Porphyrias

The porphyrias are a group of inherited metabolic disorders. They should be considered in any patient presenting with an atypical medical, psychiatric or surgical history.

Pathogenesis

There are eight different types in total and each is due to the partial deficiency of one of the enzymes involved in haem synthesis.¹ This enzyme deficiency results in the overproduction and increased excretion of toxic haem precursors (porphyrins and/or their precursors) formed prior to the enzyme defect. This leads to the various clinical and biochemical features.²

Haem is mainly synthesised in the liver and in erythroid cells and is used for haemoglobin and cytochrome synthesis. In haem synthesis, delta-aminolaevulinic acid synthase (ALA synthase) controls the conversion of glycine and succinyl coenzyme A to delta-aminolaevulinic acid. Further enzymes including porphobilinogen (PBG) then convert this to the various porphyrins until finally haem is formed.¹

Classification

In addition, an X-linked dominant protoporphyria (XLDPP) has also been classified. The enzyme deficiency isolated is ALA synthase as a result of a C-terminal deletion in the ALAS2 gene. XLDPP causes an acute, childhood-onset, cutaneous photosensitivity indistinguishable from that of EPP but appears to have a higher risk for hepatic dysfunction.

There are a number of commonly used classifications for porphyrias. They can be classified according to their clinical features:

• Acute porphyrias producing neuropsychiatric features: ADP (also known as plumboporphyria), AIP.

• Cutaneous porphyrias mostly affecting the skin: PCT, EPP, CEP.

• Mixed porphyrias with both cutaneous and neuropsychiatric features: VP, HCP.

Another classification uses the site where most of the haem precursors arise from and accumulate in:

• If this is the liver, they are known as hepatic porphyrias and include the acute and mixed porphyrias as described above as well as PCT.

• If this is the bone marrow, they are known as erythropoietic porphyrias and include the two other cutaneous porphyrias listed above.³

Porphyria epidemiology⁴

• The most common porphyria (PCT) has a prevalence of 1 in 10,000 people.

• The most common acute porphyria (AIP) has a prevalence of about 1 in 20,000 people.

• The most common erythropoietic porphyria (EPP) affects between 1 in 50,000 to 75,000 people.

• CEP is extremely rare, with prevalence estimates of 1 in 1,000,000 or less.

• Only six cases of delta-aminolevulinic acid dehydratase deficiency porphyria are documented.

• Porphyria can appear in childhood, as seen in EPP, but the onset is usually between the ages of 20 and 40 and it affects women more than men.

Porphyrias producing acute neuropsychiatric features

• The most common is AIP. HCP and VP can also show the same classic acute symptoms. ADP (plumboporphyria) is very rare.

• Only a minority of people who carry the gene develop symptoms. This means that there may be no family history.

• Frequency and severity of attacks vary widely between people. Many patients inherit porphyria but never have acute symptoms; about 80% of men and 50% of women have the condition in this latent form.

• Between attacks the patient is usually healthy.

• Acute attacks are precipitated by metabolic, hormonal and environmental factors that induce hepatic delta-aminolaevulinic acid synthase (ALA synthase) activity. This increased activity causes the haem precursors delta-aminolaevulinic acid and porphobilinogen to increase. Because of the reduced activity of one of the different enzymes needed to convert these precursors further (depending on which porphyria is present), there is pathological accumulation.

Clinical features⁵

• Acute attacks are rare and notoriously difficult to diagnose clinically.

• However, they should be considered, particularly in female patients with unexplained abdominal pain and associated neurological or psychiatric features or hyponatraemia.⁶

• Attacks can start with anxiety, restlessness and insomnia in 20-30% of patients.¹ These are part of a prodrome.

• Abdominal pain can resemble an acute abdomen and occurs in 95% of attacks.

• Autonomic disturbance can cause nausea, vomiting and constipation.

• Sympathetic overactivity causes tachycardia, hypertension and postural hypotension.

• Muscular weakness can occur. Proximal myopathy affecting the arms can progress to quadraparesis, respiratory muscle paralysis and respiratory arrest.

• Sensory neuropathy can occur often in a 'bathing trunk distribution'.

• Hyponatraemia (due to dehydration, nephrotoxicity or inappropriate antidiuretic hormone (ADH) secretion) can lead to confusion and convulsions.

• Agitation, mania, depression and hallucinations can occur and can persist between attacks.

• Urine may be dark or reddish due to the excessive excretion of haem precursors.

• Sudden death can occur during an acute attack and is thought to be due to cardiac arrhythmia.

Precipitating factors

Patients with acute porphyrias are prone to potentially fatal acute attacks. These attacks are frequently precipitated by exposure to commonly used drugs. Correctly identifying the safety or otherwise of drugs in porphyria is therefore important.⁷ Patients should also eat regular meals, since starvation can bring on attacks. Common triggers for acute attacks include:

• Drugs.⁸ There is a list of safe and unsafe drugs on the Drug Database for Acute Porphyria website.⁹

• Fasting.

• Smoking.

• Alcohol.

• Substance misuse.

• Emotional/psychological distress.

• Menstruation (premenstrual attacks can occur).

• Pregnancy.

• Infection.

Differential diagnosis

Porphyrias are frequently diagnosed late, and often after alternative, more common diagnoses have been settled upon incorrectly. In one US case series of 108 patients with acute porphyrias, the mean time from symptom onset to diagnosis was 15 years, and many patients had appendicectomies and cholecystectomies prior to the diagnosis of porphyria being made.¹⁰

Differential diagnoses include:

• Other causes of acute abdominal pain.

• Guillain-Barré syndrome.

• Epilepsy.

• Mental illness, especially psychosis.¹¹

• Other neurological conditions, including other causes of peripheral neuropathies.

Investigations

• The diagnosis might be suggested by altered urine colour and can be confirmed by finding an elevated porphobilinogen concentration in fresh urine protected from light.⁶

• 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 specialised porphyria clinics in the UK (eg, King's College Hospital in London, in Cardiff, Cambridge, Salford and Leeds).

• Between attacks, levels of aminolaevulinic acid and porphobilinogen in the urine may be normal.

• Family screening is essential to prevent acute attacks in those with latent disease.

Porphyria treatment and management⁵

Delay in diagnosis and treatment can be fatal and can lead to permanent neurological damage.

Immediate management of acute attacks

• Admit to hospital.

• Remove any precipitating factors - eg, drugs.

• Opiates can be prescribed for pain.

• Phenothiazines can be used for nausea, vomiting, anxiety and restlessness.

• Beta-blockers can reduce tachycardia and hypertension.

• Severe attacks require treatment with intravenous haem arginate.

• Intravenous glucose in water solutions are contra-indicated, as they aggravate hyponatraemia, which can prove fatal.

Further management

• Monitor plasma electrolyte levels.

• Monitor for any developing muscular weakness and neuropathy. This is often characterised by severe pain and stiffness in the thighs and back and then loss of tendon reflexes, and motor paralysis. If this begins to develop, monitor peak flow rate/perform spirometry. Ventilation may be required if respiratory muscles are affected.

• Oral glucose and intravenous glucose suppress the activity of aminolaevulinic acid synthase (the first enzyme in the haem pathway) and therefore reduce the overproduction of porphyrins and the precursors formed prior to the enzyme block. This can lead to remission.

• Haem arginate should be commenced early in an attack. It also suppresses the activity of ALA synthase. Most patients with uncomplicated attacks improve within five days. Generally this is well tolerated but it may cause phlebitis around the injection site and coagulopathy. Anaphylaxis has occurred.

• Attacks during pregnancy have been treated without any apparent adverse effects to either mother or child;¹² however, adverse pregnancy outcomes do appear to be more frequent in women with porphyria.¹³

Complication management

• Treatment of convulsions: the most commonly used anticonvulsants are porphyrogenic. Gabapentin and probably vigabatrin can be used to treat convulsions.

• Very occasionally, acute attacks are accompanied by a severe adrenergic crisis leading to posterior reversible encephalopathy syndrome (PRES).¹

• Liver transplantation has been carried out successfully in severe cases.

• Gonadotrophin-releasing hormone analogues have been used to prevent recurrent cyclic attacks in the luteal phase of the menstrual cycle in some women.

• Weekly or bi-weekly infusions of haem have been used to prevent recurrent attacks.

Prevention

• Patient education to avoid precipitating factors.

• Patient support groups exist.

• Wear a medical emergency identification bracelet or similar.

• Screening of blood relatives, using enzyme and gene studies, should be carried out so that they can take appropriate precautions to avoid attacks.

Prognosis

• Fewer than 10% of patients have recurrent acute attacks without clearly identified precipitating factors.¹ Advice about management of these attacks should be sought from a reference porphyria centre. Management of repeated attacks that are severe enough to need admission is difficult and long-term treatment with human haemin is needed. Regular treatment with a once-per-week single dose can help to control the disease.

• 1% of acute attacks can be fatal. Death is usually either from cardiac arrest or pneumonia associated with prolonged mechanical ventilation.

• Chronic hypertension or chronic kidney disease can develop in a small minority.

• Chronic liver damage can also occur.

• 10% of patients with AIP die from hepatocellular carcinoma.³

Cutaneous porphyrias

Skin lesions occur in about half of patients with VP and about a third of patients with HCP. The cutaneous manifestations are similar to those in PCT. They can be the only clinical features of these mixed porphyrias.

CEP, PCT and EPP cause light-sensitive porphyrins to build up (A, B and E respectively), which cause the skin problems but they do not cause acute attacks. However, in HCP and VP there is a build-up of light-sensitive porphyrins (C and D) plus a feedback system which raises ALA and PBG. This means that patients with HCP or VP can have both skin problems and acute attacks.

CEP - Gunther's disease

• This presents in childhood. It is the most frequent of the rare recessive porphyrias.

• Red urine that fluoresces in nappies can allow an easy bedside diagnosis.³

• There is severe photosensitivity.

• Pruritus and erythema followed by vesicle and bullous formation occur on exposure to sunlight. The bullae can rupture causing ulcers which may become infected. Scarring and disfigurement can occur on healing.

• Anaemia and splenomegaly can also occur.

• Splenectomy, chloroquine and bone marrow transplantation are all possible treatments.

EPP

• This usually presents in childhood but can present at any age.

• Clinical features include burning, itching and erythema on exposure to sunlight. There is no bullae formation and minimal scarring.

• Protoporphyrin can accumulate in the liver and lead to liver failure.

• Gallstones can occur.

• Diagnosis is by measuring free erythrocyte protoporphyrin.

• Carotene treatment may be helpful, as it raises tolerance to sunlight.

• Liver and bone marrow transplantation have been successfully carried out as treatment.

PCT

• PCT is the most common porphyria.

• Unlike other porphyrias, it is nearly always acquired rather than inherited.

• PCT is associated with alcohol abuse, oestrogens, iron overload and hepatitis C infection.

• This usually presents after the fourth decade and is more common in men.

• Skin lesions include erythema and bullae that occur on exposure to sunlight. Fragile, poorly healing skin with pruritus, hyperpigmentation and hypertrichosis are other features.

• Forehead, cheeks, ears and backs of hands are most commonly affected but all skin exposed to the sun can be affected.

• There is usually mild iron overload and liver cell damage can also occur.

• PCT is also associated with HIV and haemochromatosis as well as systemic lupus erythematosus, alcoholic liver disease and chronic active hepatitis.

• Diagnosis is by measurement of excess porphyrins in urine, blood and stool.

• Management includes avoidance of exposure to sunlight. Barrier creams may be helpful.

• Venesection may be needed for iron overload.

• Treatment with chloroquine and avoidance of alcohol and oestrogens may also help.