Porphyria Totally Explained

Everything about Porphyria totally explained

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).
   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. Although original descriptions are attributed to Hippocrates, the disease was first explained biochemically by Felix Hoppe-Seyler in 1874, and acute porphyrias were described by the Dutch physician B.J. Stokvis in 1889. Lupus erythematosus features photosensitivity, pain attacks and shares various other symptoms with porphyria.
   Not all porphyrias are genetic, and patients with liver disease who develop porphyria as a result of liver dysfunction may exhibit signs of their conditions, such as jaundice.
   Attacks of the disease can be triggered by drugs (for example barbiturates, alcohol, sulfa drugs, hormonal contraception, sedatives and certain antibiotics), other chemicals and certain foods. Fasting can also trigger attacks.
   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.

Cutaneous porphyria

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. Often there's no abdominal pain, distinguishing it from other porphyrias.
In some forms of porphyria, accumulated heme precursors excreted in the urine may cause various changes in color, after exposure to sunlight, to a dark reddish or dark brown color. Even a purple hue or pink urine may be seen. Heme precursors may also accumulate in the teeth and fingernails, giving them a reddish appearance.

Diagnosis

Porphyrin studies

Porphyria is diagnosed through spectroscopy and biochemical analysis of 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 poisoning or hereditary tyrosinemia type I.
Repeat testing during an attack and subsequent attacks may be necessary in order to detect a porphyria, as levels may be normal or near-normal between attacks. The urine screening test has been known to fail in the initial stages of a severe life threatening attack of acute intermittent porphyria.
The bulk (up to 90%) of the genetic carriers of the more common, dominantly inherited acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) have been noted in DNA tests to be latent for classic symptoms and may require DNA or enzyme testing. The exception to this may be latent postpuberty genetic carriers of hereditary coproporphyria.
As most porphyrias are rare conditions, general hospital labs typically don't have the expertise, technology or staff time to perform porphyria testing. In general, testing involves sending samples of blood, stool and urine to a reference laboratory.
Any sign of low blood sodium (hyponatremia) or weakness should be treated with the addition of hematin or heme arginate as these are signs of impending syndrome of inappropriate antidiuretic hormone (SIADH) or peripheral nervous system involvement that may be localized or severe progressing to bulbar paresis and respiratory paralysis.

Precipitating factors If drugs or hormones have caused the attack, discontinuing the offending substances is essential. Infection is one of the top causes of attacks and requires vigorous treatment.

Symptom control Pain is extremely severe, frequently out of proportion to physical signs 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 but is sometimes intractable. Hot water baths/showers may lessen nausea temporarily, though caution should be used to avoid burns or falls.

Early identification Patients with a history of acute porphyria and even genetic carriers are recommended to wear an alert bracelet or other identification at all times in case they develop severe symptoms or in case of accidents where there's a potential for drug exposure: a result of which may be they can't explain to healthcare professionals about their condition and the fact that some drugs are absolutely contraindicated.

Neurologic and psychiatric issues Patients who experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the gut. Gut dysmotility, ileus, intussusception, hypoganglionosis, encopresis in children and intestinal pseudo-obstruction have been associated with porphyrias. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system and vagal nerve dysfunction.
In these cases treatment with long-acting opioids may be indicated. Some cases of chronic pain can be difficult to manage and may require treatment using multiple modalities. Opioid dependence may develop. Depression often accompanies the disease and is best dealt with by treating the offending symptoms and if needed the judicious use of anti-depressants. Some psychotropic drugs are porphyrinogenic, limiting the pharmacotherapeutic scope.

Seizures Seizure often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: barbiturates especially must be avoided. Some benzodiazepines are safe, and, when used in conjunction with newer anti-seizure medications such as gabapentin offer a possible regime for seizure control.
Magnesium sulfate and bromides have also been used in porphyria seizures, however, development of status epilepticus in porphyria may not respond to magnesium alone. The addition of hematin or heme arginate has been used during status epilepticus.

Underlying liver disease Some liver diseases may cause porphyria even in the absence of genetic predisposition. These include hemochromatosis and hepatitis C. Treatment of iron overload may be required.

Hormone treatment Hormonal fluctuations that contribute to cyclical attacks in women have been treated with oral contraceptives and luteinizing hormones to shut down menstrual cycles. However, oral contraceptives have also triggered photosensitivity and withdrawal of oral contraceptives has triggered attacks. Androgens and fertility hormones have also triggered attacks.

Erythropoietic porphyrias

These are associated with accumulation of porphyrins in erythrocytes and are rare. The rarest is Congenital erythropoetic porphyria (C.E.P) otherwise known as Gunther's disease. Its rarity is partially due to its autosomal recessive mode of inheritance. The signs may present from birth and include severe photosensitivity, brown teeth that fluoresce in ultraviolet light due to deposition of type one porphyrins and later hypertrichosis. Haemolytic anaemia usually develops. Pharmaceutical-grade beta carotene may be used in its treatment. A bone marrow transplant has also been successful in curing CEP in a few cases, although long term results are not yet available. The pain, burning, swelling and itching that occur in erythropoietic porphyrias generally require avoidance of bright sunlight. Most kinds of sunscreen are not effective, but SPF-rated long-sleeve shirts, hats, bandanas and gloves can help. Chloroquine may be used to increase porphyrin secretion in some EPs.) and severe symptoms of depression or catatonia were uselessly and inappropriately treated with electroshock.

Vampires and werewolves

Porphyria has been suggested as an explanation for the origin of vampire and werewolf legends, based upon certain similarities between the condition and the folklore.
In January 1964, L. Illis' 1963 paper, "On Porphyria and the Ætiology of Werwolves", was published in Proceedings of the Royal Society of Medicine. Later, Nancy Garden made a connection between porphyria and the vampire belief in her 1973 book, Vampires. However, in 1985, biochemist David Dolphin's paper for the American Association for the Advancement of Science, "Porphyria, Vampires, and Werewolves: The Aetiology of European Metamorphosis Legends", gained widespread media coverage, thus popularizing the connection.
The theory has since faced heavy criticism, especially for the stigma it has placed on its sufferers. Norine Dresser's American Vampires: Fans, Victims, Practitioners (1989) treats the matter with more depth. The theory also operates on a highly-flawed premise: mainly in regards to a perceived harmful effect sunlight had on vampires. But this is a much more recent innovation in vampire "lore": its origin is from 1922, with the release of vampire movie, Nosferatu, eine Symphonie des Grauens. 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.

Famous cases

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", with a follow-up in 1968, "Porphyria in the Royal Houses of Stuart, Hanover and Prussia". 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, which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to suffer from it. In 2005 it was suggested that arsenic (which is known to be porphyrogenic) given to George III with antimony may have caused his porphyria. 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's 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 believed that Marie Stuart, Queen of Scots--King 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'd 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.
   It has also been imagined that King Nebuchadnezzar of Babylon suffered from some form of porphyria (cf. Daniel 4). 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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