not 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. all samples to detect porphyrins must be handled properly. samples should be taken during an acute attack; otherwise a false negative result may occur. samples must be protected from light and either refrigerated or preserved. if all the porphyrin studies are negative, one must consider pseudoporphyria. a careful medication review often will find the cause of pseudoporphyria. additional tests further diagnostic tests of affected organs may be required, such as nerve conduction studies for neuropathy or an ultrasound of the liver. basic biochemical tests may assist in identifying liver disease, hepatocellular carcinoma, and other organ problems. management carbohydrate administration often, empirical treatment is required if the diagnostic suspicion of a porphyria is high since acute attacks can be fatal. a high-carbohydrate diet is typically recommended; in severe attacks, a dextrose 10% infusion is commenced, which may aid in recovery by suppressing heme synthesis, which in turn reduces the rate of porphyrin accumulation. however, this can worsen cases of low blood sodium levels (hyponatraemia) and should be done with extreme caution as it can prove fatal. heme analogs hematin (trade name panhematin) and heme arginate (trade name normosang) 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 theoretically inhibit ala synthase and hence the accumulation of toxic precursors. in the united kingdom, supplies of normosang are kept at two national centers; emergency supply is available from st thomas's hospital, london. in the united states, lundbeck manufactures and supplies panhematin for infusion. heme arginate (normosang) is used during crises but also in preventive treatment to avoid crises, one treatment every 10 days. any sign of low blood sodium (hyponatremia) or weakness should be treated with the addition of hematin, heme arginate, or even tin mesoporphyrin, 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. cimetidine cimetidine has also been reported to be effective for acute porphyric crisis and possibly effective for long-term prophylaxis. symptom control pain is severe, frequently out of proportion to physical signs, and often requires the use of opiates to reduce it to tolerable levels. pain should be treated as early as medically possible. nausea can be severe; it may respond to phenothiazine drugs but is sometimes intractable. hot baths and showers may lessen nausea temporarily, though caution should be used to avoid burns or falls. early identification it is recommended that patients with a history of acute porphyria, and even genetic carriers, wear an alert bracelet or other identification at all times. this is in case they develop severe symptoms, or in case of accidents where there is a potential for drug exposure, and as a result they are unable to explain their condition to healthcare professionals. some drugs are absolutely contraindicated for patients with any form of porphyria. neurologic and psychiatric disorders patients who experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the abdomen. intestinal pseudo-obstruction, ileus, intussusception, hypoganglionosis, and encopresis in children 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. pain treatment with long-acting opioids, such as morphine, is often indicated, and, in cases where seizure or neuropathy is present, gabapentin is known to improve outcome. seizures 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 regimen for seizure control. gabapentin has the additional feature of aiding in the treatment of some kinds of neuropathic pain. 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. depression often accompanies the disease and is best dealt with by treating the offending symptoms and if needed the judicious use of antidepressants. some psychotropic drugs are porphyrinogenic, limiting the therapeutic scope. other psychiatric symptoms such as anxiety, restlessness, insomnia, depression, mania, hallucinations, delusions, confusion, catatonia, and psychosis may occur. 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. patients with the acute porphyrias (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. 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. in 2019, givosiran was approved in the united states for the treatment of acute hepatic porphyria. erythropoietic porphyria these are associated with accumulation of porphyrins in erythrocytes and are rare. 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. blood transfusion is occasionally used to suppress innate heme production. the rarest is congenital erythropoietic porphyria (cep), otherwise known as gunther's disease. the signs may present from birth and include severe photosensitivity, brown teeth that fluoresce in ultraviolet light due to deposition of type 1 porphyrins, and later hypertrichosis. hemolytic anemia 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. in december 2014, afamelanotide received authorization from the european commission as a treatment for the prevention of phototoxicity in adult patients with epp. in a 2023 industry-funded phase 2 trial, dersimelagon, an orally administered, selective melanocortin 1 receptor agonist that increases levels of skin eumelanin, was reported to have increased the duration of symptom-free sunlight exposure and quality of life compared to placebo in patients with erythropoietic protoporphyria. epidemiology rates of all types of porphyria taken together have been estimated to be approximately one in 25,000 in the united states. the worldwide prevalence has been estimated to be between one in 500 and one in 50,000 people. porphyrias have been detected in all races and in multiple ethnic groups on every continent. there are high incidence reports of aip in areas of india and scandinavia. more than 200 genetic variants of aip are known, some of which are specific to families, although some strains have proven to be repeated mutations. history the underlying mechanism was first described by felix hoppe-seyler in 1871, and acute porphyrias were described by the dutch physician barend stokvis in 1889. 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") and severe symptoms of depression or catatonia were treated with electroshock therapy. 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's 1963 paper, "on porphyria and the aetiology of werewolves," 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, 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 as potentially stigmatizing people with porphyria. a 1995 article from the postgraduate medical journal (via nih) explains: as it was believed that the folkloric vampire could move about freely in daylight hours, as opposed to the 20th century variant, congenital erythropoietic porphyria cannot readily explain the folkloric vampire but may be an explanation of the vampire as we know it in the 20th century. in addition, the folkloric vampire, when unearthed, was always described as looking quite healthy ("as they were in life"), while due to disfiguring aspects of the disease, sufferers would not have passed the exhumation test. individuals with congenital erythropoietic porphyria do not crave blood. the enzyme (hematin) necessary to alleviate symptoms is not absorbed intact on oral ingestion, and drinking blood would have no beneficial effect on the sufferer. finally, and most important, the fact that vampire reports were literally rampant in the 18th century, and that congenital erythropoietic porphyria is an extremely rare manifestation of a rare disease, makes it an unlikely explanation of the folkloric vampire. notable cases king george iii. the mental illness exhibited by george iii 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 that he had 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 derangement came in 1966, in a paper called "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 experts, including those more intimately familiar with the manifestations of porphyria, were unconvinced. many psychiatrists disagreed with the diagnosis, suggesting bipolar disorder as far more probable. 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 have had 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. this study found high levels of arsenic in king george's hair. in 2010, one analysis of historical records argued 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 king's symptoms suggest that he had porphyria and notes that the disease is "periodic, unpredictable, and hereditary". the traditional argument that george iii did not have porphyria, but rather bipolar disorder, is thoroughly defended by andrew roberts in his new biography, "the last king of america." descendants of george iii. among other descendants of george iii theorized by the authors of purple secret to have had porphyria (based on 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 uncovered better evidence that george iii's great-great-great-grandson prince william of gloucester was reliably diagnosed with variegate porphyria. mary, queen of scots. it is believed that mary, queen of scots, king george iii's ancestor, also had acute intermittent porphyria, 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. maria i—known