THE ACUTE ATTACK

WHAT IS THE ACUTE ATTACK?

The acute attack is a specific condition which arises as follows. In all porphyrias, a defective enzyme leads to a block in haem synthesis, as shown in the figure on the right. In four of the porphyrias, known as the acute porphyrias, the block occasionally becomes so severe that ALA and PBG cannot be converted to the porphyrins, and very high levels of these precursors build up in the system. These acute porphyrias are acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), as well as the rare ALA dehydratase deficiency (Doss) porphyria. The other porphyrias, including the common porphyria cutanea tarda (PCT), do not develop acute attacks.

The symptoms of the acute attack are all due to injury to the nervous system. We do not yet know quite how this comes about. There are two main theories: firstly, that ALA, PBG or a similar substance are themselves toxic and damage nerves, and secondly, that it is actually the deficiency of haem resulting from this severe block in haem synthesis which causes the damage to the nerves. Whatever the mechanism, interference with the function of the nervous system results in the following symptoms:

• Abdominal pain which is severe, unrelenting and often felt in the loins and thighs as well as the abdomen.
• Autonomic instability, leading to vomiting, constipation, hypertension and tachycardia.
• Possible motor nerve damage, resulting in paralysis.

Characteristically, the urine may be very dark which reflects the large amount of PBG and porphyrins excreted in it during this phase.

Note that this is a very specific complex of symptoms. One cannot ascribe every odd ache, pain or sense of being unwell to one's porphyria. After all, there are many people who do not have porphyria who experience pain in the abdomen or some nausea from time to time. Unfortunately there is a widely-held myth that the symptoms of the acute attack include chronic pain present for months, chronic anxiety, depression, irritability, ”nerves”, inability to cope with work or domestic life, etc., and also that these symptoms can drag on for months at a time. This is not true. The acute attack is a sudden, serious illness, usually necessitating immediate admission to hospital, which either resolves in a few days or progresses to paralysis.

WHAT CAUSES THE ACUTE ATTACK?

In many instances, the factor which triggers an acute attack can be identified. These include:

• Administration of dangerous (porphyrinogenic) medication.
• This is the commonest factor and is something that must always be guarded against. It is described in more detail below.
• Possibly, fasting and stressful physical circumstances such as illness or operations

DIAGNOSING THE ACUTE ATTACK

It is always necessary to make a positive diagnosis of the acute attack. One cannot make a diagnosis on symptoms alone. (One should not just assume that the problem is an acute attack. This frequently leads to the difficult situation where other problems are overlooked because they are incorrectly called acute attacks.) If your symptoms ARE due to porphyria, then your tests MUST be positive. In general, patients with clinically expressed porphyria also express the disease biochemically at a level easy to detect in the laboratory.

• Submit a urine sample and a blood sample to a laboratory for testing. The following tests should be done:
• Screening of urine for PBG with the Watson-Schwartz test
• Urine ALA and PBG measurement. If these tests are negative, then the symptoms are not due to an acute attack.

TREATING THE ACUTE ATTACK

It is essential that anybody with AIP, VP or HCP who experiences severe abdominal pain, should immediately cease any medication and report to a doctor. Such people must be tested for the presence of PBG which will confirm or exclude an acute attack.

Treatment begins with the immediate withdrawal of any potentially porphyrinogenic medication. Simple analgesics such as paracetamol and codeine are given for the pain. If these are inadequate to control the pain, admission to hospital will be necessary. The pain may then be controlled by morphine and pethidine. Relief of symptoms is however only part of the management. Patients with an acute attack are at risk of the following, and it is essential that the doctor checks and if necessary corrects each potential problem:

• dehydration
• disturbed levels of serum electrolytes, particularly sodium
• progression to paralysis

In most (all except the mildest attacks), the use of haem arginate must be considered. This is a synthetic compound containing haem coupled with arginine. It is marketed under the trade name Normosang® by Orphan Europe. It is given by daily intravenous injection, into a drip, for about four days. By replacing the haem which cannot be made naturally because of the porphyria, it switches off the whole process of ALA, PBG and porphyrin accumulation. It is highly effective in halting the acute attack, and typically patients begin improving within 24 hours, and are ready for discharge in 4 days. It must however be given early, as once paralysis has developed, it cannot be reversed quickly. Haem arginate is expensive and is not widely available. It is usually necessary to make enquiries in order to obtain a stock. For this reason, the sooner enquiries are made, the better.

Click here for details on obtaining haem arginate.

Haem arginate is not registered for use in the United States. Here the older compound lyophilised hematin (Panhematin®, Abbot) may be available and is also effective.

OUTCOME OF THE ACUTE ATTACK

In nearly all cases currently, provided the acute attack is quickly diagnosed and correctly treated, recovery is prompt and complete. Patients can expect to return home, free of all symptoms, within 3-4 days.

Occasional patients, particularly young women with AIP, have a more difficult course and require expert care. Where paralysis has developed (nowadays a rare complication), recovery may be prolonged. Though the attack passes quickly, the motor nerves are severely damaged and have to regrow at about 1 mm per day. Patients may require mechanical breathing assistance for several months and may not be able to walk for 6-9 months. The good news however is that this is NOT a permanent state, and they will always recover, perhaps with some minor residual weakness.

PREVENTING THE ACUTE ATTACK

The single most important factor triggering the acute attack is exposure to porphyrinogenic medication. Essentially drugs which increase the body's requirement for haem may bring about an increased production of porphyrins, a rise in ALA and PBG, and the acute attack. It is essential that patients with acute porphyrias read the information on drug safety in porphyria available from this site (follow the links on our menu) and ensure that they follow the suggestions closely. In brief:

Wherever possible, avoid all drugs if you have AIP, VP or HCP. If medication is absolutely essential, ensure that you take only those listed as safe in our lists. Never take a medication whose name does not appear in our list. This is no guarantee that it is safe. It merely means that it has not been tested. If your medical condition is so serious that only medication listed as doubtful, dangerous or unlisted must be taken, then you should do so only after the most careful assessment by and under close supervision by your doctor. You need to develop the habit of questioning your doctor and pharmacist about the safety of every drug they dispense to you, including "OTC" (over-the-counter, non-prescription) medications. You also need to get in the habit of checking the safety of your drugs on the web using this site, and the NAPOS drug safety database (For details, read Drug safety in porphyria).

REPEATED ATTACKS

It is extremely rare for patients to have more than one attack, provided they take the necessary precautions. There are a small number of female patients with AIP who do indeed suffer recurring attacks; some of these are due to the porphyrinogenic effects of their own oestrogen and progesterone, the hormones of the menstrual cycle. Specialist assistance is necessary for these patients. Repeated attacks are not a feature of VP and in our experience, the few patients with VP who were thought to be having repeated attacks frequently turned out to be suffering from some other problem or to be re-exposing themselves to porphyrinogenic substances. Read more about the management of recurrent acute attacks in Dealing with recurrent attacks of porphyria.