PATIENTS
  
 

PORPHYRIA CUTANEA TARDA (PCT)


WHAT IS PCT?

The haem synthetic pathwayPCT is just one of the seven different types of porphyria. The enzyme uroporphyrinogen decarboxylase (UROD) is defective in people with PCT (Look this up by clicking on the diagram on the right). Thus, such people convert uroporphyrin to coproporphyrin with difficulty; this results in a build up of uroporphyrin, and the succeeding porphyrins known as heptacarboxylic porphyrin, hexacarboxylic porphyrin and pentacarboxylic porphyrin. The symptoms of PCT relate directly to this.

Though most forms of porphyria are inherited, this is not true for PCT. In a relatively small percentage of patients with PCT, the disease is indeed inherited. This is known as familial PCT. These families carried a mutation in the gene for UROD, and the disease is inherited as an autosomal dominant disorder. In most cases however, the gene for UROD is normal, and the disease is therefore not genetic. In these cases, we say that PCT is an acquired disorder. Essentially what happens is that a combination of circumstances in that patient result in inhibition of the enzyme UROD;consequently the enzyme does not work as it should and the haem synthetic pathway is interrupted.


FACTORS ASSOCIATED WITH PCT

The following are the circumstances most commonly encountered in patients with PCT which are responsible for the inhibition of the enzyme. Most patients will have one or possibly more factors present.

Hepatic iron overload

Nearly all patients with PCT are found to have an excessive accumulation of iron in the liver. It appears that the extra iron has the effect of switching off UROD, with consequent PCT. Some of these patients are found to have inherited one or more genes for an unrelated disease called hereditary haemochromatosis, a disease in which a faulty gene (known as the HFE gene, which is quite separate from the UROD gene which may be mutated in familial PCT), results in uncontrolled absorption of iron by the gut until the body is overloaded with iron. In other patients, iron overload may be due to excessive alcohol consumption or to factors which we do not yet understand.

Because iron overload is so common in PCT, and if left untreated, may be dangerous in its own right, every patient with PCT has to have their iron levels checked. This we do by some specific blood tests (Serum ferritin and transferrin saturation), by looking for the common mutations which result in hereditary haemochromatosis (the C282Y and H63D mutations in the HFE gene)and, if necessary, by a liver biopsy .

Removing the excess of iron constitutes an effective treatment for PCT. This we do by regular venesection (also known as phlebotomy). As the iron levels decrease, typically over 3-4 months, so the PCT remits.

Exposure to alcohol

Most (but not all) patients with PCT are in the habit of regular alcohol consumption, often to the extent of several glasses of wine or beer, or tots of spirits, per day. It appears that the alcohol and the iron mentioned above work together to produce substances which inhibit UROD. In treating PCT, patients are advised to reduce or cease alcohol intake; we are able to advise them on how much alcohol they may take in future once we have assessed the condition of their liver and have seen the PCT improve on treatment.

Oestrogen therapy

PCT occasionally arises in women taking oestrogen as part of oral contraception, or for symptoms of the menopause. It is also seen in men receiving synthetic oestrogens (such as stilboestrol) for the treatment of prostate cancer. Though we recommend that oestrogen therapy be stopped while treatment for PCT is started, we are usually able to restart hormonal therapy once the PCT is in remission.

Hepatitis C virus infection

Hepatitis C is a form of hepatitis which results from a virus which causes chronic liver infection and liver damage. It is common in Europe and north America, though uncommon in South Africa. A small proportion of people with hepatitis C develop PCT. Such people need to have the liver disease itself assessed and if necessary treated; in such cases, PCT can usually be controlled.

HIV infection

A small number of patients infected with the HIV virus develop PCT.


HOW DO THE SYMPTOMS OF PCT COME ABOUT?

Skin changes in PCTPorphyrins are photoactive molecules. Large amounts of porphyrin accumulate in the plasma of patients with PCT, from where they gain access to the skin. The interaction of these porphyrins and sunlight results in typical photosensitivity, which is described in detail elsewhere on our site (follow the skin disease link in the menu on the left). To summarize here, the skin disease takes the form of increased skin fragility, the development of blisters, sores and scars in some-exposed areas (particular backs of the hands and the face), which may be associated with hyperpigmentation, hypopigmentation and an abnormal distribution of hair on the sides of the face (hypertrichosis).


HOW DOES PCT COMPARE WITH OTHER FORMS OF PORPHYRIA?

  1. People with PCT never develop the acute attack, which means that it is a much "safer" form of porphyria than the other common forms of porphyria, variegate porphyria (VP) and acute intermittent porphyria (AIP). the only symptom is skin disease.

  2. PCT is in most cases acquired and not inherited (as described above).

  3. Patients with PCT need not observe drug safety precautions. These drug safety precautions are designed to prevent patients with the acute porphyrias from developing the acute attack. Since patients with PCT do not develop acute attacks, all drugs are safe for them.

  4. Patients with PCT require specific examination, testing and treatment. Since PCT is usually associated with the specific factors described above, it is necessary for patients to be examined for these conditions and to see the appropriate treatment if they are found.

  5. PCT is treatable (and often curable). For the other forms of porphyria, there is little that can be done other than attempting to moderate the skin disease, to prevent the acute attack and to treat it if it occurs. In contrast, where the trigger factors for PCT (such as iron overload and alcohol exposure) are removed, the disease usually clears completely.


DRUG SAFETY IN PCT

All drugs are safe in PCT.


INVESTIGATING A PATIENT WITH PCT

Diagnosis

A diagnosis of PCT is easily established using biochemical tests. A blood sample and a urine sample are required. Patients show a positive plasma fluorescence scan with a peak at 619 nm, and a characteristic accumulation of uroporphyrin, heptacarboxylic porphyrin, hexacarboxylic porphyrin and pentacarboxylic porphyrin on urine chromatography. A stool sample is not always required but is sometimes helpful: it shows a characteristic pattern on chromatography.

We do not routinely perform genetic tests for familial PCT in South Africa. Such tests are only applicable to the small number of PCT patients with familial PCT, and are of research interest rather than of practical value in helping patients.

Looking for the factors associated with PCT

Since in most cases PCT arises as a result of other disturbances such as iron overload, alcohol- or oestrogen-associated liver injury, hepatitis C, HIV or other underlying problems, it is important at patients are properly investigated for two reasons: firstly so that these conditions can be identified and treated before they give trouble in their own right, and secondly, so that they can be removed in order to hasten the recovery of the PCT itself. The following tests are recommended:

  • Biochemical tests of liver function (bilirubin, AST, ALT, ALP, GGT, protein, albumin)
  • Hepatitis C antibody tests
  • HIV antibody tests
  • Serum ferritin and transferrin saturation
  • Haemochromatosis mutations
  • Liver biopsy.


TREATMENT OF PCT

PCT is the only form of porphyria which is truly treatable. This is because PCT is in most instances not genetic, but arises as a result of factors such as those described above which result in inhibition of the UROD enzyme. We then treat the PCT by removing or correcting those factors, the enzyme is no longer inhibited and the porphyrin levels decrease. Treatment consists of the following:

Removal or correction of underlying causes

  • Alcohol consumption must be greatly reduced or ceased.
  • Ingestion of food or vitamin supplements containing additional iron should stop.
  • Taking of oestrogen in oral contraceptives or hormone replacement therapy should stop.
  • In cases of hepatitis C or HIV infection, specific antiviral therapy may be indicated.

Reduction of liver iron stores

Regular venesection is undertaken. 500 ml of blood is removed and discarded every 2 weeks. This can be done in our clinic or by your own doctor or nurse. The procedure is safe and not particularly uncomfortable: it is exactly the same procedure used by the Blood Transfusion Services in taking blood donations.

After every venesection, the body quickly replenishes the blood which has been removed. In order to make more blood, it requires iron, which is subtracted from the liver iron stores. In this way, the amount of iron stored in the liver gradually diminishes. The effect is that the inhibition of the UROD enzyme is overcome, and the PCT improves.

Typically, this has to be repeated about 6-10 times, over 3-5 months. (Longer periods are necessary if you have hereditary haemochromatosis, where iron stores are much higher than in PCT).

Chloroquine therapy

Chloroquine, a drug developed for the treatment of malaria, is also very helpful in PCT. It has the effect of making the porphyrins stored in the liver soluble, such that they escape from the liver into the bloodstream, from where they are excreted in the urine. Thus porphyrin levels fall and the skin disease improves. In actual cases, we frequently notice an initial deterioration in the skin disease and a reddening of the urine as more porphyrins escape, but this passes after a week or two following which everything gets better. It is important to note that only a very small dose of chloroquine 2-3 times weekly is appropriate: if the dose is too large, liver damage may result in patients with PCT.


OUTCOME

Typically PCT enters remission after 2-3 months. This means that porphyrin levels return to normal and that there are no new sores, blisters or changes in the skin, and there will be no worsening of any existing unsightly changes.

Unfortunately, preexisting skin damage such as hyperpigmentation, scarring and hypertrichosis last longer, though they do tend to improve gradually over the course of a year and more. We do not recommend treatments which may potentially damage the skin such as electrolysis or waxing while the PCT is still active, but it is acceptable once the PCT is in remission.

Once in remission, the advisability of reintroducing risk factors such as alcohol (in moderation) or oestrogen therapy can be discussed with the doctor.

We recommend that porphyrins, ferritin and transferrin saturation are checked every 6-12 months in patients in remission. If they show a tendency to rise, a repeat course of just 2-3 venesections is usually sufficient to prevent PCT from recurring.

 

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