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.¹

Pathogenesis

There are 8 different types in total and each is due to the partial deficiency of one of the enzymes involved in haem synthesis.²
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.

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 then convert this to porphobilinogen and then the various porphyrins until finally haem is formed.²

Classification

More recently (2008) an X-linked dominant protoporphyria has also been classified. The enzyme deficiency isolated is ALA synthase as a result of a C-terminal deletion in the ALAS2 gene.

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

• Acute porphyrias producing neuropsychiatric features:
  • Aminolaevulinic acid dehydratase porphyria (also known as plumboporphyria)
  • Acute intermittent porphyria (AIP)
• Cutaneous porphyrias mostly affecting the skin:
  • Porphyria cutanea tarda (PCT)
  • Erythropoietic protoporphyria (EPP)
  • Congenital erythropoietic porphyria
• Mixed porphyrias with both cutaneous and neuropsychiatric features:
  • Variegate porphyria (VP)
  • Hereditary coproporphyria (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 porphyria cutanea tarda.
• If this is the bone marrow, they are known as erythropoietic porphyrias and include the two other cutaneous porphyrias listed above.³

Epidemiology

• The porphyrias are rare and can be misdiagnosed because their symptoms are easily confused with other diseases.
• Porphyria cutanea tarda (PCT) is the most common form of porphyria worldwide.⁴
• The prevalence of PCT in the UK is 1 in 25,000.⁵

Porphyrias producing acute neuropsychiatric features

• The most common is acute intermittent porphyria (AIP).
• Hereditary coproporphyria (HCP) and variegate porphyria (VP) can also show the same classic acute symptoms.
• Aminolaevulinic acid dehydratase porphyria (plumboporphyria) is very rare.
• Only 10-15% of people who carry the gene develop symptoms.¹ This means that there may be no family history.
• Frequency and severity of attacks varies widely between people, with the disease remaining latent in some people even in the presence of precipitating factors.
• Attacks most commonly affect people aged in their 30s and are more common in women.
• 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.⁶

Clinical features

• Attacks can start with anxiety, restlessness and insomnia in 20-30% of patients.² 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 factors¹

• Drugs - safe and unsafe drugs on the European Porphyria Initiative website⁷
• Fasting
• Smoking
• Alcohol
• Substance misuse
• Emotional/psychological distress
• Menstruation (premenstrual attacks can occur)
• Pregnancy
• Infection

Differential diagnosis

• Guillain-Barré syndrome
• Epilepsy
• Mental illness
• Neurological deficits

Investigations

• Initial rapid testing for urinary porphobilinogen level using one of a number of testing kits will diagnose the most common causes of acute attacks (acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP)).⁸
• Second-line testing can then be carried out to establish the specific type of porphyria.⁸
• This includes measurement of erythrocyte porphobilinogen deaminase activity and urine, faecal and plasma porphyrin levels.
• Testing should be carried out on samples obtained before starting haem therapy. Protect urine samples from light.
• Care should be taken as these second-line tests do lack sensitivity and specificity. Urinary porphyrins can also be raised in other conditions including liver dysfunction.⁸
• Between attacks, levels of aminolaevulinic acid and porphobilinogen in the urine may be normal.
• Enzyme activity measurement and DNA testing can confirm the type of acute porphyria and allow family studies.⁸ Family screening is essential to prevent acute attacks in those with latent disease.

Management

Delay in diagnosis and treatment can be fatal and can lead to permanent neurological damage.⁸

Immediate management

• Admit to hospital.
• Remove any precipitating factors, e.g. drugs.
• Opiates can be prescribed for pain.¹
• Phenothiazines can be used for nausea, vomiting, anxiety and restlessness.⁸
• Betablockers can reduce tachycardia and hypertension.

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 and intravenous glucose suppresses the activity of aminolaevulinic acid synthase (the first enzyme in the haem pathway) and therefore reduces the overproduction of porphyrins and the precursors formed prior to the enzyme block. This can lead to remission.¹
• Haem arginate should be commenced early in an attack. It also suppresses the activity of aminolaevulinic acid synthase.^1,8 Most patients with uncomplicated attacks improve within 5 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.

Complication management

• Treatment of convulsions: the most commonly used anticonvulsants are porphyrogenic. Treat any underlying hyponatraemia by fluid restriction.¹ Gabapentin, and probably vigabatrin, can be used to treat convulsions.⁸
• Very occasionally, acute attacks are accompanied by a severe adrenergic crisis with dangerous hypertension, encephalopathy, seizures, and ischaemic changes on a CT brain scan.²
• Liver transplantation has been carried out successfully in severe cases.⁹
• 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 biweekly infusions of haem have been used to prevent recurrent attacks.

Prevention

• Patient education to avoid precipitating factors.
• Patient support groups exist (see links below).
• Wear a MedicAlert® bracelet.
• 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.² 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.¹ Death is usually either from cardiac arrest or pneumonia associated with prolonged mechanical ventilation.¹⁰
• Chronic hypertension or chronic renal failure can develop in a small minority.
• Chronic liver damage can also occur.
• 10% of patients with acute intermittent porphyria die from hepatoma.³

Cutaneous porphyrias

Skin lesions occur in about half of patients with variegate porphyria (VP) and about a third of patients with hereditary coproporphyria (HCP).¹ The cutaneous manifestations are similar to those in porphyria cutanea tarda (PCT). They can be the only clinical features of these mixed porphyrias.

Congenital erythropoietic porphyria (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.

Erythropoietic protoporphyria (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.¹
• 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.¹¹
• Liver and bone marrow transplantation have been successfully carried out as treatment.¹²

Porphyria cutanea tarda

• This usually presents after the 4th decade.³ It 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.
• Porphyria cutanea tarda (PCT) can be familial but is usually sporadic and results from exposure to certain drugs or chemicals including oral contraceptives and alcohol.
• PCT is associated with hepatitis C, HIV and haemochromatosis¹ 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.

Document references

1. Thadani H, Deacon A, Peters T; Diagnosis and management of porphyria. BMJ. 2000 Jun 17;320(7250):1647-51.
2. Puy H, Gouya L, Deybach JC; Porphyrias. Lancet. 2010 Mar 13;375(9718):924-37. [abstract]
3. Kauppinen R; Porphyrias. Lancet. 2005 Jan 15-21;365(9455):241-52. [abstract]
4. OMIM; Porphyria Cutanea Tarda. #176100.
5. Elder GH, Smith SG, Smyth SJ; Laboratory investigation of the porphyrias. Ann Clin Biochem. 1990 Sep;27 ( Pt 5):395-412.
6. Solis C, Martinez-Bermejo A, Naidich TP, et al; Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. Arch Neurol. 2004 Nov;61(11):1764-70. [abstract]
7. European Porphyria Initiative; Provides information and support to families affected by porphyria supports and encourages medical research.
8. Anderson KE, Bloomer JR, Bonkovsky HL, et al; Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005 Mar 15;142(6):439-50. [abstract]
9. Seth AK, Badminton MN, Mirza D, et al; Liver transplantation for porphyria: who, when, and how? Liver Transpl. 2007 Sep;13(9):1219-27. [abstract]
10. Pischik E, Bulyanitsa A, Kazakov V, et al; Clinical features predictive of a poor prognosis in acute porphyria. J Neurol. 2004 Dec;251(12):1538-41.
11. Mathews-Roth MM; Carotenoids in erythropoietic protoporphyria and other photosensitivity diseases. Ann N Y Acad Sci. 1993 Dec 31;691:127-38. [abstract]
12. Rand EB, Bunin N, Cochran W, et al; Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria. Pediatrics. 2006 Dec;118(6):e1896-9. Epub 2006 Oct 30. [abstract]

Internet and further reading

• Cardiff Porphyria Service; Specialises in the diagnosis and treatment of the porphyrias in the UK.
• British Porphyria Association; Established for patients, doctors, hospitals and research establishments in order to improve the understanding of porphyria.
• European Porphyria Initiative; Provides information and support to families affected by porphyria supports and encourages medical research.
• Dermatology Information System (DERMIS); Images showing different cutaneous porphyrias.
• OMIM; Porphyria, Acute intermittent. #176000
• OMIM; Porphyria Varigata. #176200.
• OMIM; Porphyria, Congenital erythropoietic. #263700.

Acknowledgements