How to spot zebras – acute porphyria

What is it?

Porphyrias are a group of rare, mostly inherited disorders of the haem pathway. Problems arise because of a build-up of haem precursors released from either the liver or bone marrow, resulting in two main presentations:

• Acute attacks, dominated by severe abdominal pain with neurological features, due to excess hepatic haem precursors causing toxic damage to nerves.
• Skin problems, typically blistering lesions or acute photosensitivity, due to excess porphyrins in the skin reacting with sunlight.

There are eight different porphyrias, which can be grouped into those presenting with acute attacks (acute porphyrias) and those presenting with light-sensitive skin problems (skin porphyrias), although there is some overlap. All of them are diagnostically challenging, but it is particularly important for GPs to think about the possibility of acute porphyrias. These are easily missed because they present with non-specific symptoms commonly experienced by young adults and because the diagnosis is rarely considered. The consequences of delayed diagnosis and treatment can be devastating and attacks are occasionally fatal.

This article will focus only on the key acute porphyrias – acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP).

Prevalence

As many as one in 2000 people carry a genetic defect for one of the acute porphyrias but most of them will never have an acute attack and many are never diagnosed. The prevalence of symptomatic acute porphyria is about 10 per million, of which acute intermittent porphyria is the most common type.

Presentation

Acute attacks of porphyria occur five times more frequently in women than in men, and the typical patient is a young woman between the ages of 18 and 40. It is extremely rare for children to have attacks. The presenting complaint is nearly always severe abdominal pain and vomiting, typically developing over a period of several hours to a few days. Clinical examination is often unremarkable.

The following clinical features may be present during an attack:

• Severe, poorly localised abdominal pain.
• Pain in back and legs.
• Nausea, vomiting and constipation.
• Agitation, insomnia, rarely psychosis
  • Contrary to popular belief, long-term mental health problems are no more frequent in porphyria than in other chronic illnesses, and there is no evidence that King George III suffered from any kind of porphyria!
• Dark orange or red urine.
• Tachycardia and hypertension.
• Hyponatraemia.
• Neurological complications – seizures, progressive motor neuropathy leading to paralysis and respiratory failure in severe attacks.

Blisters and fragile skin affecting light exposed sites such as face and hands occur frequently in variegate porphyria, and less commonly in hereditary coproporphyria, but are not a feature of acute intermittent porphyria.

Differential diagnosis

An acute attack of porphyria can mimic an acute abdominal emergency (such as appendicitis or cholecystitis) and may lead to unnecessary surgery. Premenstrual attacks of porphyria may be confused with endometriosis. Severe attacks with neuropathy and paralysis may be misdiagnosed as Guillain-Barré syndrome. Pain in attacks is typically out of proportion to physical signs and sadly some patients are misdiagnosed as having a functional disorder or opiate seeking behaviour.

Investigation

Some of the factors that make this diagnosis more likely include:

• Combination of severe abdominal pain with hyponatraemia or neurological features (such as seizures, paralysis, change in behaviour).
• History of previous similar episodes resulting in hospital admissions, unnecessary operations, or specialist referrals.
• Female of child-bearing age.
• Exposure to a known attack trigger:
  • Certain drugs can trigger attacks (including commonly prescribed medication such as oral or depot contraception, trimethoprim, erythromycin). See follow-up section for more information on drug safety in porphyria
  • Alcohol, especially binge drinking
• Hormone fluctuations including the menstrual cycle (increased risk of attacks premenstrually) and pregnancy.
• Reduced calorie intake.
• Stress.
• Family history of porphyria – acute porphyrias are inherited as autosomal dominant conditions although penetrance is low.
• Dutch South African ancestry (higher frequency of variegate porphyria) or Swedish ancestry (higher frequency of acute intermittent porphyria.

What should you do?

• For patients with current symptoms:
  • Collect a random, light-protected urine sample in a plain container for porphobilinogen and porphyrin measurement. Urine porphobilinogen excretion is always increased during an acute attack of porphyria while a normal result excludes an attack.
  • Contact the National Acute Porphyria Service for advice about immediate management (details below).
• If symptoms have resolved:
  • Collect samples as below for porphyrin biochemistry
    • Random, light-protected urine sample (plain container)
    • Light-protected blood sample (full blood count tube)
    • Small light-protected stool sample
  • Contact a specialist porphyria centre for advice

Diagnosis

Patients may suffer from symptoms for many years before the diagnosis of acute porphyria is eventually made, sometimes despite referrals to various specialists and repeated hospital admissions. Conversely, a few patients become convinced that porphyria is the cause of their health problems after carrying out their own research, and actively seek testing, sometimes inappropriately. If porphyria is suspected, it is helpful to seek advice about definitive testing from a specialist porphyria centre as this can effectively rule out porphyrias as a cause of previous illness.

Follow up

All patients with an acute porphyria (including patients with a genetic diagnosis who have never had symptoms) should take steps to reduce their risk of an attack. In particular, all medication should be checked for safety in acute porphyria. A list of safe medication can be found at www.cardiff-porphyria.org. Most patients will benefit from referral to a specialist porphyria centre.

Patients with acute attacks usually need hospital treatment, including infusions of intravenous haem arginate. A few severely affected patients are managed with hormonal manipulation or regular haem arginate infusions to try to prevent attacks.

The National Acute Porphyria Service provides urgent advice 24/7 regarding patients living in England, Scotland or Wales. Please phone 02920 747747 and ask for the on-call porphyria service. Patients with symptomatic porphyria should be under the care of one the porphyria centres based at King’s College Hospital in London or University Hospital of Wales in Cardiff.

Further information including details of specialist centres can be found on the website of the British Porphyria Association www.porphyria.org.uk.

Dr Penelope Stein is a consultant in haematological medicine at King’s College Hospital. Dr Michael Badminton is a consultant in medical biochemistry and immunology at the University Hospital of Wales in Cardiff.