Porphyria

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Porphyrias are a group of 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). They manifest with either skin problems or with neurological complications (or occasionally both).

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The term derives from the Greek πορφύρα, porphura, meaning “purple pigment”. The name is likely to have been a reference to the purple discolouration of some body fluids in patients during an attack.^[1] Although original descriptions are attributed to Hippocrates, the disease was first explained biochemically by Felix Hoppe-Seyler in 1874,^[2] and acute porphyrias were described by the Dutch physician B.J. Stokvis in 1889.^[3][1]

Porphyrias have been detected in all races, multiple ethnic groups on every continent including Caucasians, Asians, Africans, Peruvian/Mexican Hispanics, Native Americans, Laplanders and Australian aborigines. There are high incidence reports of AIP in areas of India and Scandinavia and over 200 genetic variants of AIP, some of which are specific to families, although some strains have proven to be repeated mutations.

The Scandinavian source of porphyria has been traced to the Sámi ethnic group. Their language, as well as the languages of Finland, Estonia, Hungary, Transylvania, and Bulgaria have ties to languages in small groups of people living in Russia on both sides of the Urals and are branches of Uralic languages and Altaic languages (the Finno-Ugric Languages).

The links between porphyrias and mental illness have been noted for decades. In the early 1950s patients with porphyrias (occasionally referred to as “Porphyric Hemophilia”^[4]) and severe symptoms of depression or catatonia were uselessly and inappropriately treated with electroshock.

Porphyria has been suggested as an explanation for the origin of vampire and werewolf legends, based upon a number of similarities between the condition and the folklore that was first speculated upon by biochemist David Dolphin in 1985. His ruminations gave rise to a popular urban legend which accepts this association as factual, though it is historically and factually baseless. Porphyria cutanea tarda presents clinically as a pathological sensitivity of skin exposed to light causing scarring, hair growth and disfiguration. Additionally, it was believed that the patients’ missing heme could be absorbed through the stomach, correlating with the legends’ hematophagy.^[5]

The insanity exhibited by King George III evidenced in the regency crisis of 1788 has inspired several attempts at retrospective diagnosis. The first, written in 1855, thirty-five years after his death, concluded he suffered from acute mania. M. Guttmacher, in 1941, suggested manic-depressive psychosis as a more likely diagnosis, The first suggestion that a physical illness was the cause of King George’s mental derangements came in 1966, in a paper “The Insanity of King George III: A Classic Case of Porphyria”^[6], with a follow-up in 1968, “Porphyria in the Royal Houses of Stuart, Hanover and Prussia”^[7]. The papers, by a mother/son psychiatrist team, were written as though the case for porphyria had been proven, but the response demonstrated that many, including those more intimately familiar with actual manifestations of porphyria, were unconvinced. The theory is treated in Purple Secret^[8], which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to suffer from it.^[9] In 2005 it was suggested that arsenic (which is known to be porphyrogenic) given to George III with antimony may have caused his porphyria.^[10] Despite the lack of direct evidence, the notion that George III (and other members of the royal family) suffered from porphyria has achieved such popularity that many forget that it is merely a hypothesis. The insanity of George III is the basis of the plot in The Madness of King George, a 1994 British film based upon the 1991 Alan Bennett play, The Madness of George III. The closing credits include the comment that the illness suffered by King George has been attributed to porphyria.

It is suspected that Mary, Queen of Scots–George III’s grandmother six times removed–also suffered from acute intermittent porphyria, although this is subject to much debate. It is assumed she inherited the disorder, if she had it, from her father, James V of Scotland; both father and daughter endured well-documented attacks that some believe fall within the constellation of symptoms of porphyria.

Other commentators have suggested that Vincent van Gogh may have suffered from acute intermittent porphyria.^[11]

It has also been imagined that King Nebuchadnezzar of Babylon suffered from some form of porphyria (cf. Daniel 4).^[12] The symptoms of the various porphyrias are so wide-ranging that nearly any constellation of symptoms can be attributed to one or more of them.

The poet Robert Browning, also, notoriously wrote a poem called Porphyria’s Lover, which aside from a literal interpretation of the word also compares love itself to a form of disorder.

Paula Frias Allende, the daughter of the Chilean novelist Isabel Allende, fell into a porphyria-induced coma in 1991 which inspired Isabel Allende to write the autobiographical book Paula, dedicated to her daughter.

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The 8 porphyrias are:

1. Acute intermittent Porphyria (AIP)
2. ALA dehydratase deficiency
3. Porphyria cutanea tarda (PCT)
4. Congenital Erythropoetic Porphyria (CEP)
5. Hepatoerythropoetic Porphyria (HEP)
6. Erythopoetic Protoporphyria (EPP)
7. Hereditary coproporphyria (HCP)
8. Variegate Porphyria (VP)

These disorders can also be divided based on the type of precursors that accumulate and the subsequent manifestations that occur. ALA dehydratase deficiency (Plumboporphyria) and AIP are characterized by the accumulation of -aminolevulinic acid (ALA) and Porphobilinogen (PBG). Their manifestations are primarily neuropathic. PCT, CEP, HEP and EEP are characterized by accumulation of porphyrin and have cutaneous manifestations only. HCP and VP have accumulation of porphyrin precursors and porphyrins. They have both neuropathic and cutaneous manifestations.

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In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, respiratory and P450 liver cytochromes.

Deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. Heme function plays a central role in cellular metabolism. This is not the main problem in the porphyrias; most heme synthesis enzymes—even dysfunctional enzymes—have enough residual activity to assist in heme biosynthesis. The principal 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 the location of accumulation, whether they induce photosensitivity, and whether the intermediate is excreted (in the urine or feces).

There are eight enzymes in the heme biosynthetic pathway, four of which—the first one and the last three—are in the mitochondria, while the other four are in the cytosol. Defects in any of these can lead to some form of porphyria.

The hepatic porphyrias are characterized by acute neurological attacks (seizures, psychosis, extreme back and abdominal pain and an acute polyneuropathy), while the erythropoietic forms present with skin problems, usually a light-sensitive blistering rash and increased hair growth.

Variegate porphyria (also porphyria variegata or mixed porphyria), which results from a partial deficiency in PROTO oxidase, manifests itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. All other porphyrias are either skin- or nerve-predominant.

Evaluation of family members is necessary to identify latent porphyria. All acute porphyrias are autosomal dominant except for ALA-D which is autosomal recessive.

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The acute attack is 5 times more common in females.

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The most common precipitants are

• Drugs – (e.g. barbiturates, alcohol, sulfa drugs, hormonal contraception, sedatives and certain antibiotics), Nitisinone
• Menstrual cycle
• Alcohol
• Infection
• Steroid hormones
• Fasting

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Screening test for Porphyria is Watson-Schwartz test. Porphobilinogen reacts with Ehrlich’s reagent in acidic solution to form red pigment.

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• Patients with hepatic porphyrias (PCT, AIP, HCP, VP) are at increased risk over their life for hepatocellular carcinoma (primary liver cancer) and may require monitoring. Other typical risk factors for liver cancer need not be present, such as hepatitis B or C, iron overload or alcoholic cirrhosis.
• The neuropathic effects can progress and become severe leading to irreversible neurologic damage
  • Guillian-Barre type syndrome with paralysis
  • Bulbar dysfunction
  • Respiratory failure
  • Death

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