Porphyrias are a group of rare inherited or acquired disorders of certain enzymes that normally participate in the production of porphyrins and heme. They manifest with either neurological complications or skinproblems, or occasionally both. Porphyrias are classified in two ways, by symptoms and by pathophysiology. Symptomatically, acute porphyrias primarily present with nervous system involvement, often with severe abdominal pain, vomiting, peripheral neuropathy and mental disturbances. Cutaneous porphyrias present with skin manifestations often after exposure to sun due to the accumulation of excess porphyrins near the surface of the skin. Physiologically, porphyrias are classified as hepatic or erythropoietic based on the sites of accumulation of heme precursors, either in the liver or bone marrow and red blood cells. The term "porphyria" is derived from the Greek πορφύρα, porphyra, meaning "purple pigment". The name is likely to have been a reference to the purple discolouration of feces and urine when exposed to light in patients during an attack. Although original descriptions are attributed to Hippocrates, the disease was first explained biochemically by Felix Hoppe-Seyler in 1871, and acute porphyrias were described by the Dutch physician Barend Joseph Stokvis in 1889.
- 1 Signs and symptoms
- 2 Diagnosis
- 3 Pathogenesis
- 4 Treatment
- 5 Prognosis
- 6 Epidemiology
- 7 Culture and history
- 8 Notable cases
- 9 As seen on House
- 9.1 Acute intermittent porphyria
- 9.2 Erythropoietic protoporphyria
- 9.3 Hereditary coproporphyria
- 9.4 Variegate Porphyria
- 9.5 Other appearances
- 9.6 And a final connection
- 9.7 External links
Signs and symptoms
The acute, or hepatic, porphyrias primarily affect the nervous system, resulting in abdominal pain, vomiting, acute neuropathy, muscle weakness, seizures, and mental disturbances, including hallucinations, depression, anxiety, and paranoia. Cardiac arhythmias and tachycardia may develop as the autonomic nervous system is affected. Pain can be severe and can, in some cases, be both acute and chronic in nature. Constipation is frequently present, as the nervous system of the gut is affected, but diarrhea can also occur.
Given the many presentations and 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.
Not all porphyrias are genetic, and patients with liver disease who develop porphyria as a result of liver dysfunction may exhibit other signs of their condition, such as jaundice.
Patients with acute porphyria (acute intermittent porphyria), hereditary coproporphyria, variegate porphyria) 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.
The cutaneous, or 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 is no abdominal pain, distinguishing it from other porphyrias. Patients often have a delay on onset of visible symptoms even though they experience them from the outset of exposure. Patients often experience the exposure as a feeling of many pins being stuck into their skin, followed by a burning sensation, which then expands to the whole affected area. Exposure can result in severe to moderate burns dependind on the level of excess porphyria the Patient has on a regular basis. Patients experience an increased sensitivity to heat from any source including their own bodies. It is not unknown for patients to attempt to rip their skin off in pain.
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 red urine may be seen.
Porphyria is diagnosed through 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 hereditary tyrosinemia type I. In cases of mercury poisoning or arsenic poisoning induced porphyria, other changes in porphyrin profiles appear, most notably elevations of uroporphyrins I & III, coproporphyrins I & III and pre-coproporphyrin.
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 post-puberty genetic carriers of hereditary coproporphyria.
As most porphyrias are rare conditions, general hospital labs typically do 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 has to consider pseudoporphyria. A careful medication review often will find the inciting cause of pseudoporphyria.
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.
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 pain 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.
Subtypes of porphyrias depend on what enzyme is deficient.
|Enzyme||Associated porphyria||Type of porphyria||Inheritance||Symptoms||Prevalence|
|δ-aminolevulinate (ALA) synthase||X-linked sideroblastic anemia (XLSA)||Erythropoietic||X-linked|
|δ-aminolevulinate dehydratase (ALAD)||Doss porphyria/ALA dehydratase deficiency||Hepatic||Autosomal recessive||Abdominal pain, neuropathy||Extremely rare (less than 10 cases ever reported)|
|Hydroxymethylbilane (HMB) synthase (or PBG deaminase)||Acute intermittent porphyria (AIP)||Hepatic||Autosomal dominant||Periodic abdominal pain, peripheral neuropathy, psychiatric disorders, tachycardia||1 in 10,000-20,000|
|Uroporphyrinogen (URO) synthase||Congenital erythropoietic porphyria (CEP)||Erythropoietic||Autosomal recessive||Severe photosensitivity with erythema, swelling and blistering. Hemolytic anemia, enlarged spleen||1 in 1,000,000 or less.|
|Uroporphyrinogen (URO) decarboxylase||Porphyria cutanea tarda (PCT)||Hepatic||Autosomal dominant||Photosensitivity with vesicles and bullae||1 in 10,000|
|Coproporphyrinogen (COPRO) oxidase||Hereditary coproporphyria (HCP)||Hepatic||Autosomal dominant||Photosensitivity, neurologic symptoms, colic||1 in 500,000|
|Protoporphyrinogen (PROTO) oxidase||Variegate porphyria (VP)||Mixed||Autosomal dominant||Photosensitivity, neurologic symptoms, developmental delay||1 in 300 in South Africa, 1 in 75.000 in Finland|
|Ferrochelatase||Erythropoietic protoporphyria (EPP)||Erythropoietic||Autosomal recessive||Photosensitivity with skin lesions. Gallstones, mild liver dysfunction||1 in 75,000-200,000|
|Transient erythroporphyria of infancy||Purpuric skin lesions|
Like many rare diseases, there is unfortunately very little research being done to cure the various types of porphyria. As such, treatment focusses on preventative measures and management of symptoms. Moreover, because the diseases are related but have different underlying causes, it is unlikely that one single cure could be discovered that would be effective in treating each of the eight types.
Carbohydrates and heme
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 glucose 10% infusion is commenced, which may aid in recovery.
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' 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 or 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.
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 immediate and vigorous treatment.
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, 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.
It is recommended that patients with a history of acute porphyria, and even genetic carriers, wear an Medic 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 any patients with any porphyria.
Neurologic and psychiatric problems
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.
Clinical 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 can set off porphyria attacks, limiting the therapeutic scope.
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 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
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.
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. 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. 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.
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.
All of the porphyrias are lifelong conditions that require management and constant treatment. However, patients who follow their dietary and drug restrictions as well as their treatment plan can expect to live a close to normal lifespan.
The prevalence of all types of porphyria taken together has been estimated to be approximately 1 in 25,000 in the United States. The worldwide prevalence has been estimated to be somewhere between 1 in 500 to 1 in 50,000 people.
Because porphyria is an inherited disorder, when a case is diagnosed, it is often prudent to test other blood relatives for the same enzyme deficiencies. Although in half of cases the levels will be normal, and in most of the rest of cases they will be abnormal but the patient suffers no symptoms, because the conditions have several triggers, persons with abnormal levels can be told to avoid the triggers for their particular condition to avoid the possibility of a potentially fatal attack.
Persons with the condition who wish to have children often consult a genetic counsellor who can discuss the risks of the condition in their children and how to properly manage their health if they turn out to inherit the faulty gene.
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") 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' 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 connection. One example is the comic book Ultimate Comics Avengers 3 #1 (October 2010), in which writer Mark Millar employed porphyria as the explanation for vampires in that fictional universe.
The theory has since faced criticism, especially for the stigma it has placed on its sufferers. Norine Dresser's 1989 book American Vampires: Fans, Victims, Practitioners deals with this.
The theory also operates on a flawed premise, mainly in regard to a perceived harmful effect sunlight had on vampires, a property relatively late to vampire belief. There are about eight different types of porphyria; four of these can sometimes cause sensitivity to light: Erythropoietic Protoporphyria (EPP) or Protoporphyria, Congenital Erythropoietic Porphyria (C.E.P.), Porphyria Cutanea Tarda (PCT) and Variegate Porphyria.
The mental illness exhibited by George III of the United Kingdom 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 Bipolar disorder 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. Many psychiatrists disagreed with Hunter's 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 suffer from it. The authors demonstrated a single point mutation in the PPOX gene, but not one which has been associated with disease. 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 is merely a hypothesis. In 2010 an exhaustive analysis of historical records revealed 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, (William II, German Emperor'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.
It is believed that Mary, Queen of Scots – King George III's great-great-great-great-great-grandmother – also suffered from 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.
Vlad III the Impaler (the inspiration for Dracula) was also said to have suffered from acute porphyria, which may have started the notion that vampires were allergic to sunlight.
Other commentators have suggested that Vincent van Gogh may have suffered from acute intermittent porphyria. It has also been speculated that King Nebuchadnezzar of Babylon suffered from some form of porphyria. 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.
Paula Frías Allende, the daughter of the Chilean novelist Isabel Allende, fell into a porphyria-induced coma in 1991,which inspired Isabel to write the biographical book Paula, dedicated to her.
As seen on House
Acute intermittent porphyria
Acute intermittent porphyria (AIP) is a rare sub-type that can be passed on by receiving one copy of the faulty gene from a single parent. It is characterized by a deficiency of the enzyme porphobilinogen deaminase. Acute intermittent porphyria is the second most common form of porphyria (porphyria cutanea tarda being the most common). Its incidence is estimated to be between 5 and 10 in 100,000, but this is likely underestimated because of positive cases not being induced, and long periods of latency, with an estimation that it is latent in 90% of cases.
Mechanism of disease
A Swedish study indicated that approximately 90% of cases of acute intermittent porphyria are due to a mutation that causes decreased amounts of the enzyme, and to a lesser degree by a mutation that causes decreased activity of each enzyme molecule.
Under normal circumstances, heme synthesis begins in the mitochondrion, proceeds into the cytoplasm, and finishes back in the mitochondrion. However, without porphobilinogen deaminase, a necessary cytoplasmic enzyme, heme synthesis cannot finish, and the metabolite porphobilinogen accumulates in the cytoplasm.
Additional factors must also be present such as hormones, drugs, and dietary changes that trigger the appearance of symptoms. Symptoms of AIP may include abdominal pain, constipation, and muscle weakness.
Patients with AIP are commonly misdiagnosed with psychiatric diseases. Ironically, treatment with anti-psychotics increases the accumulation of porphrobiliogen, thus aggravating the disease enough that it may prove fatal.
Symptoms in AIP can be variable. They include abdominal pain which is severe and poorly localized (most common, 95% of patients experience), Urinary symptoms (Dysuria, urinary retention/incontinence or dark urine), peripheral neuropathy (patchy numbness and paresthesias), Proximal motor weakness (usually starting in upper extremities which can progress to include respiratory impairment and death), autonomic nervous system involvement (circulating catecholamine levels are increased, may see tachycardia, high blood pressure, sweating, restlessness and tremor), neuropsychiatric symptoms (anxiety, agitation, hallucination, hysteria, delirium, depression), Electrolyte abnormalities (Hyponatremia may be due to hypothalamic involvement leading to SIADH that may lead to seizures). Unlike other porphyrias, rash is not typically seen in AIP.
A high-carbohydrate (10% glucose) infusion is recommended, which may aid in recovery. If drugs have caused the attack, discontinuing the offending substances is essential. Infection is 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. Nausea can be severe; it may respond to phenothiazine drugs but is sometimes intractable. Hot water baths or showers may lessen nausea temporarily, but can present a risk of burns or falls.
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 that they cannot explain to healthcare professionals about their condition and the fact that some drugs are absolutely contraindicated. An attack of acute intermittent porphyria may be precipitated by one of the "four Ms": medication, menstruation, malnutrition, maladies.
Patients that experience frequent attacks can develop chronic neuropathic pain 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 opioids may 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. Earl Campbell from University of Maryland performed the first successful clinical trial. Although results for this trial are still undergoing rigorous testing.
Seizures often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: Barbituates must be avoided as they commonly precipitate symptoms. Some benzodiazepines are safe, and, when used in conjunction with newer anti-seizure medications such as gabapentin, offer a possible regimen for seizure control.
Urine from a person experiencing an acute attack may be red or "port wine" in color because of the presence of porphyrins. In addition, urine of AIP sufferers may turn purple when exposed to ultraviolet light for a period of time.
In addition to its appearance in Honeymoon, acute intermittent porphyria is also mentioned briefly in Guardian Angels. Porphyria is again briefly mentioned as the possible cause of "relapsing and remitting" symptoms (suggesting acute intermittent porphyria) in Whatever It Takes. AIP has also made two appearances on Scrubs: in the thirteenth episode of season 4, "My Ocardial Infarction," and in the ninth episode of season 7, "My Dumb Luck." It also appeared in
- Castle: Vampire Weekend (Season 2, Episode 6)
- Grey's Anatomy: The Time Warp (Season 6, Episode 15).
- CSI: Crime Scene Investigators: Justice is Served (Season 1, Episode 21) aired 26 April 2001.
- Series 4, episode 2 of Doc Martin.
As seen in Finding Judas in Alice Hartman. She was suffering from extreme abdominal pain, gallstones and a rash that resembled necrotizing fasciitis. This diagnosis was notable as House missed it, but Robert Chase came up with the answer just before House ordered an amputation
Erythropoietic protoporphyria (EPP) is a more mild form but very painful form of porphyria. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the tissue. The severity varies significantly from individual to individual. This form can be inherited from a single parent with a faulty gene (where one parent suffers from the disorder), or when both parents have a recessive faulty gene (and neither suffers from the disorder).
A common symptom is very painful photosensitivity, manifesting itself as a burning and itching sensation on the surface of the skin. At times the itching sensations are almost unbearable. Rubbing the affected areas with ice can be the only relief, and that is only temporary. The usual anti-itch remedies, including cortisone antihistamine topical preparations, and Calamine lotion generally provide little or no relief. If a patient presents with a medical history of anti-itch preparation inefficacy, EPP should be considered.
EPP usually first presents in childhood, and most often affects the face and the upper surfaces of the arms, hands, and feet and the exposed surfaces of the legs. Most patients, if the EPP is not as severe, manifest symptoms with onset of puberty when the male and female hormone levels elevate during sexual development and maintenance. More severe EPP can manifest in infancy. Exposure to even indoor light sources can cause the rash, and the infant, if clothed only in a diaper, will break out everywhere except under the diaper. EPP can be triggered through exposure to sun even though the patient is behind glass. Even the ultraviolet emissions from arc welding with the use of full protective mask have been known to trigger EPP.
Prolonged exposure to the sun can lead to edema and blistering. At times the immediate damage can be so severe that the individual can lose the skin in sheets. After many years, chronically sun-exposed skin may become thick and wrinkled if no beta-Carotene and other carotenoids and no lutein and other xanthophylls are ingested.
Another aspect of the painfulness of EPP is the painful abdomen, which may manifest as generalized pain, or may imitate an appendicitis. Some healthy appendices have been removed due to this mimic. Since porphyria is not that common, most doctors don't even think to do blood porphyrin levels when symptoms present. For doctors that are familiar with porphyria, it is generally considered insignificant and irrelevant compared to the possibility of a pending burst appendix, especially since porphyrin levels cannot be generally be received back immediately due to lab protocols.
Moderate and severe cases can present with pelvic and shoulder girdle muscle weakness. This is because porphyrins are poisonous to the body and produce nerve damage. Damage to nerves of the digestive system not only cause nerve pain in the abdominal area, but also cause slow movement of the bowels, especially the large intestine. Patients can therefore develop a larger than normal diameter of the large intestine, at times causing a condition called megacolon. The damage of nerves to the oesophagus and to the stomach valve muscles (sphincters) can cause stomach reflux. One of the ironies of these digestive condition is that one of the medical treatments of these digestive conditions is Reglan, to which some porphyrics have a very strong adverse reaction.
Porphyrin toxins are neurotropic and shut down the nerve trunks one by one until the individual has difficulty with fine motor tasks, like turning phonebook pages, has difficulty speaking (develops dystonic speech that is almost unintelligible), and develops difficulty breathing. The porphyrin neurotoxins have caused some patients to present to the emergency room not only in pain but also seeming to be neurotic, or even psychotic. Once glucose is infused, those episodes subside, and if they don't, healthy red blood cell infusion in whole also helps, due to the naturally occurring glucose in the infused blood. These patients will often present with a very enlarged spleen due to having to process defective red blood cells. At times poking around on the spleen can cause elevation of body temperature by at least two degrees Fahrenheit. The liver may also be tender.
People with EPP are also at increased risk to develop gallstones. In a small percentage of cases, protoporphyrin accumulates to toxic levels in the liver, leading to liver failure.
Case reports suggest that EPP is prevalent globally. The prevalence has been estimated somewhere between 1 in 75,000 and 1 in 200,000. An estimated 5,000-10,000 individuals worldwide have EPP.
Treatment and prognosis
There is no cure for this disorder; however, symptoms can usually be managed by limiting sun exposure. Protective clothing is also very helpful. Since the photosensitivity results from light in the visible spectrum, most sunscreens (with the exception of light-reflecting substances such as zinc oxide) are of little use. Some individuals may decrease their sun sensitivity with daily doses of beta carotene, though a recent meta analysis of carotene treatment has called its effectiveness into question. Some patients gradually build a protective layer of melanin by regularly exposing themselves for short times to ultraviolet radiation.
EPP is considered one of the least severe of the porphyrias. The ferrochelatase enzyme is the last step before actual heme production and then actual hemoglobin production. The steps before protoporphyrin production also have enzymes that produce intermediaries. If the first enzyme in the production process is defective, that porphyria is generally the most severe. If the next enzyme in the step-wise process is the defective one, the porphyria is generally less severe, and-so-on until the ferrochelatase step. One thing to keep in mind is the fact that low blood sugar activates the cytochrome p450 system. The cytochrome p450 system is the system that contains the subsystem that produces the porphyrin ring. Therefore infusion of glucose into the blood stream to produce slightly higher than normal blood sugar produces relief. Transfusion of healthy blood cells in whole blood into the patient also gives relief. Protoporphyrins sometimes accumulate to toxic levels in the liver, causing liver failure; if this occurs, a liver transplant becomes necessary.
The individual symptoms of this condition are multiple, and many of those symptoms can occur in other conditions. Therefore other diagnoses are often made and the patient can go through life as an undiagnosed and untreated person with EPP.
There are numerous ongoing clinical trials of experimental treatments for the condition.
Erythropoietic protoporphyria was first described in 1953 by Kosenow and Treibs and completed in 1960 by Magnus et al. at the St John's Institute of Dermatology] in London.
Hereditary coproporphyria is an acute hepatic porphyria. HCP is caused by a deficiency of the enzyme coproporphyrinogen oxidase, coded for by the CPOX gene, and can be inherited from a single parent with the disease, although it can occur if even a single copy of the gene is present. Unlike acute intermittent porphyria, individuals with HCP can present with skin conditions similar to those found in porphyria cutanea tarda in addition to the acute attacks of abdominal pain, vomiting and neurological dysfunction characteristic of acute porphyrias. Like other porphyrias, attacks of HCP can be induced by certain drugs, environmental stressors or diet changes. Biochemical and molecular testing can be used to narrow down the diagnosis of a porphyria and identify the specific genetic defect. Although all porphyrias are rare, the exact incidence of HCP is difficult to determine, as not all persons who carry the gene for the disease will develop clinically notable symptoms.
Signs and symptoms
Clinically, patients affected with HCP present similarly to those with other acute porphyrias, such as acute intermittent porphyria and variegate porphyria. Patients with HCP and VP can present with symptoms shared between the acute and cutaneous porphyrias. This includes the acute attacks of abdominal pain, nausea, vomiting, diarrhea, tachycardia, high blood pressure and seizures, as well as the cutaneous findings seen in porphyria cutanea tarda, namely increased skin fragility (which can result in bleeding from a minor trauma), bullous lesions after exposure to sunlight and increased scarring.
Individuals with HCP may be asymptomatic in the absence of triggering factors. Common triggers include certain drugs, alcohol, hormonal changes, and dietary changes. Sunlight and other ultraviolet light can trigger the skin manifestations. Persons with one copy of the CPOX mutations can present with these findings at an earlier age than those with two copies.
HCP is caused by mutations in the CPOX gene, which codes for the enzyme coproporphyrinogen oxidase. This enzyme is responsible for the sixth step in the heme biosynthetic pathway, converting coproporphyrinogen III to protoporphyrinogen IX. The CPOX gene is located at chromosome 3q11.2-q12.1, has 6 introns and 7 exons and produces an mRNA strand that is 2675 bases in length. It is inherited in from a single parent, meaning that a deficiency of 50% of the normal enzyme activity is enough to cause symptoms. As reproductive fitness is not impacted, individuals who merely have a single copy of the gene have been reported. Along with other acute porphyrias HCP demonstrates reduced penetrance, meaning not all individuals who carry a disease-causing mutation will express symptoms.
Individuals who are homozygous for a specific mutation (K404E) or compound heterozygous with a null allele in CPOX have a more severe erythropoietic porphyria, harderoporphyria, characterized by neonatal jaundice, hyperbilirubinemia, enlargement of the liver and spleen and skin lesions upon exposure to ultraviolet light. HCP is a rare disease, but the exact incidence is difficult to determine due to the reduced penetrance of the acute porphyrias. The incidence of harderoporphyria is even lower, with less than 10 cases reported worldwide.
The identification of a specific porphyria is based on the results of laboratory findings, including blood, urine and stool tests. HCP can be distinguished from most other acute porphyrias by the cutaneous findings. VP presents similarly, but can be distinguished based on urine and stool porphyrin analysis, typically done using high performance liquid chromatography with fluorescence detection. The results of biochemical testing for porphyrias are most informative when samples are collected during an acute attack. Typically, the distinguishing metabolite for HCP and VP is the presence of protoporphyrin in the plasma and feces of individuals affected with VP.
There is no cure for HCP caused by the deficient activity of coproporphyrinogen oxidase. Treatment of the acute symptoms of HCP is the same as for other acute porphyrias. Acute attacks can be severe enough to cause death if not treated quickly and correctly. Hospitalization is typically required for administration of hemin, and appropriate drug selection is key to avoid exacerbating symptoms with drugs that interact poorly with porphyrias. Proper drug selection is most difficult when it comes to treatment of the seizures that can accompany HCP, as most anti-seizure medications can make the symptoms worse. Gabapentin and levetiracetam are two anti-seizure drugs that are thought to be safe.
In patients where management of symptoms is difficult even with hemin, liver transplant is an option before the symptoms have progressed to advanced paralysis. Combined liver and kidney transplants are sometimes undertaken in patients with renal failure.
Long term treatment of acute porphyrias is centered around the avoidance of acute attacks by eliminating precipitating factors, such as drugs, dietary changes, and infections. Females often have attacks coincident with their menstrual cycle, which can be managed effectively with hormonal birth control. Because of the reduced penetrance of HCP, family members of a patient may carry the same mutation without ever presenting with symptoms. Molecular analysis of CPOX is the best way to identify these patients, as they will not express a biochemical phenotype on laboratory testing unless they are symptomatic. Identification of asymptomatic patients allows them to adjust their lifestyle to avoid common triggering factors.
Variegate porphyria (also known as "Mixed hepatic porphyria", "Mixed porphyria", "South African genetic porphyria" is another form of porhyria that can be inherited from a single parent. It can have acute (severe but usually not long-lasting) symptoms along with symptoms that affect the skin. The disorder results from low levels of the enzyme responsible for the seventh step in heme production.
Many people with this disorder never experience symptoms. When symptoms occur, they can include acute attacks (similar to acute intermittent porphyria), skin damage, or both. Acute attacks usually begin in adulthood and cause abdominal pain, vomiting, diarrhea and constipation. During an attack, a person may also experience muscle weakness, seizures, and mental changes such as anxiety and hallucinations. These signs and symptoms are triggered by nongenetic factors such as certain drugs, dieting or fasting, certain hormones and stress.
Some people with variegate porphyria have skin that is overly sensitive to sunlight. Areas of skin exposed to the sun develop severe blistering, scarring, changes in pigmentation, and increased hair growth. Exposed skin becomes fragile and is easily damaged.
Rarely, the signs and symptoms of variegate porphyria can begin in infancy or early childhood. In such cases, the signs and symptoms are usually more severe than those starting later in life. In addition to the health problems described above, children with this disorder may have mental retardation and grow more slowly than other children.
In South Africa, the prevalence of variegate porphyria is approximately 1 in 300. In Finland, the prevalence is approximately 1 in 75.000. When it does occur in other populations (such as Switzerland), it can be with different mutations than in South Africa. It is also found in Argentina, Sweden, and Australia.
Mutations in the PPOX gene cause variegate porphyria. The PPOX gene makes a membrane bound mitochondrial enzyme called protoporphyrinogen oxidase, which is critical to the chemical process that leads to heme production. The activity of this enzyme is reduced by 50 percent in most people with variegate porphyria. In severe cases that begin early in life, the enzyme is almost completely inactive. Nongenetic factors such as certain drugs, stress, and others listed above can increase the demand for heme and the enzymes required to make heme. The combination of this increased demand and reduced activity of protoporphyrinogen oxidase disrupts heme production and allows byproducts of the process to accumulate in the liver, triggering an acute attack. Inheriting one copy of the defective gene from an affected parent is sufficient to cause the disorder. More severe cases result from inheriting two copies of the defective gene.
The entire PPOX gene has about 8kb with 13 exon sequences. It was successfully cloned from a cDNA library in 1995 revealing that, after processing, it is 477 nucleotides long. It has previously been thought that the PPOX gene was located on human chromosome 14, however mapping experiments (FISH) have shown that it is near 1q22. An additional aggravating mutation affecting variegate porphyria can be found at 6p21.3 on the HFE gene.
Liver transplant has been used in the treatment of this condition.
- Chris Taub was almost positive that Irene had acute intermittent porphyria in Guardian Angels, but House sided with Henry Dobson and treated for vasculitis.
- After Eric Foreman re-tests Casey Alfonso in Whatever It Takes and realizes she never had polio, he suggests porphyria as the most likely diagnosis. However, House realizes it is deliberate thallium poisoning.
- In Don't Ever Change, House believes Roz's sudden embrace of orthodox Judaism is the result of the neurological symptoms of porphyria.
- One of the differential diagnoses of Jona in Emancipation was porphyria.
- Lawrence Kutner suggested Nozick had porphyria in The Itch, but House noted the patient had no liver symptoms.
- Allison Cameron suggested that porphyria might be causing Lucy Palmeiro's psychosis in The Socratic Method.
- In Fools for Love, House thought Tracy might have porphyria and ordered treatment for it.
- In You Must Remember This, Chase suggested Nadia might have porphyria, but she had no abdominal pain.
- In Bombshells, Martha M. Masters suggested Ryan's abdominal bleeding might be caused by acute intermittent porphyria, but there were no abdominal cramps to go along with it.
- In Charity Case, the team thinks Benjamin Byrd has porphyria and that his extreme generosity is a neurological symptom.
- In Post Mortem Chase guesses Dr. Peter Treiber has porphyria and starts treating him for it over the objections of the rest of the team.
And a final connection
In the final episode of Black Adder the Third "Duel and Duality", Edmund Black Adder (Rowan Atkinson), disguised as Prince George survives a cannon duel with the Duke of Wellington (Stephen Fry). Feeling that his honor has been satisfied, the Duke doesn't insist on killing "the prince", but becomes enraged with George's "servant" (the real prince dressed like a manservant, played by Hugh Laurie) claims to be the real prince. The Duke shoots the real George dead when King George III, clearly suffering neurological symptoms (and insisting his son marry a cabbage), comes along looking for his son. Edmund claims to be the real prince and the Duke confirms this to the king.
- American Porphyria Foundation
- European Porphyria Initiative
- The British Porphyria Association
- The Drug Database for Acute Porphyria - comprehensive database on drug porphyrinogenicity
- Orphanet's disease page on Porphyria
- Porphyria at NIH
- Porphyria at Wikipedia - this article was largely developed from the Wikipedia articles on this subject
- Porphyria at Mayo Clinic
- Duel and Duality at IMDB
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|Season 8||Porphyria||Paraneoplastic syndrome|