Haematology - The porphyrias

This group of rare metabolic disorders can be diagnosed using appropriate biochemical tests, says Dr David Rees

Haem is essential for every active cell in the body (Photograph: SPL)
Haem is essential for every active cell in the body (Photograph: SPL)

The porphyrias are a group of metabolic disorders associated with impaired haem synthesis. Haem is important in haemoglobin and many enzymes, and is essential for every active cell in the body; 85% is synthesised in the bone marrow, and most of the remainder in the liver.

Haem is synthesised from simple molecules by a series of enzymatic reactions; deficiencies of these enzymes cause the different porphyrias. Most of the symptoms of porphyria are due to the accumulation of metabolic precursors rather than actual haem deficiency. Porphyria symptoms fall into two main groups: acute and cutaneous.

Acute porphyrias

The acute porphyrias are characterised by intermittent, unpredictable episodes of abdominal pain, sometimes with back or leg pain. Other symptoms include nausea, vomiting, constipation and occasionally neurological or behavioural problems.

Typically pain is severe for three to five days, although this is variable, and patients are well between attacks. Many patients inherit porphyria but never suffer acute symptoms; about 80% of men and 50% of women have the condition in this latent form.

Acute attacks

Most people experience only one or two attacks, but a few have recurrent episodes of severe pain, and these are usually women with attacks associated with menstruation. Acute attacks are classically precipitated by certain events, particularly exposure to some drugs including progesterones and estrogens, hormonal changes associated with menstruation, carbohydrate starvation, stress and excessive alcohol; often there are no obvious precipitants or several act together.

The symptoms and signs of an acute attack are not specific. The abdomen is usually soft and non-tender, and typically patients have tachycardia and hypertension.

Unless there is a known family or personal history of porphyria, other causes of acute abdominal pain should be considered and excluded before investigation for acute porphyria.

In primary care, the possibility of a new diagnosis of acute porphyria may arise in patients with a history of unexplained recurrent abdominal pain, and sometimes other unusual symptoms, including a spectrum of psychiatric or behavioural abnormalities. Acute porphyrias are rarely the cause of such problems and almost never the explanation for predominantly psychiatric symptoms.

Confirming the diagnosis

If acute porphyria seems a possibility, the most important test is to measure urine levels of porphobilinogen; this can be done on a small urine sample, which should be largely protected from light.

In some circumstances it may be easier to refer the patient to a specialist porphyria clinic (for example as are found in King’s College Hospital in London, in Cardiff, Cambridge, Salford and Leeds).

If there is a definite family history, DNA analysis is often the most direct way to make the diagnosis, which can sometimes be organised through a genetics clinic or one of the porphyria clinics.

Patients with known acute porphyria which is symptomatic should be under regular review in a porphyria clinic. Acute episodes are usually managed in hospital with analgesia and haem arginate infusions.

Choosing safe drugs

The most common problem in general practice involves choosing safe drugs for co-existent illnesses. Many patients will have lists of safe drugs, and the Welsh Medicines Information Service can provide specific advice; the NAPOS (Norwegian Porphyria Centre – there is a UK-specific section) website also provides information on the safety of specific drugs (www.drugs-porphyria.org). The oral contraceptive pill is the most commonly used drug that is contraindicated in acute porphyria.

 Main types of porphyria
  Inheritance Main clinical features
Neurovisceral symptoms
Acute intermittent porphyria Autosomal dominant; most prevalent in Scandinavia Acute abdominal pain
ALA dehydratase deficiency Autosomal recessive; very, very rare Neuropathy
Neurovisceral and cutaneous symptoms
Variegate porphyria Autosomal dominant; prevalent in white South Africans Bullous skin rash, acute abdominal pain
Hereditary coproporphyria Autosomal dominant Bullous skin rash, acute abdominal pain
Cutaneous symptoms
Erythropoietic protoporphyria Coinheritance of common mild mutation and rare severe mutation Burning and pruritus in sun-exposed areas
Porphyria cutanea tarda Usually acquired Bullous skin rash, hypertrichosis
Congenital erythropoietic porphyria Autosomal recessive; very rare Severe photosensitivity with tissue loss; haemolytic anaemia

Cutaneous porphyrias

Porphyrin molecules generate free radicals and oxidative stress on exposure to sunlight, resulting in the photosensitive skin damage which is characteristic of cutaneous porphyrias. Two main patterns of skin disease are found: bullous lesions and acute painful photosensitivity.

Bullous porphyria

In bullous porphyria, skin damage occurs on sun exposed areas, typically the face and backs of hands. The skin is typically very fragile, with minimal trauma causing blisters which take up to a month to heal. Healed blisters and bullae can result in milia (white papules), brown discoloration and hypertrichosis.

Porphyria cutanea tarda is the commonest porphyria, typically presenting with the features described. Unlike other porphyrias, it is nearly always acquired rather than inherited, and is associated with alcohol abuse, estrogens, iron overload and hepatitis C infection.

Treatment of bullous porphyrias includes sun avoidance, opaque sun screen (Dundee cream) and protective clothing. Additionally, porphyria cutanea tarda responds to venesection if there is iron overload, and low dose chloroquine. Measuring porphyrins in faeces, urine and plasma confirms the diagnosis.

Acute painful photosensitivity

Acute painful photosensitivity is caused by erythropoietic protoporphyria, which is the commonest inherited porphyria. Usually symptoms begin in early childhood, often with children crying or in pain on exposure to sunlight. The skin may be oedematous or red, and chronic exposure causes waxy scarring of sun exposed areas.

Usually these are the only symptoms, although rarely serious and life-threatening liver damage can occur. Detecting high levels of red cell protoporphyrins on blood testing confirms diagnosis. Treatment involves sun avoidance, opaque sunscreens and oral beta-carotene.

Summary

Although porphyrias are rare, accurate diagnoses can be made with appropriate biochemical testing. Rarer types of porphyria are included in the table. The British Porphyria Association offers support and information to affected individuals and families.

  • Dr Rees is a consultant haematologist at King’s College Hospital NHS Foundation Trust, London

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