Porphyria

This article is about the disease. For the poem by Robert Browningsee Porphyria's Lover.

The porphyrias are inherited or acquired disorders of certain enzymesin the hemebiosynthetic pathway (also called porphyrinpathway). 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).

Overview

In humans, porphyrinsare 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 urineor feces).

Subtypes

There are eight enzymesin the heme biosynthetic pathway: the first and the last three are in the mitochondria, while the other four are in the cytosol.

1. δ-aminolevulinate (ALA) synthase
2. δ-aminolevulinate (ALA) dehydratase
3. hydroxymethylbilane (HMB) synthase
4. uroporphyrinogen (URO) synthase
5. uroporphyrinogen (URO) decarboxylase
6. coproporphyrinogen (COPRO) oxidase
7. protoporphyrinogen (PROTO) oxidase
8. ferrochelastase

Hepatic porphyrias

Image:Heme synthesis.png 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 Africadescended 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 arrhythmiasand tachycardia(fast heart rate) may develop as the autonomic nervous systemis affected. Pain can be severe and can, in some cases, be both acute and chronic in nature. Constipationis frequently present, as the nervous system of the gut is affected.

The erythropoietic porphyrias primarily affect the skin, causing photosensitivity(photodermatitis), blisters, necrosis of the skin and gums, 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. Accumulated heme precursors may also accumulate in the teeth and fingernails, giving them a reddish appearance.

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. In nearly all cases of acute porphyria syndromes, urinary PBG is markedly elevated except for the very rare ALA dehydratase deficiency or in patients with symptoms due to lead poisoningor hereditary tyrosinemia type I.

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 studiesfor neuropathy or an ultrasoundof the liver.

Treatment

Acute porphyria

A high-carbohydrate diet is typically recommended; in severe attacks, a glucose10% infusion is commenced, which may aid in recovery. If drugs have caused the attack, discontinuing the offending substances is essential. Infectionis one of the top causes of attacks and 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. Nauseacan be severe; it may respond to phenothiazine drugs but is sometimes intractable. Hot water baths/showers may lessen nausea temporarily.

Hematinand haem arginateare the drugs of choice in acute porphyria, in the United Statesand the United Kingdomrespectively. 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 theoretically inhibit ALA synthase and hence the accumulation of toxic precursors. In the United Kingdom, supplies of this drug are maintained at two national centers. In the United States, one company manufactures Panhematin for infusion. The American Porphyria Foundation has information regarding the quick procurement of the drug.

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: a result of which may be they cannot explain to healthcare professionals about their condition and the fact that some drugs are absolutely contraindicated.

Patients who experience frequent attacks can develop chronic neuropathicpain in extremities as well as chronic pain in the gut.This is thought to be due to axonal nerve deterioration in affected areas of the nervous system. In these cases treatment with long-acting opioidsmay be indicated. Some cases of chronic pain can be difficult to manage and may require treatment using multiple modalities. Depression often accompanies the disease and is best dealt with by treating the offending symptoms and if needed the judicious use of anti-depressants.

Seizuresoften accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: barbituratesmust be avoided. Some benzodiazapines are safe and when used in conjuction with newer anti-seizure medications offer a possible regime for seizure control.

Culture and history

Vampires and werewolves

Porphyria has been suggested as an explanation for the origin of vampireand werewolflegends, 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 fictionthan on the original folkloric beliefs. A theory that the blood drinking attributed to vampires would alleviate the symptoms of porphyria does not stand up to scientific scrutiny (Adams 1999).

Historical patients

Modern medicine has suggested that the insanity exhibited by King George IIIwas 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 VI & Iand Mary I of Scotlandprobably suffered from the disease. Queen Anne of Great Britainsuffered from the disease as well. Queen Victoria's granddaughter Charlotte(a sister of Wilhelm II) and Prince William of Gloucesteralso suffered from the disease. New research indicates that Vincent van Goghmay have suffered from acute intermittent porphyria as well (Loftus & Arnold 1991). Erik Vachon, the little-known builder whose character was combined with that of Svengali to create "The Phantom of the Opera" probably suffered from erythopoeic porphyria.

It has also been suggested that King Nebuchadnezzar of Babylonsuffered from some form of Porphyria (cf. Daniel 4, see Beveridge 2003).

References

• Adams C. Did vampires suffer from the disease porphyria--or not? The Straight Dope 7 May 1999 Article
• 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.
• Beveridge A. The madness of politics. J R Soc Med 2003;96:602-4. PMID 14645615.
• Kauppinen R. Porphyrias. Lancet2005;365:241-52. PMID 15652607.
• Loftus LS, Arnold WN. Vincent van Gogh's illness: acute intermittent porphyria? BMJ1991;303:1589-91. PMID 1773180.
• Thadani H, Deacon A, Peters T. Diagnosis and management of porphyria. BMJ 2000;320:1647-51. Fulltext. PMID 10856069.

External links

• American Porphyria Foundation
• European Porphyria Initiative
• Porphynet - informative site on porphyrins and the porphyriasde:Porphyrie

es:Porfiria fr:Porphyrie io:Porfirio it:Porfiria fi:Porfyria sv:Porfyri

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It uses material from the http://en.wikipedia.org/wiki/Porphyria Wikipedia article Porphyria.