Porphyria
From Freepedia
- This article is about the disease. For the poem by Robert Browning see Porphyria's Lover.
The porphyrias are inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway (also called porphyrin pathway). They are broadly classified as hepatic porphyrias or erythropoietic porphyrias, based on the site of the overproduction and mainly accumulation of the porphyrins (or their chemical precursors).
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Overview
In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, and cytochrome.
Deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. This is, however, not the main problem; most enzymes—even when less functional—have enough residual activity to assist in heme biosynthesis. The largest problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine in which tissue they accumulate, whether they are photosensitive, and how the compound is excreted (in the urine or feces).
Subtypes
There are eight enzymes in the heme biosynthetic pathway: the first and the last three are in the mitochondria, while the other four are in the cytosol.
- δ-aminolevulinate (ALA) synthase
- δ-aminolevulinate (ALA) dehydratase
- hydroxymethylbilane (HMB) synthase
- uroporphyrinogen (URO) synthase
- uroporphyrinogen (URO) decarboxylase
- coproporphyrinogen (COPRO) oxidase
- protoporphyrinogen (PROTO) oxidase
- ferrochelastase
Hepatic porphyrias
The hepatic porphyrias include:
- ALA dehydratase deficiency
- acute intermittent porphyria (AIP): a deficiency in HMB synthase
- hereditary coproporphyria (HCP): a deficiency in COPRO oxidase
- variegate porphyria (VP): a deficiency in PROTO oxidase
- porphyria cutanea tarda (PCT): a deficiency in URO decarboxylase
Erythropoietic porphyria
The erythropoietic porphyrias include:
- X-linked sideroblastic anemia (XLSA): a deficiency in ALA synthase
- congenital erythropoietic porphyria (CEP): a deficiency in URO synthase
- erythropoietic protoporphyria (EPP): a deficiency in ferrochelatase
Porphyria variegata
Variegate porphyria (also porphyria variegata or mixed porphyria) results from a partial deficiency in PROTO oxidase, manifesting itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. It may first occur in the second decade of life; there is a cohort of sufferers living in South Africa descended from a single person from the Netherlands, Berrit Janisz, who emigrated in the 17th century.
Signs and symptoms
The hepatic porphyrias primarily affect the nervous system, resulting in abdominal pain, vomiting, acute neuropathy, seizures, and mental disturbances, including hallucinations, depression, anxiety, and paranoia. Cardiac arrhythmias and tachycardia (fast heart rate) may develop as the autonomic nervous system is affected. Pain can be severe and can, in some cases, be both acute and chronic in nature. Constipation is frequently present, as the nervous system of the gut is affected.
The erythropoietic porphyrias primarily affect the skin, causing photosensitivity, blisters, itching, and swelling, and increased hair growth on areas such as the forehead.
In some forms of porphyria, accumulated heme precursors excreted in the urine may change its color, after exposure to sunlight, to a dark reddish or dark brown color. Even a purple hue may be seen.
Attacks of the disease can be triggered by drugs (e.g. barbiturates, alcohol, sulfa drugs, oral contraceptives, sedatives, and certain antibiotics), other chemicals, certain foods, and exposure to the sun. Fasting can also trigger attacks.
Diagnosis
Porphyria is diagnosed through tests on blood, urine, and stool. In general, urine estimation of porphobilinogen (PBG) is the first step if acute porphyria is suspected. As a result of feedback, the decreased production of heme leads to increased production of precursors, PBG being one of the first substances in the porphyrin synthesis pathway.
More extensive testing is done with spectroscopy (porphyrins have a characteristic absorption spectrum) and other chemical analyses. As all porphyria are rare conditions, this typically involves sending samples of blood, stool and urine to a reference laboratory. Often, empirical treatment is required if the diagnosic suspicion is high.
Further diagnostic tests of affected organs may be required, such as nerve conduction studies for neuropathy or an ultrasound of the liver.
Treatment
Acute porphyria
A high-carbohydrate diet is typically recommended; in severe attacks, a glucose 10% infusion is commenced, which may aid in recovery. If drugs have caused the attack, discontinuing these is essential. Infection requires vigorous treatment. Pain is extremely severe and almost always requires the use of opiates to reduce it to tolerable levels. Pain should be treated early as medically possible due to its severity. Nausea can be severe. It may respond to phenothiazine drugs. It may be intractable. I.V. hydration is therefore even more important.
Hematin and haem arginate are the drugs of choice in acute porphyria in the United States and the United Kingdom respectively. These drugs need to be given very early in an attack to be effective. Effectiveness varies amongst individuals. They are not curative drugs but can shorten attacks and reduce the intensity of an attack. Side effects are rare but can be serious. These heme-like substances inhibit ALA synthase and hence the accumulation of toxic precursors. In the United Kingdom, supplies of this drug are maintained at two national centers.
Patients with a history of acute porphyria are recommended to wear an alert bracelet or other identification at all times in case they develop severe symptoms as a result of which they cannot explain to healthcare professionals about their condition and the fact that some drugs are absolutely contraindicated.
Culture and history
Vampires and werewolves
Porphyria has been suggested as an explanation for the origin of vampire and werewolf legends, based upon a number of superficial similarities between the condition and the folklore. These ideas may have developed from a misunderstanding of the nature of porphyria and concentrate more on the traits from modern vampire and werewolf fiction than on the original folkloric beliefs.
Historical patients
Modern medicine has suggested that the insanity exhibited by King George III was the result of porphyria. Recent research has shown that porphyria is another hereditary disease plaguing the British royal family (besides hemophilia), apparently from the line of the monarchs of Scotland. Research has shown that both James I and Mary I of Scotland probably suffered from the disease. Queen Anne of Great Britain suffered from the disease as well. Queen Victoria's granddaughter Charlotte (a sister of Wilhelm II) and Prince William of Gloucester also suffered from the disease. New research indicates that Vincent van Gogh may have suffered from acute intermittent porphyria as well (Loftus & Arnold 1991).
References
- Anderson KE, Bloomer JR, Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR, Desnick RJ. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med 2005;142:439-50. PMID 15767622.
- Kauppinen R. Porphyrias. Lancet 2005;365:241-52. PMID 15652607.
- Loftus LS, Arnold WN. Vincent van Gogh's illness: acute intermittent porphyria? BMJ 1991;303:1589-91. PMID 1773180.
- Thadani H, Deacon A, Peters T. Diagnosis and management of porphyria. BMJ 2000;320:1647-51. Fulltext. PMID 10856069.
