What is porphyria?

• Porphyria is a general term describing a heterogeneous group of metabolic diseases that involve errors in the pathway of haem synthesis
• Haem is part of the haemoglobin molecule, which is the oxygen-carrying component of red blood cells
• Most cases are inherited (genetic), although sporadic cases are seen
• One form of this disease is Porphyria Variegate (‘South African porphyria’)
• The accumulation of substances, called porphyrins, results in a range of presentations, ranging from an acute neurological (potentially fatal) disease to a more chronic cutaneous (skin) disease process (metabolites are the products of metabolism, the process by which living organism builds or breaks down substances needed for living)
• A wide range of drugs (including alcohol and oral contraceptives) can precipitate porphyria in genetically predisposed individuals
• The diagnosis usually depends on the detection of faecal and/or urinary porphyrins
• The avoidance of potential harmful drugs and the screening of family members form the basis of disease control

Porphyria is a name given to a group of diseases that involve errors in the pathway of haem biosynthesis, resulting in the accumulation and excretion of precursor molecules called porphyrins. Precursor molecules are substances made during the process of metabolism, which eventually form the final molecules of the metabolic process.

Porphyria is not a single disease but rather a collective term for a number of conditions that are all characterised by the overproduction of porphyrin compounds. The diseases are all the result of a variety of problems with enzymes in the haem synthesis pathway. Haem is an important constituent of heamoglobin which is responsible for carrying oxygen from the lungs to other parts of the body. In patients with porphyria the production of haem is disturbed as a result of defective enzymes which are involved in the control of haem synthesis.

As a consequence of these defects there may be an accumulation of metabolites that cause the clinical manifestations of the disease. Several different substances, including alcohol and many drugs can precipitate episodes of porphyria. Metabolites are the products of metabolism, the process by which living organism build or break down of substances needed for living.

Depending on the particular type of porphyria, patients may present with neurological and/or skin manifestations, which may include some of the following:

• Abdominal pain, vomiting and constipation (90% of patients)
• Weakness or inability to move a limb due to nerve damage
• Abnormal sensation due to nerve damage
• High blood pressure and abnormally fast heart rate
• Psychiatric disorders such as confusion, depression, anxiety or episodes marked by hallucinations (hearing voices or seeing illusions)
• Blistering of the skin

Most cases of these heterogeneous metabolic diseases have a genetic/inherited cause, one example being Porphyria Variegate. This genetic condition, although still rare, is more frequently found in the South African Caucasian population than in any other population on Earth.

Many different forms of porphyria have been described. The excess production of porphyrins occurs either in the liver (hepatic or liver porphyries) or in the bone marrow (erythropoeitic or bone marrow porphyrias).

Haem is the iron-containing molecule that, when bound to globin chains (alpha and beta), forms haemoglobin. Haemoglobin performs the main functions of red cells, which are to carry oxygen to tissues and, to a lesser extent, return carbon monoxide from the tissue to the lungs.

Haemoglobin synthesis occurs in red blood cells. This process can be summarised and simplified as follows:

Glycynesin and Succinyl CoA -> Delta-aminolaevulinic acid -> Porphobilinogen -> Uroporphyrinogen -> Coproporphyrinogen -> Protoporphyrinogen -> Protoporphyrin -> Haem Haemoglobin acids

Note: (1) to (5) refer to the more common sites of enzymatic defects (see classification below). The point of detailing this pathway is to show where the porphyrins, the products which build up and cause problems, are formed.

Each of these defects is the result of different enzymatic defects, which cause production blocks at different levels (see the synthesis illustration). All but porphyria cutanea tarda (PCT) are genetic diseases. PCT can be familial, but is more commonly found sporadically and is then usually associated with liver disease, such as alcoholic liver cirrhosis or lead poisoning.

There is overlap between the acute and non-acute forms.

What are the main symptoms and signs of porphyria?

The disease presents in a variety of ways, which can be divided as follows:

Acute porphyria is a clinical syndrome dominated by involvement of the nervous system and can potentially, though infrequently, be fatal. It is often precipitated by drugs or other diseases. Common symptoms include:

• Gastro-intestinal complaints – abdominal pain, nausea and vomiting, diarrhoea or constipation
• Central nervous system involvement – convulsions (seizures), irritability, anxiety and behavioral changes
• Cardiovascular system involvement – dysrhythmias (abnormal heart rhythm) and blood pressure which goes up and down (labile)
• Other complaints, such as dark urine

Non-acute/cutaneous porphyria is a chronic disease caused by the accumulation of porphyrins in the skin, causing photosensitive skin lesions. These lesions are most prominent on the exposed areas of the skin (face and hands / forearms) and can be disfiguring. Common features and symptoms include:

• Blisters
• Erosions and scarring of skin
• Changes in pigmentation (and skin colour)
• Hyperthrichosis (abnormal increase in hair growth)
• Fragility of the skin

How do the different forms of porphyria differ from each other?

• Acute intermittent porphyria is a genetic disease (autosomal dominant – inherited by 50% of the offspring of either sex of a person with the disease), presenting in adult life with acute attacks. It is often precipitated by drugs, alcohol or oral contraceptives. Chronic skin lesions are not seen. It is common in Scandinavian countries.
• Porphyria variegata is diagnosed more often in South Africa (relative to the population) than any other country, and is also called ‘South African porphyria’. It is a genetic disease with a high frequency in descendants of the early European settlers in the Eastern Cape. Both acute porphyria and cutaneous porphyria are found within this condition.
• Hereditary coproporphyria are extremely rare and broadly similar to porphyria variegate.
• Porphyria cutanea tarda has a genetic predisposition in many individuals, but is often found sporadically and associated with alcoholic liver disease. Bullous (blister-like) skin (cutaneous) lesions predominate.
• Congenital (erythropoietic) porphyria is a rare (autosomal recessive – an affected gene is required from each parent) genetic trait. Its victims show extreme sensitivity to sunlight and develop disfiguring scars (cutaneous porphyria).
• Erythropoietic protoporphyria is more common than congenital porphyria and is inherited as an autosomal dominant trait. Cutaneous (and rarely hepatic) presentations are seen.

Which drugs can precipitate porphyria?

There are many drugs than can potentially precipitate porphyria and no one list is complete! The list of drugs includes commonly used antibiotics, anti-depressants, the oral contraceptive pill, medications for the control of blood pressure and the medication for the lowering of blood cholesterol levels.

A complete list has been added as an addendum at the end.

How is porphyria diagnosed?

• Clinical picture: Porphyria is suspected in a patient showing the clinical symptoms, especially (but not exclusively) if a family history of porphyria is given.
• Urinary porphyrins and precursors: These tests are only positive in acute attacks (such as AIP, PV and HCP). Urine needs to be transported to the laboratory in a container protecting it from light, otherwise false positive results can arise.
• Faecal porphyrins: Faecal porphyrins are demonstrable in chronic/cutaneous porphyria and thus found in most forms of porphyria, excluding AIP.
• Fluorescence emission spectroscopy: This special investigation can be performed on plasma to differentiate porphyria variegate from other forms of acute or cutaneous porphyria.

How is porphyria treated?

Acute Porphyria

The management of acute episodes is largely supportive. Patients are hospitalised, usually under specialist care.

The principles in the management are the following:

• Possible precipitants should be identified and avoided
• Symptomatic treatment usually involves potent pain killers (such as opoids like morphine) and phenothiazides for nausea, vomiting and anxiety
• A high carbohydrate intake is usually maintained, sometimes in the form of an intravenous infusion of a glucose solution, as this may decrease porphyrin production
• Intravenous infusion of haematin arginate. It works by replenishing haem stores within the body. By negative feedback, this inhibits the initial rate-limiting enzyme of the haem synthetic pathway, ALA synthase. The formation of porphyrins and the precursors ALA and PBG are almost immediately reduced to low levels, and the symptoms improve in the majority of patients. Haem arginate is safe. The most frequent complication is phlebitis (inflammation of blood vessel) at the site of infusion.

The therapy is extremely expensive and should be restricted to attacks complicated by severe symptoms, hyponatraemia (low sodium level in blood), convulsions, neuropathy (nerve damage) or attacks that do not improve within 24 hours, as well as to patients who suffer frequent repeated acute attacks and in whom experience has shown that the attack will not settle unless haem arginate is given. Used for these indications haem arginate is cost-effective.

Cutaneous Porphyria

The management of this chronic condition includes:

• Strict avoidance of any possible precipitants (drugs and alcohol)
• Skin lesion are sun (photo-) sensitive, so avoiding exposure to direct sunlight and sunblock are important measures
• Topical treatment is often decided on after dermatological (skin specialist) consultation
• Some forms (the minority) require specific medical therapy. For example, patients with PCT may require volumes of blood to be removed in the cases of liver cirrhosis (when iron overload can be demonstrated by histology) or Chloroquine. Oral B-carotene provides effective protection against sun sensitivity in case of erythropoietic protoporphyria.

How is porphyria prevented?

An accurate diagnosis and early detection is of paramount importance. Family members should be screened (see below), and where affected, precipitants and alcohol must be avoided. All affected patients (even when no active disease is present) should wear a Medical Alert bracelet or necklace. Patients should always inform any health care professional of their affliction, especially when any form of medication (even topical) is prescribed.

Although the list of possible precipitating agents grows constantly, it is wise for any patient to carry a list with them, especially when visiting a doctor. Any responsible physician should have similar lists or reference books.

What is the outcome of porphyria?

The outcome of acute porphyria depends mainly on the degree of neurological damage present on presentation. Death is uncommon, but weakness may persist (due to peripheral neuropathy). Patients with Porphyria Variegate can have disfiguring skin lesions, developmental disorders and neurological symptoms. Acute exacerbations (if promptly diagnosed) are infrequently fatal.

When to see your doctor

Family members of known patients should be screened. Examples of such screening tests differ for the specific forms of porphyria, and include:

• Measurements of specific enzymes (erythrocyte porphobilinogen deaminase and ALA synthetase) in case of acute intermittent porphyria
• Tests for specific genes for porphyria
• Fluorescence emission spectroscopy in patients with possible porphyria Variegate

List of drugs which can precipitate porphyria

Drugs that should be avoided at all cost (*), as they are known to precipitate acute porphyria, or drugs that should be used with extreme caution, are: