Porphyria- The Vampire disease

Abhishek JhaGrp- 18

What is it?

• Group of rare diseases in which metabolic substances called porphyrins accumulate in body.

• Porphyrins produce heme , which carries oxygen in the blood; but in the porphyrias, there is a deficiency (inherited or acquired) of the enzymes that transform the various porphyrins into others, leading to abnormally high levels of these substance.

• This manifests with either neurological complications or skin problems or occasionally both.

• Term porphyria is derived from the Greek porphyra, meaning "purple pigment a reference to the color of the porphyrins.

• The disease was first explained biochemically by Felix Hoppe-Seyler in 1871 and acute porphyrias were described by the Dutch physician Barend Stokvis in 1889.

• Porphyria's are classified in two ways, by symptoms and by pathophysiology.

• Symptomatically 1. Acute 2. Cutaneous

• Pathophysiology1. Hepatic2. Erythropoitic -based on the sites of accumulation of heme precursors, either in the liver or bone marrow and red blood cells

Acute porphyria

• acute intermittent porphyria

• ALA dehydratase (porphobilinogen synthase) porphyria

Acute porphyria

• Acute porphyrias primarily affect the nervous system, which appear quickly and can be life-threatening and resulting in episodic crises known as acute attacks.

• Acute porphyria attacks are rare before puberty and after menopause in women.

• Symptoms may last one to two weeks and usually improve slowly after the attack.

Signs occur during acute porphyria

• Severe abdominal pain• Swelling of the abdomen (abdominal distention)• Pain in your chest, legs or back• Constipation or diarrhea• Vomiting• Insomnia• Heartbeat you can feel (palpitations)• High blood pressure• Anxiety or restlessness• Seizures• Mental changes, such as confusion, hallucinations, disorientation or paranoia• Breathing problems• Muscle pain, tingling, numbness, weakness or paralysis• Red or brown urine

• The relatively low occurrence of porphyria, the patient may initially be suspected to have other, unrelated conditions. For instance, the polyneuropathy of acute porphyria may be mistaken for Guillain-Barre syndrome, and porphyria testing is commonly recommended in those situations

Cutaneous porphyria• X-linked dominant protoporphyria (XLDPP)

• congenital erythropoietic porphyria (CEP)

• porphyria cutanea tarda (PCT) • erythropoietic protoporphyria (EPP)

• variegate porphyria

• hereditary coproporphyria

Congenital erythropoietic porphyria

Cutaneous porphyrias

• Cutaneous porphyrias include forms of the disease that cause skin symptoms as a result of oversensitivity to sunlight, but these forms don't usually affect nervous system. Attacks may last for several days. With some forms, signs and symptoms may start during infancy or childhood.

• Sensitivity to the sun and sometimes artificial light, causing burning pain Sudden painful skin redness (erythema) and swelling (edema) Blisters that take weeks to heal Itching Fragile skin Scars or skin color changes from healing blisters Increased hair growth Red or brown urine

Two distinct patterns of skin disease are seen in porphyria:

• Immediate photosensitivity This is typical of XLDPP and EPP. Following a variable period of sun-exposure ,typically about 30 minutes, patients complain of severe pain, burning and discomfort in sun-exposed areas, there may be some redness and swelling of the skin

• Vesiculo-erosive skin disease -occur blistering (vesicles) and open sores (erosions). It is the pattern of skin disease seen in CEP, PCT, VP and HCP.-Changes are noted only in sun-exposed areas such as the backs of the hands and face. Milder skin disease, consists of increased skin fragility in exposed areas with a tendency to form blisters and erosions particularly after minor knocks or scrapes. These heal slowly, often leaving small scars which may be lighter or darker than normal skin.

cutanea tarda & variegate porphyria

• More severe skin disease is sometimes seen in PCT, with more prominent lessons, darkening of exposed skin such as the face and hypertrichosis: abnormal hair growth on the face, particularly the cheeks

• term photoutilation is used to describe the severe shortening of digits and loss of skin appendages such as hair and nails, and severe scarring of the skin with progressive disappearance of ears, lips and nose. These patients may also show deformed, discolored teeth, gum and eye abnormalities

Diagnosis

• Blood , urine and stool test may revel kidney problem and other problem special test measure prophyrin in blood.

• The test measure the concentration of porphyrins and their precursors ALA and PBG which will be very high in patient with an attack of acute porphyria.

Risk factor• Certain drugs (barbiturates or sulfonamide antibiotics or, less often,

birth control pills, or some drugs that affect the mind or behavior, known as psychoactive drugs)

• Chemicals • Dieting or fasting• Smoking• Physical stress, such as infections or other illnesses• Liver disease• Emotional stress• Alcohol use• Menstrual hormones• Sun exposure• Excess iron in your body

Pathogenesis • 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.

Epidemiology

• The prevalence of all types of porphyria taken together has been estimated to be approximately 1 in 25,000 in the United States.[31] The worldwide prevalence has been estimated to be somewhere between 1 in 500 to 1 in 50,000 people.

Culture and History• Porphyrias have been detected in all races, multiple ethnic

groups on every continent including Africans, Asians, Australian aborigines, Caucasians, Peruvian, Mexican, Native Americans, and Sami. 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 links between porphyrias and mental illness have been noted for decades. In the early 1950s patients with porphyrias (occasionally referred to as "Porphyric Hemophilia"[33]) and severe symptoms of depression or catatonia were treated with electroshock.

Vampires and werewolves

• Porphyria has been suggested as an explanation for the origin of vampire and werewolf legends, based upon certain perceived similarities between the condition and the folklore.

• In January 1964, L. Illis' 1963 paper, "On Porphyria and the Aetiology of Werwolves", was published in Proceedings of the Royal Society of Medicine. Later, Nancy Garden argued for a connection between porphyria and the vampire belief in her 1973 book, Vampires. 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 idea.

• The theory has been rejected by a few folklorists and researchers as not accurately describing the characteristics of the original werewolf and vampire legends or the disease and for potentially stigmatizing sufferers of porphyria

• The mental illness 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",[37] with a follow-up in 1968, "Porphyria in the Royal Houses of Stuart, Hanover and Prussia".[38] 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. Many psychiatrists disagreed with Hunter's diagnosis, suggesting bipolar disorder as far more probable. The theory is treated in Purple Secret,[39] which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to suffer from it.[40] In 2005 it was suggested that arsenic (which is known to be porphyrogenic) given to George III with antimony may have caused his porphyria.[41] 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. In 2010 an exhaustive analysis of historical records concluded that the porphyria claim was based on spurious and selective interpretation of contemporary medical and historical sources

• The mental illness 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 of the film include the comment that the illness suffered by King George has been attributed to porphyria and that it is hereditary. Among other descendants of George III, theorised by the authors of Purple Secret to have suffered from porphyria (based upon analysis of their extensive and detailed medical correspondence), were his great-great-granddaughter Princess Charlotte of Prussia (Emperor William II's eldest sister) and her daughter Princess Feodora of Saxe-Meiningen. They had more success in being able to uncover reliable evidence that George III's great-great-great-grandson Prince William of Gloucester was reliably diagnosed with variegate porphyria.[43]

• It is believed that Mary, Queen of Scots – King George III's great-great-great-great-great-grandmother – also suffered from acute intermittent porphyria,[44] although this is subject to much debate. It is assumed she inherited the disorder, if indeed she had it, from her father, James V of Scotland; both father and daughter endured well-documented attacks that could fall within the constellation of symptoms of porphyria.

• Maria I of Portugal, known as "Maria the Pious" or "Maria the Mad" due to both her religious fervour and her acute mental illness that made her incapable of handling state affairs after 1792, is also thought to have suffered from porphyria. Francis Willis, the same physician that treated George III, was even summoned by the Portuguese court, but returned to England after the Portuguese court set him limits as to what treatments he could see through. Contemporary sources, such as the Secretary of State for Foreign Affairs Luís Pinto, noted that the Queen suffered from ever-worsening stomach pains and abdominal spasms — hallmarks of porphyria.[45]

• Vlad III was also said to have suffered from acute porphyria, which may have started the notion that vampires were allergic to sunlight.[46]

• Other commentators have suggested that Vincent van Gogh may have suffered from acute intermittent porphyria.[47] It has also been speculated that King Nebuchadnezzar of Babylon suffered from some form of porphyria (cf. Daniel 4).[48] However, the symptoms of the various porphyrias are so extensive that a wide constellation of symptoms can be attributed to one or more of them.[

citation needed]

• Physician Archie Cochrane was born with porphyria, which caused health problems throughout his life.[49]

• Paula Frías Allende, the daughter of the Chilean novelist Isabel Allende, fell into a porphyria-induced coma in 1991,[50] which inspired Isabel to write the biographical book Paula, dedicated to her.

Complications Dehydration Vomiting due to an attack of acute porphyria can lead to dehydration, which may require that you receive fluids through a vein (intravenously). Breathing difficulties Acute porphyrias can cause muscle weakness and paralysis, which can cause breathing problems. Low sodium in blood /hyponatremia: linked to problems with sodium and water handling in your body. High blood pressure Porphyrin buildup can damage your kidneys and may result in high blood pressure (hypertension). Chronic kidney failureLiver damagePermanent skin damage When your skin heals after cutaneous porphyria, it may have an abnormal appearance and coloring. Scars may remain on your skin as well, and lasting skin problems may cause your hair to fall out

Preventions • Although there's no way to prevent porphyria, if you have the disease, these

steps may help prevent symptoms:• Avoid medications known to trigger acute attacks. Ask your doctor for a list of

safe and unsafe drugs.• Don't use alcohol or illegal drugs.• Avoid fasting and dieting that involves severe calorie restriction.• Don't smoke.• Minimize sun exposure. When you're outdoors, wear protective clothing and

use a broad-spectrum sunscreen with a high sun protection factor (SPF).• Treat infections and other illnesses promptly.• Take steps to reduce emotional stress.• Because porphyria is an inherited disorder, your siblings and other family

members may want to consider genetic testing to determine if they have the disease.

Treatment

• Treatment of acute porphyrias focuses on providing rapid treatment of symptoms and preventing complications. This may require hospitalization in severe cases. Treatment may include::1. hematin given through a vein(intravenously) , a medication that is a form of heme, to limit the body's production of porphyrin.2. Medication to control pain, nausea and vomiting3. Intravenous sugar (glucose) or sugar taken by mouth, if able, to maintain an adequate intake of carbohydrates.4. Intravenous fluids to combat dehydration

• Treatment of cutaneous porphyrias focuses on reducing exposure to sunlight and the amount of porphyrins in your body to help eliminate your symptoms. This may include::1. Drawing blood (phlebotomy)- Drawing a certain amount of blood from one of veins reduces the iron in body, which decreases porphyrins2.Medications: Drugs used to treat malaria — hydroxychloroquine (Plaquenil) or, less often, chloroquine (Aralen) — can absorb excess porphyrins and help body get rid of them more quickly than usual3. Beta carotene- increase your skin's tolerance to sunlight.4. Vitamin D- Supplements may be recommended to replace vitamin D deficiency caused by avoidance of sunlight