn from a very early age to avoid the sun.

This contrasts with the skin disease of variegate porphyria and porphyria cutanea tarda (PCT). These patients do not have an immediate reaction to the sun. Often they are even unaware that the sun has any influence on their condition. However, they develop blistering, sores and scabs on the skin of the hands and face. Patients with EPP do not show these changes.

In summary then, patients with EPP react very quickly and badly to the sun, but are left with much less permanent damage, whereas patients with VP and PCT suffer no immediate ill effects from the sun, but go on to show signs of permanent damage.

In some cases however with continued sun exposure, the skin of the patient with EPP may become coarse, thickened and rough. This is particularly noted over the bridge of the nose and the knuckles.

Liver Damage

In EPP, the red blood cells produce vast amounts of a porphyrin known as protoporphyrin. This has three effects:

• Its accumulation in the red blood cell (as well as the interruption in the formation of haem) may result in a mild anaemia. This is usually of no significance. 
   
• Large amounts of protoporphyrin escape into the plasma and from there into the skin. Since porphyrins are light-sensitive, this probably accounts for the severe skin reaction to sun evinced in EPP. 
   
• Large amounts of protoporphyrin pass through the liver where they are excreted into the bowel, emerging eventually in the stool. These large amounts of protoporphyrin may crystallise out in the bile (causing gallstones) and very occasionally sufficient may deposit in the liver to interfere with the normal functioning of liver cells. Such patients can eventually develop cirrhosis and liver failure. It must be stressed that this outcome is extremely rare. Indeed, recent research suggests that it is not the EPP alone which causes the liver damage; one has to inherit other less well-understood factors as well which is why the liver problems are uncommon. It is however necessary to know of it, as patients with EPP should have check-ups from time to time to ensure that this is not happening.

How is EPP Diagnosed?

The finding of very elevated amounts of protoporphyrin in the red blood cells is characteristic. For the sake of completeness however we normally test the urine and stool as well.

Treatment of EPP

This is largely directed to amelioration of the skin disease.

Reduce exposure to the sun

In the initial stages, this is the most effective action to be taken. Patients should limit their exposure to the sun to a period which they know from experience will not result in a painful reaction. They can increase the amount of time they spend outdoors by avoiding the hottest part of the day, emerging early in the morning and later in the afternoon. A sensible choice of clothing such as closed shoes, a hat, and long sleeves will be very helpful. Clothes should be made of cotton rather than artificial fibres, as this is a better sunscreen. Obviously as much of the body as possible should be covered, particularly the forearms, legs and feet; the hands if possible.

It must be stressed that conventional suntan preparations are useless. Though they may exclude the short wavelengths of ultraviolet light, which causes sunburn, they do not block out those longer wavelengths of light which excite skin disease in porphyria. People with photosensitivity due to porphyria need to protect themselves against both long and short (UVA and UVB) wavelengths. Increasingly however, we are recognising that neither UVA nor UVB is good for normal people either, so modern sunscreens are improving in their ability to block both. The only agents which may be of use are those containing zinc or titanium dioxide. These are often thick, greasy and opaque. Agents which may be helpful include those with micronised titanium dioxide and high SPF values, which are less opaque and more cosmetically acceptable.

Use of beta carotene and canthaxanthine

Beta carotene is a substance which is converted in the body to vitamin A. It is also an important constituent of carrots and is responsible for their yellow colour. Beta carotene in high doses builds up a protective layer in the skin which is extremely useful in improving the skin disease of EPP. When taken in sufficient amounts, the photosensitivity decreases. This means that such people can tolerate increased amounts of exposure to the sun before they develop their typical skin reaction. Almost all people with EPP treated with carotene have been improved to some extent, often markedly so. In some cases, people have been able to live entirely normal lives with no skin reactions whatsoever.

To achieve this effect, carotene has to be taken in large doses, sufficient to cause a yellow discolouration of the skin. If there is no discolouration then there is no improvement.

Vitamin A taken in large doses is not effective and is dangerous. Beta carotene is very safe; as it is poorly converted in the body to vitamin A and there is no risk of becoming toxic. No side effects of beta carotene are known, other than the yellowing of the skin.

A related substance called canthaxanthine may be combined with the beta carotene. This works just as well, but the resulting discolouration of the skin resembles more closely a natural tan rather than the yellowish colour of beta carotene alone. This combination has also been shown to be of benefit to patients with EPP. Canthaxanthine is safe. However, when taken in very large doses, it may cause some deposition of crystals in the retina of the eye. This has given rise to concern, though it has not been shown in actual fact to endanger sight.

Unfortunately beta carotene is only available commercially at present in cap[sules and pills containing very small doses. Vitaforce, carotene A (Pharma Natura) contains only 1500 units of beta carotene (or about 3 mg per capsule). The average adult daily dose of beta carotene is from 50-150 mg daily. It is not feasible to take up to 50 capsules of beta carotene per day! Canthaxanthine is not available in a commercially prepared form at present.

Arrangements can be made for canthaxanthine and beta carotene in adequate dosage, to be made available to patients with EPP through private pharmacists, or directly from the suppliers. Our patients find it most practical to buy carotene in powder form in large containers, and then take it in teaspoonfuls! . Contact us for details of availability.

Treatment With Beta-Carotene

The required dose is from 50-150 mg daily. In practice, we have found that the best method is for the patient to be given the bottles of the raw ingredients themselves, to learn how much (in teaspoons) the required dose is by an initial weighing, and then to dose him or herself with the powder by the teaspoon and wash it down with juice.

We recommend a starting dose of 100 mg daily. This can be increased to 150 mg daily or reduced to 50 mg daily as necessary. It may take 2 or 3 months before a clinical result is evident. This coincides with the onset of the pigmentation. Once a response is obtained, the dose should be reduced to the minimum required for an effect.

Since the skin disease is worst during the summer months, it is advisable to start the beta-carotene towards the end of winter, maintain it during summer, and then reduce it during autumn and winter again. 

Treatment With Beta Carotene And Canthaxanthine

If using a carotene/canthaxanthine mixture, they should be mixed in the ratio 2 parts beta-carotene and 3 parts canthaxanthine powder. The total dose is the same as for beta-carotene on its own.

We recommend that patients on canthaxanthine undergo eye examinations at 3-6 monthly intervals to ensure that there is no deposition within the retina. Should there be, we would advise that the canthaxanthine be stopped and beta carotene used alone.

Protection Against Liver Injury

It is highly recommended that all patients with EPP have their liver functions tested at least annually. All that is necessary is that a single blood test is taken and the liver functions analysed. Should there be any disturbance, specialist advice should be sought. Under such circumstances, additional treatment measures can be suggested which may allow this porphyrin to be safely cleared from the liver. These include the long term use of oral cholestyramine or charcoal which bind porphyrins and allow their excretion.