ACUTE SYMPTOMS IN PORPHYRIA

The acute attack represents the most dramatic presentation of the acute porphyrias (variegate porphyria, acute intermittent porphyria, hereditary coproporphyria and ALA dehydratase porphyria). Left untreated, it may potentially result in severe complications and may even be fatal.

CLINICAL FEATURES

The following features are seen in the typical acute attack:

Abdominal pain

Almost without exception, patients complain of severe pain which is:

• felt diffusely throughout the abdomen
• often extends into the lower back and thighs
• is continuous, severe and unrelenting
• often leads to pleas for powerful analgesics.

Nausea, vomiting and constipation

Approximately 50% of patients complain of nausea and may vomit, though this feature is seldom particularly striking. Constipation is often present on questioning but is rarely volunteered spontaneously by the patient.

Autonomic disturbance

Most patients will have evidence of hypertension and tachycardia. Only in the most severe cases are these striking; the commonly-encountered pattern is one of a mild rise in blood pressure and pulse rate which is seen to decrease once the attack comes under control.

Biochemical disturbance

There is usually evidence of dehydration with a mildly elevated serum urea concentration. More severe attacks may be accompanied by hyponatraemia. The cause of the hyponatremia is not established; our own experience suggests that it is more likely due to renal salt wasting than to inappropriate ADH secretion. The most severe attacks may showed evidence of hyponatraemia and hypomagnesaemia as well as hyponatremia.

COMPLICATIONS OF THE SEVERE ACUTE ATTACK

Seizures

Tonic-clonic seizures may be seen during the acute attack of porphyria and are usually associated with:

• Hyponatremia.
• Very high doses of pethidine (meperidine): the metabolite of pethidine, norpethidine, is epileptogenic in high doses.
• Very severe acute attack of porphyria, which may be associated with a metabolic encephalopathy.

Paralysis

Severe attacks may be followed by an acute motor neuropathy, which may evolve to profound quadriparesis and cranial nerve paralysis over a period of 6-12 hours. This is a typical lower motor neurone palsy with profound paralysis, hypotonia and absent reflexes. Electromyography will show evidence of axonal necrosis and and denervation.

Adrenergic crisis

This is a rare manifestation of an accelerated acute attack. Patients manifest an adrenergic crisis suggestive of pheochromocytoma or thyroid storm, with severely elevated heart rate and blood pressure, and confusion or coma. CT or MRI scanning may show brain defects suggestive of infarction; these are however frequently symptoms of reversible ischaemia, and both the radiological lesions and the clinical picture improve once the attack settles.

EVOLUTION OF THE ACUTE ATTACK

Milder presentations of the acute attack, particularly in patients with variegate porphyria (VP), may begin improving spontaneously after approximately 24 hours. In most patients however—in our experience, approximately 60% of patients with VP and almost all patients withacute intermittent porphyria—spontaneous resolution may be delayed by days or weeks, or will progress to the severe complications listed above, particularly motor neuropathy and quadriparesis. These patients benefit greatly from the early administration of haem arginate, which leads to rapid resolution of clinical symptoms and signs, and, provided it is given early enough, will prevent progression to complications such as neuropathy.

Motor neuropathy represents severe damage to the nervous system and recovery is frequently prolonged. Where compete quadriparesis is present, recovery normally proceeds as follows:

• requirement for manual ventilation, approximately 6-8 weeks
• time before hands can be used to manipulate objects: 8-12 weeks
• time to walking with support: 5-6 months
• time to near-full recovery: approximately 12 months.

We must however stress that even profound quadriparesis is usually associated with near-complete recovery, even though this may take a year to achieve.

PATHOGENESIS OF THE ACUTE ATTACK

The pathogenesis of the acute attack is as yet imperfectly understood. There is an invariable association between high levels of ALA and PBG and the clinical syndrome, which has led some authorities to believe that these compounds may in themselves be neurotoxic. The evidence is however inconclusive, and there is also evidence to support alternative hypotheses; among these the suggestion that ALA and PBG are surrogate markers for other neurotoxic compounds (possibly false neurotransmitters,) or that the problem results from severe intracellular haem deficiency.

Whatever the molecular mechanism, it is believed that the acute attack is the result of hyperinduction of the haem synthetic pathway; in other words, in response to a trigger factor, the rate-limiting enzyme ALA synthase is derepressed, resulting in is a massive flux of porphyrins and their precursors through the haem synthetic pathway which in turn results in the elevated levels of ALA and PBG.

PRECIPITATING FACTORS FOR THE ACUTE ATTACK

Administration of porphyrinogenic medication

A large number of drugs may result in induction of the haem synthetic pathway, and exposure to these so-called porphyrinogenic drugs represents the commonest factor resulting in the acute attack

The menstrual cycle

Occasional patients with acute intermittent porphyria (AIP) showed a pattern of recurrent acute attacks typically arising one or two days prior to the onset of menstruation. In our own experience, we have not yet encountered this in patients with variegate porphyria (VP ).

Other factors

Other factors stated to be associated with acute attacks but more difficult to prove include stress and infection.

Indeterminate

Fairly commonly, patients present with an acute attack for which no obvious precipitating factor can be found.

DIAGNOSIS OF THE ACUTE ATTACK

Making a diagnosis of the acute attack of porphyria on clinical grounds alone frequently leads to misidentification and the labeling of patients as having acute attacks when in fact they have nothing of the sort. It is therefore essential that the acute attack is always confirmed by the appropriate biochemical tests. In order of reliability these are:

• demonstration of elevated urinary ALA and PBG levels by a quantitative technique
• a positive screening test for PBG (the Watson-Schwartz reaction): a test which can be performed in the doctor's rooms. This is described here: Simple screening test for the acute attack.

For practical purposes, the demonstration of elevated PBG levels is always evidence for the acute attack in patients with variegate porphyria and hereditary coproporphyria. In patients with acute intermittent porphyria, PBG levels may be elevated even in remission, and in this situation, one should be guided by the symptoms.

MANAGEMENT

Details will be found in the following page: Management of the acute attack.

RECURRENT ACUTE ATTACKS

A pattern of frequently recurring attacks is unusual, particularly in patients with variegate porphyria. It is essential to seek laboratory proof that the so-called recurrent acute attacks are genuinely associated with elevations of ALA and PBG. See the following page for more details: Dealing with recurrent acute attacks of porphyria.