Porphyria

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Porphyria
Urine of patient with porphyria.png
Left figure is urine on the first day while the right figure is urine after 3 days of sun exposures showing the classic change in color to purple.
Pronunciation
Specialty Hematology, dermatology, neurology
SymptomsDepending on subtype–abdominal pain, chest pain, vomiting, confusion, constipation, fever, seizures, blisters with sunlight [1] [2]
Usual onsetRecurrent attacks that last days to weeks [2]
CausesUsually genetic [2]
Diagnostic method Blood, urine, and stool tests, genetic testing [2]
Differential diagnosis Lead poisoning, alcoholic liver disease [3]
TreatmentDepends on type and symptoms [2]
Frequency1 to 100 in 50,000 people [1]

Porphyria is a group of diseases in which substances called porphyrins build up, negatively affecting the skin or nervous system. [1] The types that affect the nervous system are also known as acute porphyria, as symptoms are rapid in onset and last a short time. [1] Symptoms of an attack include abdominal pain, chest pain, vomiting, confusion, constipation, fever, high blood pressure, and high heart rate. [1] [2] [4] The attacks usually last for days to weeks. [2] Complications may include paralysis, low blood sodium levels, and seizures. [4] Attacks may be triggered by alcohol, smoking, hormonal changes, fasting, stress, or certain medications. [2] [4] If the skin is affected, blisters or itching may occur with sunlight exposure. [2]

Porphyrin

Porphyrins are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent porphyrin is porphine, a rare chemical compound of exclusively theoretical interest. Substituted porphines are called porphyrins. With a total of 26 π-electrons, of which 18 π-electrons form a planar, continuous cycle, the porphyrin ring structure is often described as aromatic. One result of the large conjugated system is that porphyrins typically absorb strongly in the visible region of the electromagnetic spectrum, i.e. they are deeply colored. The name "porphyrin" derives from the Greek word πορφύρα (porphyra), meaning purple.

Nervous system Control the whole body function

The nervous system is the part of an animal that coordinates its actions by transmitting signals to and from different parts of its body. The nervous system detects environmental changes that impact the body, then works in tandem with the endocrine system to respond to such events. Nervous tissue first arose in wormlike organisms about 550 to 600 million years ago. In vertebrates it consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and spinal cord. The PNS consists mainly of nerves, which are enclosed bundles of the long fibers or axons, that connect the CNS to every other part of the body. Nerves that transmit signals from the brain are called motor or efferent nerves, while those nerves that transmit information from the body to the CNS are called sensory or afferent. Spinal nerves serve both functions and are called mixed nerves. The PNS is divided into three separate subsystems, the somatic, autonomic, and enteric nervous systems. Somatic nerves mediate voluntary movement. The autonomic nervous system is further subdivided into the sympathetic and the parasympathetic nervous systems. The sympathetic nervous system is activated in cases of emergencies to mobilize energy, while the parasympathetic nervous system is activated when organisms are in a relaxed state. The enteric nervous system functions to control the gastrointestinal system. Both autonomic and enteric nervous systems function involuntarily. Nerves that exit from the cranium are called cranial nerves while those exiting from the spinal cord are called spinal nerves.

In medicine, describing a disease as acute denotes that it is of short duration and, as a corollary of that, of recent onset. The quantitation of how much time constitutes "short" and "recent" varies by disease and by context, but the core denotation of "acute" is always qualitatively in contrast with "chronic", which denotes long-lasting disease. In addition, "acute" also often connotes two other meanings: sudden onset and severity, such as in acute myocardial infarction (AMI), where suddenness and severity are both established aspects of the meaning. It thus often connotes that the condition is fulminant, but not always. The one thing that acute MI and acute rhinitis have in common is that they are not chronic. They can happen again, but they are not the same case ongoing for months or years.

Contents

Most types of porphyria are inherited from a person's parents and are due to a mutation in one of the genes that make heme. [2] They may be inherited in an autosomal dominant, autosomal recessive, or X-linked dominant manner. [1] One type, porphyria cutanea tarda, may also be due to increased iron in the liver, hepatitis C, alcohol, or HIV/AIDS. [1] The underlying mechanism results in a decrease in the amount of heme produced and a build-up of substances involved in making heme. [1] Porphyrias may also be classified by whether the liver or the bone marrow is affected. [1] Diagnosis is typically made by blood, urine, and stool tests. [2] Genetic testing may be done to determine the specific mutation. [2]

Heredity passing of traits to offspring from its parents or ancestor

Heredity is the passing on of traits from parents to their offspring, either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic information of their parents. Through heredity, variations between individuals can accumulate and cause species to evolve by natural selection. The study of heredity in biology is genetics.

Mutation A permanent change of the nucleotide sequence of the genome of an organism

In biology, a mutation is the alteration of the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA.

Gene Basic physical and functional unit of heredity

In biology, a gene is a sequence of nucleotides in DNA or RNA that codes for a molecule that has a function. During gene expression, the DNA is first copied into RNA. The RNA can be directly functional or be the intermediate template for a protein that performs a function. The transmission of genes to an organism's offspring is the basis of the inheritance of phenotypic trait. These genes make up different DNA sequences called genotypes. Genotypes along with environmental and developmental factors determine what the phenotypes will be. Most biological traits are under the influence of polygenes as well as gene–environment interactions. Some genetic traits are instantly visible, such as eye color or number of limbs, and some are not, such as blood type, risk for specific diseases, or the thousands of basic biochemical processes that constitute life.

Treatment depends on the type of porphyria and a person's symptoms. [2] The treatment of porphyria of the skin generally involves the avoidance of sunlight. [2] The treatment for acute porphyria may involve giving intravenous heme or a glucose solution. [2] Rarely a liver transplant may be carried out. [2]

Glucose A simple form of sugar

Glucose (also called dextrose) is a simple sugar with the molecular formula C6H12O6. Glucose is the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using energy from sunlight. There it is used to make cellulose in cell walls, which is the most abundant carbohydrate. In energy metabolism, glucose is the most important source of energy in all organisms. Glucose for metabolism is partially stored as a polymer, in plants mainly as starch and amylopectin and in animals as glycogen. Glucose circulates in the blood of animals as blood sugar. The naturally occurring form of glucose is D-glucose, while L-glucose is produced synthetically in comparably small amounts and is of lesser importance.

The frequency of porphyria is unclear. [1] It is estimated that it affects 1 to 100 per 50,000 people. [1] Rates vary around the world. [2] Porphyria cutanea tarda is believed to be the most common type. [1] The disease was described at least as early as 370 BC by Hippocrates. [5] The underlying mechanism was first described by Felix Hoppe-Seyler in 1871. [5] The name porphyria is from the Greek πορφύρα, porphyra, meaning "purple", a reference to the color of the urine that may occur during an attack. [5]

Hippocrates ancient Greek physician

Hippocrates of Kos, also known as Hippocrates II, was a Greek physician of the Age of Pericles, who is considered one of the most outstanding figures in the history of medicine. He is often referred to as the "Father of Medicine" in recognition of his lasting contributions to the field as the founder of the Hippocratic School of Medicine. This intellectual school revolutionized medicine in ancient Greece, establishing it as a discipline distinct from other fields with which it had traditionally been associated, thus establishing medicine as a profession.

Felix Hoppe-Seyler German physiologist and chemist

Ernst Felix Immanuel Hoppe-Seyler, né Felix Hoppe, was a German physiologist and chemist, and the principal founder of the disciplines of biochemistry and molecular biology.

Greek language language spoken in Greece, Cyprus and Southern Albania

Greek is an independent branch of the Indo-European family of languages, native to Greece, Cyprus and other parts of the Eastern Mediterranean and the Black Sea. It has the longest documented history of any living Indo-European language, spanning more than 3000 years of written records. Its writing system has been the Greek alphabet for the major part of its history; other systems, such as Linear B and the Cypriot syllabary, were used previously. The alphabet arose from the Phoenician script and was in turn the basis of the Latin, Cyrillic, Armenian, Coptic, Gothic, and many other writing systems.

Signs and symptoms

A skin rash in a person with porphyria Prfr1.jpg
A skin rash in a person with porphyria

Acute porphyrias

The acute porphyrias are acute intermittent porphyria (AIP), variegate porphyria (VP), aminolevulinic acid dehydratase deficiency porphyria (ALAD) and hereditary coproporphyria (HCP). These diseases primarily affect the nervous system, resulting in episodic crises known as acute attacks. The major symptom of an acute attack is abdominal pain, often accompanied by vomiting, hypertension (elevated blood pressure), and tachycardia (an abnormally rapid heart rate).

Acute intermittent porphyria human disease

Acute intermittent porphyria (AIP) is a rare autosomal dominant metabolic disorder affecting the production of heme resulting from a deficiency of the porphobilinogen deaminase. It is the most common of the acute porphyrias.

Variegate porphyria Human disease

Variegate porphyria, also known by several other names, is an autosomal dominant porphyria that can have acute 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. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.

Aminolevulinic acid dehydratase deficiency porphyria porphyria that has symptom abdominal pain, has symptom neuropathy, has symptom autonomic instability and has symptom psychosis

Aminolevulinic acid dehydratase deficiency porphyria is a neuropsychiatric condition, disease can present during early childhood with acute neurologic symptoms that resemble those encountered in acute intermittent porphyria. The condition is extremely rare, with fewer than 10 cases ever reported.

The most severe episodes may involve neurological complications: typically motor neuropathy (severe dysfunction of the peripheral nerves that innervate muscle), which leads to muscle weakness and potentially to quadriplegia (paralysis of all four limbs) and central nervous system symptoms such as seizures and coma. Occasionally, there may be short-lived psychiatric symptoms such as anxiety, confusion, hallucinations, and, very rarely, overt psychosis. All these symptoms resolve once the acute attack passes.

Tetraplegia, also known as quadriplegia, is paralysis caused by illness or injury that results in the partial or total loss of use of all four limbs and torso; paraplegia is similar but does not affect the arms. The loss is usually sensory and motor, which means that both sensation and control are lost. Tetraparesis or quadriparesis, on the other hand, means muscle weakness affecting all four limbs. It may be flaccid or spastic.

Central nervous system part of the nervous system consisting of the brain and spinal cord

The central nervous system (CNS) is the part of the nervous system consisting of the brain and spinal cord. The CNS is so named because it integrates the received information and coordinates and influences the activity of all parts of the bodies of bilaterally symmetric animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish—and it contains the majority of the nervous system. Many consider the retina and the optic nerve, as well as the olfactory nerves and olfactory epithelium as parts of the CNS, synapsing directly on brain tissue without intermediate ganglia. As such, the olfactory epithelium is the only central nervous tissue in direct contact with the environment, which opens up for therapeutic treatments. The CNS is contained within the dorsal body cavity, with the brain housed in the cranial cavity and the spinal cord in the spinal canal. In vertebrates, the brain is protected by the skull, while the spinal cord is protected by the vertebrae. The brain and spinal cord are both enclosed in the meninges. Within the CNS, the interneuronal space is filled with a large amount of supporting non-nervous cells called neuroglial cells.

A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened; fails to respond normally to painful stimuli, light, or sound; lacks a normal wake-sleep cycle; and does not initiate voluntary actions. Coma patients exhibit a complete absence of wakefulness and are unable to consciously feel, speak or move. Comas can be derived by natural causes, or can be medically induced.

Given the many presentations and the relatively low occurrence of porphyria, patients may initially be suspected to have other, unrelated conditions. For instance, the polyneuropathy of acute porphyria may be mistaken for Guillain–Barré syndrome, and porphyria testing is commonly recommended in those situations. [6]

Chronic porphyrias

The non-acute porphyrias are X-linked dominant protoporphyria (XLDPP), congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and erythropoietic protoporphyria (EPP). None of these are associated with acute attacks; their primary manifestation is with skin disease. For this reason, these four porphyrias—along with two acute porphyrias, VP and HCP, that may also involve skin manifestations—are sometimes called cutaneous porphyrias.

Skin disease is encountered where excess porphyrins accumulate in the skin. Porphyrins are photoactive molecules, and exposure to light results in promotion of electrons to higher energy levels. When these return to the resting energy level or ground state, energy is released. This accounts for the property of fluorescence typical of the porphyrins. This causes local skin damage.

Two distinct patterns of skin disease are seen in porphyria:

Cause

The porphyrias are generally considered genetic in nature.

Triggers

Acute porphyria can be triggered by a number of drugs, most of which are believed to trigger it by interacting with enzymes in the liver which are made with heme. Such drugs include: [7] [8] [9]

Genetics

Subtypes of porphyrias depend on which enzyme is deficient.

Porphyria typeDeficient enzyme Type of porphyriaInheritanceSymptoms Prevalence
X-linked dominant protoporphyria (XLDPP) 5-aminolevulinate (ALA) synthase (ALAS) Erythropoietic X-linked dominant Photosensitivity, cirrhosis [10] Rare; about 50 cases reported [11]
Aminolevulinate dehydratase deficiency porphyria (ALADP) 5-aminolevulinate dehydratase (ALAD)Hepatic Autosomal recessive [12] Abdominal pain, neuropathy [12] Extremely rare; fewer than 10 cases ever reported. [13]
Acute intermittent porphyria (AIP) Hydroxymethylbilane synthase (HMBS) formerly porphobilinogen deaminase (PBGD)Hepatic Autosomal dominant [12] Periodic abdominal pain, peripheral neuropathy, psychiatric disorders, tachycardia [12] 1 in 10,000 [14] –20,000 [14]
Congenital erythropoietic porphyria (CEP) uroporphyrinogen synthase (UROS) Erythropoietic Autosomal recessive [12] Severe photosensitivity with erythema, swelling and blistering. Hemolytic anemia, splenomegaly [12] 1 in 1,000,000 or less. [15]
Porphyria cutanea tarda (PCT) uroporphyrinogen decarboxylase (UROD) HepaticApproximately 80% sporadic, [16] 20% Autosomal dominant [12] Photosensitivity with vesicles and bullae [12] 1 in 10,000 [17]
Hereditary coproporphyria (HCP) coproporphyrinogen oxidase (CPOX) Hepatic Autosomal dominant [12] Photosensitivity, neurologic symptoms, colic [12] 1 in 500,000 [17]
Harderoporphyria coproporphyrinogen oxidase (CPOX) Erythropoietic Autosomal recessive [12] Jaundice, anemia, enlarged liver and spleen, often neonatal. Photosensitivity later.Extremely rare; fewer than 10 cases ever reported.
Variegate porphyria (VP) protoporphyrinogen oxidase (PPOX) Hepatic Autosomal dominant [18] Photosensitivity, neurologic symptoms, developmental delay1 in 300 in South Africa [17]
1 in 75,000 in Finland [19]
Erythropoietic protoporphyria (EPP) Ferrochelatase (FECH)Erythropoietic Autosomal dominant [12] Photosensitivity with skin lesions. Gallstones, mild liver dysfunction [12] 1 in 75,000 [17] –200,000 [17]

Pathogenesis

Heme synthesis--note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow) Heme synthesis.svg
Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)

In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, and P450 liver cytochromes.

The body requires porphyrins to produce heme, which is used to carry oxygen in the blood among other things, 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 one or more of these substances. Porphyrias are classified in two ways, by symptoms and by pathophysiology. Physiologically, porphyrias are classified as liver or erythropoietic based on the sites of accumulation of heme precursors, either in the liver or in the bone marrow and red blood cells. [20]

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. Hereditary coproporphyria, which is characterized by a deficiency in coproporphyrinogen oxidase, coded for by the CPOX gene, may also present with both acute neurologic attacks and cutaneous lesions. All other porphyrias are either skin- or nerve-predominant.

Diagnosis

Porphyrin studies

Porphyria is diagnosed through biochemical analysis of blood, urine, and stool. [15] [21] 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. [22] 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. [23] In cases of mercury- or arsenic poisoning-induced porphyria, other changes in porphyrin profiles appear, most notably elevations of uroporphyrins I & III, coproporphyrins I & III, and pre-coproporphyrin. [24]

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.[ citation needed ]

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.[ citation needed ]

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. [15] 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. [15]

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

Acute porphyria

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 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 hyponatraemia and should be done with extreme caution as it can prove fatal. [25]

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. [26] In the United States, Lundbeck manufactures and supplies Panhematin for infusion. [27]

Heme arginate (NormoSang) is used during crises but also in preventive treatment to avoid crises, one treatment every 10 days.[ citation needed ]

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.[ citation needed ]

Cimetidine has also been reported to be effective for acute porphyric crisis and possibly effective for long-term prophylaxis. [28]

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. [29]

Neurologic and psychiatric problems

Patients who experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the abdomen. [30] 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. [31]

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. [32]

Seizures

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. [31]

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. [33]

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. [34]

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. [35]

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.[ citation needed ]

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. [15] Blood transfusion is occasionally used to suppress innate heme production.

The rarest is congenital erythropoietic 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 1 porphyrins, and later hypertrichosis. Hemolytic anemia usually develops. Pharmaceutical-grade beta carotene may be used in its treatment. [36] A bone marrow transplant has also been successful in curing CEP in a few cases, although long-term results are not yet available. [37]

In December 2014, afamelanotide received authorization from the European Commission as a treatment for the prevention of phototoxicity in adult patients with EPP. [38]

Epidemiology

Rates of all types of porphyria taken together have been estimated to be approximately one in 25,000 in the United States. [39] The worldwide prevalence has been estimated to be between one in 500 and one in 50,000 people. [40]

History

Porphyrias have been detected in all races and in multiple ethnic groups on every continent, including Africans, Aboriginal Australians, Caucasians, Chinese, Filipinos, Peruvians, Mexicans, Native Americans, and Sami. 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.

The underlying mechanism was first described by Felix Hoppe-Seyler in 1871, [41] and acute porphyrias were described by the Dutch physician Barend Stokvis in 1889. [42] [43]

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" [44] ) 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 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, 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. [45] [46]

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. [47]

Notable cases

George III in his coronation robes Allan Ramsay - King George III in coronation robes - Google Art Project.jpg
George III in his coronation robes

The mental illness exhibited by King 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", [48] with a follow-up in 1968, "Porphyria in the Royal Houses of Stuart, Hanover and Prussia". [49]

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, [50] which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to have had it. [51]

In 2005, it was suggested that arsenic (which is known to be porphyrogenic) given to George III with antimony may have caused his porphyria. [52] 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. [53]

Mary, Queen of Scots c. 1578. Mary, Queen of Scots after Nicholas Hilliard.jpg
Mary, Queen of Scots c. 1578.

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 that King George had has been attributed to porphyria and that it is hereditary. 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. [54]

It is believed that Mary, Queen of Scots, King George III's ancestor, also had acute intermittent porphyria, [55] 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 in a c. 1790s portrait attributed to Giuseppe Troni or Thomas Hickey. Maria I, Queen of Portugal - Giuseppe Troni, atribuido (Turim, 1739-Lisboa, 1810) - Google Cultural Institute.jpg
Maria I of Portugal in a c. 1790s portrait attributed to Giuseppe Troni or Thomas Hickey.

Maria I of Portugal—known as "Maria the Pious" or "Maria the Mad" because of both her religious fervor and her acute mental illness, which made her incapable of handling state affairs after 1792 – is also thought to have had porphyria. Francis Willis, the same physician who treated George III, was even summoned by the Portuguese court but returned to England after the court limited the treatments he could oversee. Contemporary sources, such as Secretary of State for Foreign Affairs Luís Pinto, noted that the queen had ever-worsening stomach pains and abdominal spasms: hallmarks of porphyria. [56]

Vlad III was also said to have had acute porphyria, which may have started the notion that vampires were allergic to sunlight. [57]

Other commentators have suggested that Vincent van Gogh may have had acute intermittent porphyria. [58] It has also been speculated that King Nebuchadnezzar of Babylon had some form of porphyria as described in Daniel 4. [59] 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. [60]

Paula Frías Allende, the daughter of the Chilean novelist Isabel Allende, fell into a porphyria-induced coma in 1991, [61] which inspired Isabel to write the memoir Paula, dedicated to her.

Related Research Articles

Heme metal complex of ferrous ion and porphyrin; component of hemoglobin and some other biologically important hemoproteins

Heme or haem is a coordination complex "consisting of an iron ion coordinated to a porphyrin acting as a tetradentate ligand, and to one or two axial ligands." The definition is loose, and many depictions omit the axial ligands. Many porphyrin-containing metalloproteins have heme as their prosthetic group; these are known as hemoproteins. Hemes are most commonly recognized as components of hemoglobin, the red pigment in blood, but are also found in a number of other biologically important hemoproteins such as myoglobin, cytochromes, catalases, heme peroxidase, and endothelial nitric oxide synthase.

Rhabdomyolysis condition in which damaged skeletal muscle breaks down rapidly

Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of the muscle breakdown products, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure.

Kidney failure disease where the kidneys fail to adequately filter waste products from the blood

Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys no longer function. It is divided into acute kidney failure and chronic kidney failure. Symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, or confusion. Complications of acute disease may include uremia, high blood potassium, or volume overload. Complications of chronic disease may include heart disease, high blood pressure, or anemia.

Cholecystitis cholangitis that is characterized by an inflammation that is located in the gallbladder

Cholecystitis is inflammation of the gallbladder. Symptoms include right upper abdominal pain, nausea, vomiting, and occasionally fever. Often gallbladder attacks precede acute cholecystitis. The pain lasts longer in cholecystitis than in a typical gallbladder attack. Without appropriate treatment, recurrent episodes of cholecystitis are common. Complications of acute cholecystitis include gallstone pancreatitis, common bile duct stones, or inflammation of the common bile duct.

Hereditary coproporphyria Human disease

Hereditary coproporphyria (HCP) is a disorder of heme biosynthesis, classified as an acute hepatic porphyria. HCP is caused by a deficiency of the enzyme coproporphyrinogen oxidase, coded for by the CPOX gene, and is inherited in an autosomal dominant fashion, although homozygous individuals have been identified. Unlike acute intermittent porphyria, individuals with HCP can present with cutaneous findings 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. Overall, porphyrias are rare diseases. The combined incidence for all forms of the disease has been estimated at 1:20,000. The exact incidence of HCP is difficult to determine, due to its reduced penetrance.

Porphyria cutanea tarda is the most common subtype of porphyria. The disease is named because it is a porphyria that often presents with skin manifestations later in life. The disorder results from low levels of the enzyme responsible for the fifth step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.

Erythropoietic protoporphyria acute porphyria characterized by a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the tissue

Erythropoietic protoporphyria is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the red blood cells (erythrocytes), plasma, skin, and liver. The severity varies significantly from individual to individual.

Iron overload Human disease

Iron overload indicates accumulation of iron in the body from any cause. The most important causes are hereditary haemochromatosis (HHC), a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions.

Gauchers disease human disease characterized by deficiency of the enzyme glucocerebrosidase which results in the accumulation of harmful quantities of the glycolipid glucocerebroside throughout the body

Gaucher's disease or Gaucher disease (GD) is a genetic disorder in which glucocerebroside accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low blood platelet count and enlargement of the liver and spleen, and is caused by a hereditary deficiency of the enzyme glucocerebrosidase, which acts on glucocerebroside. When the enzyme is defective, glucocerebroside accumulates, particularly in white blood cells and especially in macrophages. Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow.

Abdominal pain Stomach aches

Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues.

Gunther disease congenital human disease

Gunther disease, is a congenital form of erythropoietic porphyria. The word porphyria originated from the Greek word porphura. Porphura actually means "purple pigment", which, in suggestion, the color that the body fluid changes when a person has Gunther's disease. It is a rare, autosomal recessive metabolic disorder affecting heme, caused by deficiency of the enzyme uroporphyrinogen cosynthetase. It is extremely rare, with a prevalence estimated at 1 in 1,000,000 or less. There have been times that prior to birth of a fetus, Gunther's disease has been shown to lead to anemia. In milder cases patients have not presented any symptoms until they have reached adulthood. In Gunther's disease, porphyrins are accumulated in the teeth and bones and an increased amount are seen in the plasma, bone marrow, feces, red blood cells, and urine.

Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic disorders. The term inborn errors of metabolism was coined by a British physician, Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism was published in 1923.

Protoporphyrinogen oxidase protein-coding gene in the species Homo sapiens

Protoporphyrinogen oxidase is an enzyme that in humans is encoded by the PPOX gene.

Interstitial nephritis type of nephritis affecting the interstitium of the kidneys surrounding the tubules

Interstitial nephritis, also known as tubulointerstitial nephritis, is inflammation of the area of the kidney known as the interstitium, which consists of a collection of cells, extracellular matrix, and fluid surrounding the renal tubules. In addition to providing a scaffolding support for the tubular architecture, the interstitium has been shown to participate in the fluid and electrolyte exchange as well as endocrine functions of the kidney. There are a variety of known factors that can provoke the inflammatory process within the renal interstitium, including pharmacologic, environmental, infectious and systemic disease contributors. The spectrum of disease presentation can range from an acute process to a chronic condition with progressive tubular cell damage and renal dysfunction.

Erythropoietic porphyria is a type of porphyria associated with erythropoietic cells. In erythropoietic porphyrias, the enzyme deficiency occurs in the red blood cells.

Hemin chemical substance

Hemin is an iron-containing porphyrin with chlorine that can be formed from a haem group, such as haem b found in the haemoglobin of human blood.

Pseudoporphyria

Pseudoporphyria is a bullous photosensitivity that clinically and histologically mimics porphyria cutanea tarda. The difference is that no abnormalities in urine or serum porphyrin is noted on laboratories. Pseudoporphyria has been reported in patients with chronic renal failure treated with hemodialysis and in those with excessive exposure to ultraviolet A (UV-A) by tanning beds.

Harderoporphyria

Harderoporphyria is a rare disorder of heme biosynthesis, inherited in an autosomal recessive manner caused by specific mutations in the CPOX gene. Mutations in CPOX usually cause hereditary coproporphyria, an acute hepatic porphyria, however the K404E mutation in a homozygous or compound heterozygous state with a null allele cause the more severe harderoporphyria. Harderoporphyria is the first known metabolic disorder where the disease phenotype depended on the type and location of the mutations in a gene associated with multiple disorders.

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