Porphyria

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Porphyria
Porphyria

The name porphyria is taken from the Greek root for “purple” (porphyra). Porphyrias are a group of 8 inherited or acquired disorders of heme biosynthesis. A deficiency in any of the 8 enzymes in the biosynthetic pathway can result in the accumulation and excretion of intermediary metabolites. Patients generally present with either neurovisceral (acute) or cutaneous symptoms but sometimes they may have mixed symptoms. One of the earliest descriptions of porphyria was made by B.J. Stokvis, MD, in 1889. In 1930, the German chemist Hans Fischer described porphyrins as “The compounds which make grass green and blood red.” In 1937, Jan Gosata Walenstrom coined the term “porphyria”; he published research identifying one type of porphyria, acute intermittent porphyria (AIP). By 1960, all 8 types of porphyria had been described, as well as environmental factors that affect the course of the disease.  Porphyria research in the 1980s and 1990s identified the molecular defects in each type.

Heme is a vital component of blood (hemoglobin), liver enzymes (cytochrome P450), muscle (myoglobin), catalase, peroxidase, nitric oxide synthases, tryptophan pyrrolase, and adenyl cyclase. The majority of heme produced (approximately 80%) is used for hemoglobin. During heme production, in most tissues, heme itself is necessary to halt further heme production. Therefore, a problem with any 1 of the 8 enzymes in the heme biosynthesis pathway can lead to an overproduction of heme that will continue until that critical level is achieved. With many of the types of porphyria, hospitalization, transfusion, and heme therapy may be necessary. Comorbid iron overload may occur in some instances and iron chelation may be needed. A variety of drugs and substances like barbiturates, sulfonamides, and many others can induce an attack and/or intensify symptoms. In some types, glucose and carbohydrates may help to suppress symptoms, and particular diets may be suggested. Carbohydrate or caloric restrictions are typically not recommended, even for short periods of time.

Neurovisceral or Acute Porphyrias

Acute intermittent porphyria (AIP): autosomal dominant, and the most common and severe form of inherited hepatic porphyria, with an incidence rate of 10 in 10,000.

AIP disrupts the third step in the heme biosynthesis pathway (HBP) and results in the buildup of the porphobilinogen (PGB) metabolite. AIP predominately affects females and occurs after puberty. To date, 120 different mutations have been identified, any of which may lead to a deficiency in the porphobilinogen deaminase (PBGD) enzyme (also called hydroxymethylbilane [HMB] synthase), resulting in the buildup of porphobilinogen. There are 3 types of AIP. In type 1, PBGD activity and enzyme levels fall to about 50%. In type 2, PBGD activity is decreased in non-erythroid cells only. In type 3, structurally abnormal enzymes cause a decrease in enzyme activity. Symptoms include nausea, vomiting, abdominal distension, bowel obstruction, urinary retention, hypertension, peripheral neuropathy, muscle weakness, rapid heartbeat, anxiety, confusion, hallucinations, and seizures.

ALA dehydratase porphyria (ADP): autosomal recessive and extremely rare, with 6-10 known cases.

ADP disrupts the second step in HBP and results in the buildup of the aminolevulinic acid (ALA) metabolite; a defected chromosome 9q34 leads to a deficiency of the delta-aminolevulinic acid dehydratase (ALAD) enzyme needed to convert ALA to PBG. Associated symptoms are similar to AIP. Homozygotes have nearly a complete deficiency in enzyme activity. Heterozygotes have about a 50% deficiency and are not associated with an inherited porphyria. However, heterozygotes are highly susceptible to lead toxicity (presenting with similar symptoms), which is why this type is sometimes referred to as “plumboporphyria.”

Hepatic coproporphyria (HCP): autosomal dominant, frequent in Europe and North America.

HCP disrupts the sixth step in the HBP and results in the buildup of the coproporphyrinogen metabolite. There are 9 mutations responsible for a defect in the coproporphyrinogen oxidase enzyme. Five of the mutations are missense mutations. Symptoms are predominately neurovisceral and similar to AIP, but about 30% of the time, comorbid cutaneous symptoms are observed. As coproporphyrinogen builds up, it can inhibit PBGD, leading to an increase in PGB as well as coproporphyrinogen, and to a lesser extent ALA. Neurological symptoms may be attributed to the ALA buildup. Normal laboratory tests may indicate lead poisoning, so lead levels should be obtained to rule it out.

Mixed Neurovisceral and Cutaneous Porphyrias

Variegate porphyria (VP): autosomal dominant, prevalent in South Africa.

VP disrupts the seventh step in the HBP and results in the buildup of the protoporphyrinogen IX metabolite. In South Africa, the R59W mutation is the most prevalent and accounts for about 95% of all cases. This founder gene mutation can be traced back to a Dutch couple who settled at the Cape of Good Hope in 1688. Because of a defect in the protoporphyrinogen oxidase (PPO) enzyme, protoporphyrinogen IX builds up, inhibiting PBGD. Acute attacks may be indistinguishable from PCT and have symptoms similar to both AIP and PCT. 

Cutaneous Porphyrias

Porphyria cutanea tarda (PCT): the most common of the porphyrias and can be inherited or acquired with an incident rate of 1 in 25,000, with 3 unique types.  

PCT disrupts the fifth step in the HBP and results in the buildup of the uroporphyrinogen metabolite. A deficient uroporphyrinogen decarboxylase (UROD) enzyme is the cause. The UROD still functions but at about a 50% deficiency. Symptoms are cutaneous, and sun-exposed areas of the skin may blister or peel after minor trauma. On sun-exposed areas, increased hair growth may be seen, and the skin may become thick and dark. For type 1, it is mainly an acquired or sporadic form of porphyria (80%-90%). Ethanol, estrogen, iron, diabetes mellitus, uremia, and chemicals like hexachlorobenzene are associated with PCT. In 1950, 4000 people in Turkey acquired PCT because seeds contaminated with hexachlorobenzene were ingested. Patients with hemochromatosis are 4 times more likely to develop PCT. A mutation of at least 1 of the hemochromatosis (HFE) genes is present in 65% of PCT patients. Iron overload is also common in many patients with PCT. Type 2 is an autosomal-dominant condition, and liver function tests are usually abnormal. Type 3 is also inherited but only affects non-erythroid cells.

Congenital erythropoietic porphyria (CEP), or Gunther disease: autosomal recessive and rare, with 200 reported cases.

CEP disrupts the fourth step in the HBP and results in the buildup of the hydroxymethylbilane metabolite. More than 35 mutations of the UROS gene can result in a dysfunctional uroporphyrinogen III CoA synthase enzyme. The most common is the C73R mutation (33%). The age of onset varies and the severity of the disease can range from fatal to severe photosensitivity and transfusion dependency, and finally, mild photosensitivity.  Severe photosensitivity can be seen after birth, and red blood cell (RBC) hemolysis can occur. Sun-exposed areas of skin can have massive blistering and scarring, often resulting in ruptures and infections. Extensive damage to sun-exposed appendages like the nose, lips, ears, fingers, hands, and feet may occur. Hypertrichosis (excessive hair growth) on the face and hands is common. Patients may also have deposits of porphyrins in the teeth that give them a reddish-brown tint called erythrodontia. Anemia may occur because of a shortened life span of RBCs; this shortened life span increases heme synthesis and can result in a worsening of symptoms.

Erythropoietic protoporphyria (EPP): autosomal dominant or recessive, the third most-common porphyria.

EPP disrupts either the first step or the eighth and final step in the HBP. A disruption in the ferrochelatase (FECH) enzyme (the last step) results in the buildup of the protoporphyrin IX metabolite. The FECH type is considered autosomal recessive and there are at least 25 mutations that can disrupt or alter the FECH enzyme. The delta-aminolevulinic acid synthase 2 (ALAS2) enzyme disorder is autosomal dominant and is also referred to as X-linked protoporphyria (XLP) because that gene is located on the X chromosome. This enzyme is responsible for converting glycine and succinyl-CoA to ALA. A poorly functioning ALAS2 gene can short-circuit the entire HBP. Furthermore, it causes an increase in the production of the ALAS2 enzyme in bone marrow. This is virtually male specific because it is X-linked. Cutaneous symptoms of EPP include a range of photosensitivities for sun-exposed skin, including swelling, mild to severe burning, itching, and redness of the skin, higher risk of gallstones, and potential liver damage.

Hepatoerythropoietic porphyria (HEP): autosomal recessive and rare, with approximately 20 known cases.

Again, the fifth step in the HBP is disrupted, resulting in the buildup of the uroporphyrinogen metabolite. However, in this case, it is a matter of the extent of UROD functioning. Enzyme activity is only about 5% to 10%, compared to 50% activity in PCT. Symptoms include normochromic anemia, erythrodontia, pink urine, and similar cutaneous symptoms to CEP, except serum iron levels are normal. Patients may also have neurological symptoms as well.

Porphyria and Historical Figures

Throughout history, there have been several notable historical figures suspected of suffering from porphyrias. King Nebuchadnezzar of Babylon is one such example, but there is no definitive proof except for a Bible passage describing his madness. King George III of England is another prominent historical figure, but his symptoms could also be attributed to lead poisoning. In the 1994 movie The Madness of King George, they even go as far as crediting porphyria as the cause of his mental illness. In the book Purple Secret: Genes, 'Madness' and the Royal Houses of Europe, authors John C.G. Röhl et al examine historical records for evidence of porphyrias in King George III and his descendants. They suggest that it followed their lineage to present-day British royalty. Medical historians also suspect that Vincent van Gogh suffered from AIP, and that it was exacerbated by malnutrition and absinthe abuse, once again, a subjective conclusion. Many of the historical claims of porphyrias are based on a range of symptoms that might be attributed to other conditions. There is an inherent difficulty in diagnosing some types of porphyrias. Making a differential diagnosis of AIP proves to be especially difficult, which is why it is dubbed the “little imitator.” To date, only Prince William of Gloucester was ever reliably diagnosed, and he had VP. In 1972, while taking part in the Goodyear International Air Trophy, Prince William crashed his plane and was pronounced dead at the age of 30. Because of his diagnosis, all British royal children are routinely screened for porphyrias.

Porphyria and the Occult

Porphyrias have also been proposed as an explanation for vampire and werewolf legends. In 1985, Dr. David Dolphin gave a point-by-point explanation about the similarities in folklore to symptoms of porphyrias. His rational was that during the Middle Ages, with limited medical and scientific knowledge, porphyria symptoms might have been misconstrued as something supernatural. He further describes how porphyria symptoms might have been the basis behind the concept that sunlight kills vampires. Persons afflicted with CEP may seldom venture out in the daylight because of extreme photosensitivity. The sun could inflict massive skin damage and cause horrible disfigurements to the afflicted hands, feet or face. It can be so severe that their faces might seem mutilated and distorted. Their lips, noses or ears could actually recede or fall off and excessive hair growth may make them appear like a wolf or animal. Persons suffering from CEP may have erythrodontia, potentially coupled with receding gums that could create the appearance of fangs. Dr. Dolphin goes on to discuss an aversion to garlic as well. He postulates that garlic stimulates red blood cell and heme production, which results in a worsening of symptoms. Because symptoms like peripheral neuropathy, abdominal distention, and nausea are present during acute attacks, garlic might actually inflict pain and cause a person suffering from porphyria to become sick. He also suggested that because porphyrias are ultimately a disease of heme and modern treatments are infusions of blood products, persons afflicted with the disease may have instinctually tried to drink large quantities of blood to alleviate their symptoms. This is a horrendous conclusion that is not supported by any evidence. If blood were ingested, the compounds needed to remain asymptomatic would be quickly destroyed by stomach acid and have no beneficial effect.

Dr. Dolphin was not the first to draw such conclusions; in fact, many books and papers have been written on the subject. In 1963, the Proceedings of the Royal Society of Medicine, which is now the Journal of the Royal Society of Medicine, published the paper “On porphyria and the ætiology of werewolves.” Its main thesis was that because of a lack of scientific and medical knowledge in the Middle Ages, the legends of the werewolves were spawned from accounts of porphyria. It has even been suggested that Vlad III, Prince of Wallachia, more commonly known by his infamous surname Dracula, suffered from porphyria. In some circles, porphyrias are actually called the “vampire disease.” However, any association with vampires does a great disservice to the poor souls who suffer from these diseases.

Reference

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