Porphyria
Encyclopedia
Porphyrias are a group of inherited or acquired disorders of certain enzyme
s in the heme
bio-synthetic pathway (also called porphyrin
pathway). They are broadly classified as acute (hepatic) porphyrias and cutaneous (erythropoietic) porphyrias, based on the site of the overproduction and accumulation of the porphyrins (or their chemical precursors). They manifest with either neurological complications or skin problems (or occasionally both). A clinically induced and histologically
identical condition is called pseudoporphyria
. Pseudoporphyria is characterized by normal serum and urine porphyrin levels.
The term derives 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 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 Stokvis
in 1889.
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.
, resulting in abdominal pain
, vomiting
, acute neuropathy, muscle weakness, seizure
s, and mental disturbances, including hallucination
s, depression
, anxiety
, and paranoia
. Cardiac arrhythmias and tachycardia
(high heart rate) 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-Barré syndrome
, and porphyria testing is commonly recommended in those situations. Systemic lupus erythematosus
features photosensitivity and pain attacks and shares various other symptoms with porphyria.
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 (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.
, causing photosensitivity
(photodermatitis
), blister
s, 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.
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.
and 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
- 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
.
of the liver. Basic biochemical tests may assist in identifying liver disease
, hepatocellular carcinoma
, and other organ problems.
s, porphyrin
s are the main precursors of heme
, an essential constituent of hemoglobin
, myoglobin
, catalase
, peroxidase
, respiratory and P450 liver cytochrome
s.
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 enzyme
s 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 porphyria
s are characterized by acute neurological attacks (seizure
s, psychosis
, extreme back
and abdominal pain
and an acute polyneuropathy
), while the erythropoietic forms
present with skin problems, usually a light-sensitive blistering rash and increased hair growth
.
Variegate porphyria
(also porphyria variegata or mixed porphyria), which results from a partial deficiency in PROTO oxidase, manifests itself with skin lesions similar to those of porphyria cutanea tarda
combined with acute neurologic attacks. All other porphyrias are either skin- or nerve-predominant.
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.
Precipitating factors
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 vigorous treatment.
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, 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.
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 any patients with any porphyria.
Neurologic and psychiatric issues
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 opioid
s may be indicated. Some cases of chronic pain can be difficult to manage and may require treatment using multiple modalities. Opioid dependence may develop.
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 are porphyrinogenic, limiting the therapeutic scope.
Seizures
Seizures often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: barbiturate
s especially must be avoided. Some benzodiazepine
s 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
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.
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.
. 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.
, Asians
, Australian aborigines
, Caucasians
, Peru
vian, 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.
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.
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.
evidenced in the regency crisis of 1788 has inspired several attempts at retrospective diagnosis
. The first, written in 1855, thirty-five years after his death, concluded he suffered from acute mania
. M. Guttmacher, in 1941, suggested manic-depressive psychosis as a more likely diagnosis. The first suggestion that a physical illness was the cause of King George's mental derangements came in 1966, in a paper "The Insanity of King George III: A Classic Case of Porphyria", 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. 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
(Emperor William II
's eldest sister) and her daughter Princess Feodora of Saxe-Meiningen
. They had more success in being able to uncover reliable evidence that George III's great-great-great-grandson Prince William of Gloucester
was reliably diagnosed with variegate porphyria.
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 some believe fall within the constellation of symptoms of porphyria.
Vlad III the Impaler
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 imagined that King Nebuchadnezzar of Babylon suffered from some form of porphyria (cf. Daniel 4). 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 Allende to write the autobiographical book Paula
, dedicated to her daughter.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s in the heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
bio-synthetic pathway (also called porphyrin
Porphyrin
Porphyrins are a group of organic compounds, many naturally occurring. One of the best-known porphyrins is heme, the pigment in red blood cells; heme is a cofactor of the protein hemoglobin. Porphyrins are heterocyclic macrocycles composed of four modified pyrrole subunits interconnected at...
pathway). They are broadly classified as acute (hepatic) porphyrias and cutaneous (erythropoietic) porphyrias, based on the site of the overproduction and accumulation of the porphyrins (or their chemical precursors). They manifest with either neurological complications or skin problems (or occasionally both). A clinically induced and histologically
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
identical condition is called pseudoporphyria
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 is characterized by normal serum and urine porphyrin levels.
The term derives from the Greek
Greek language
Greek is an independent branch of the Indo-European family of languages. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. Its writing system has been the Greek alphabet for the majority of its history;...
πορφύρα, porphyra, meaning "purple
Purple
Purple is a range of hues of color occurring between red and blue, and is classified as a secondary color as the colors are required to create the shade....
pigment
Pigment
A pigment is a material that changes the color of reflected or transmitted light as the result of wavelength-selective absorption. This physical process differs from fluorescence, phosphorescence, and other forms of luminescence, in which a material emits light.Many materials selectively absorb...
". The name is likely to have been a reference to the purple discolouration of feces and urine in patients during an attack. Although original descriptions are attributed to Hippocrates
Hippocrates
Hippocrates of Cos or Hippokrates of Kos was an ancient Greek physician of the Age of Pericles , and is considered one of the most outstanding figures in the history of medicine...
, the disease was first explained biochemically by Felix Hoppe-Seyler in 1871, and acute porphyrias were described by the Dutch physician Barend Stokvis
Barend Joseph Stokvis
Barend Joseph Stokvis was a Dutch physician and professor of physiology and pharmacology who is mainly remembered for his description of acute porphyria in 1889. As a researcher in chemical pathology he made contributions to the understanding of a number of diseases...
in 1889.
The prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of all types of porphyria taken together has been estimated to be approximately 1 in 25,000 in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
. The worldwide prevalence has been estimated to be somewhere between 1 in 500 to 1 in 50,000 people.
Acute porphyrias
The acute, or hepatic, porphyrias primarily affect the nervous systemNervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
, resulting in abdominal pain
Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, acute neuropathy, muscle weakness, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, and mental disturbances, including hallucination
Hallucination
A hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...
s, depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, and paranoia
Paranoia
Paranoia [] is a thought process believed to be heavily influenced by anxiety or fear, often to the point of irrationality and delusion. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy concerning a perceived threat towards oneself...
. Cardiac arrhythmias and tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
(high heart rate) may develop as the autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
is affected. Pain can be severe and can, in some cases, be both acute and chronic in nature. Constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
is frequently present, as the nervous system of the gut is affected, but diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
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-Barré syndrome
Guillain-Barré syndrome
Guillain–Barré syndrome , sometimes called Landry's paralysis, is an acute inflammatory demyelinating polyneuropathy , a disorder affecting the peripheral nervous system. Ascending paralysis, weakness beginning in the feet and hands and migrating towards the trunk, is the most typical symptom...
, and porphyria testing is commonly recommended in those situations. Systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
features photosensitivity and pain attacks and shares various other symptoms with porphyria.
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
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
.
Patients with acute porphyria (AIP
Acute intermittent porphyria
Acute intermittent porphyria is a rare autosomal dominant metabolic disorder affecting the production of heme, the oxygen-binding prosthetic group of hemoglobin. It is characterized by a deficiency of the enzyme porphobilinogen deaminase. Acute intermittent porphyria is the second most common...
, HCP
Hereditary coproporphyria
Hereditary coproporphyria is a type of acute porphyria that is associated with a deficiency of the enzyme coproporphyrinogen III oxidase....
, VP
Variegate porphyria
Variegate porphyria is an autosomal dominant porphyria that can have acute symptoms along with symptoms that affect the skin...
) are at increased risk over their life for hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
(primary liver cancer) and may require monitoring. Other typical risk factors for liver cancer need not be present.
Cutaneous porphyrias
The cutaneous, or erythropoietic, porphyrias primarily affect the skinSkin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, causing photosensitivity
Photosensitivity
Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.- Human medicine :Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...
(photodermatitis
Photodermatitis
Photodermatitis, sometimes referred to as "sun poisoning" or photoallergy is a form of allergic contact dermatitis in which the allergen must be activated by light to sensitize the allergic response, and to cause a rash or other systemic effects on subsequent exposure...
), blister
Blister
A blister is a small pocket of fluid within the upper layers of the skin, typically caused by forceful rubbing , burning, freezing, chemical exposure or infection. Most blisters are filled with a clear fluid called serum or plasma...
s, necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
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.
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.
Porphyrin studies
Porphyria is diagnosed through spectroscopySpectroscopy
Spectroscopy is the study of the interaction between matter and radiated energy. Historically, spectroscopy originated through the study of visible light dispersed according to its wavelength, e.g., by a prism. Later the concept was expanded greatly to comprise any interaction with radiative...
and biochemical analysis of blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
, urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, and stool
Feces
Feces, faeces, or fæces is a waste product from an animal's digestive tract expelled through the anus or cloaca during defecation.-Etymology:...
. In general, urine estimation of porphobilinogen
Porphobilinogen
Porphobilinogen is a pyrrole involved in porphyrin metabolism.It is generated by aminolevulinate and the enzyme ALA dehydratase. PBG is then converted into hydroxymethyl bilane by the enzyme porphobilinogen deaminase, also known as hydroxymethylbilane synthase.Acute intermittent porphyria causes...
(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
Tyrosinemia
Tyrosinemia is an error of metabolism, usually inborn, in which the body cannot effectively break down the amino acid tyrosine. Symptoms include liver and kidney disturbances and mental retardation...
. In cases of
mercury
Mercury poisoning
Mercury poisoning is a disease caused by exposure to mercury or its compounds. Mercury is a heavy metal occurring in several forms, all of which can produce toxic effects in high enough doses...
- or arsenic poisoning
Arsenic poisoning
Arsenic poisoning is a medical condition caused by increased levels of the element arsenic in the body. Arsenic interferes with cellular longevity by allosteric inhibition of an essential metabolic enzyme...
-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
Acute intermittent porphyria
Acute intermittent porphyria is a rare autosomal dominant metabolic disorder affecting the production of heme, the oxygen-binding prosthetic group of hemoglobin. It is characterized by a deficiency of the enzyme porphobilinogen deaminase. Acute intermittent porphyria is the second most common...
.
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
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
or enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
testing. The exception to this may be latent post-puberty genetic carriers of hereditary coproporphyria.
As most porphyrias are rare conditions
Rare disease
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear...
, 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
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...
. A careful medication review often will find the inciting cause of pseudoporphyria
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...
.
Additional tests
Further diagnostic tests of affected organs may be required, such as nerve conduction studies for neuropathy or an ultrasoundMedical ultrasonography
Diagnostic sonography is an ultrasound-based diagnostic imaging technique used for visualizing subcutaneous body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions...
of the liver. Basic biochemical tests may assist in identifying liver disease
Liver disease
Liver disease is a broad term describing any single number of diseases affecting the liver.-Diseases:* Hepatitis, inflammation of the liver, caused mainly by various viruses but also by some poisons , autoimmunity or hereditary conditions...
, hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
, and other organ problems.
Pathogenesis
In humanHuman
Humans are the only living species in the Homo genus...
s, porphyrin
Porphyrin
Porphyrins are a group of organic compounds, many naturally occurring. One of the best-known porphyrins is heme, the pigment in red blood cells; heme is a cofactor of the protein hemoglobin. Porphyrins are heterocyclic macrocycles composed of four modified pyrrole subunits interconnected at...
s are the main precursors of heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
, an essential constituent of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
, myoglobin
Myoglobin
Myoglobin is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in almost all mammals. It is related to hemoglobin, which is the iron- and oxygen-binding protein in blood, specifically in the red blood cells. The only time myoglobin is found in the...
, catalase
Catalase
Catalase is a common enzyme found in nearly all living organisms that are exposed to oxygen, where it catalyzes the decomposition of hydrogen peroxide to water and oxygen...
, peroxidase
Peroxidase
Peroxidases are a large family of enzymes that typically catalyze a reaction of the form:For many of these enzymes the optimal substrate is hydrogen peroxide, but others are more active with organic hydroperoxides such as lipid peroxides...
, respiratory and P450 liver cytochrome
Cytochrome
Cytochromes are, in general, membrane-bound hemoproteins that contain heme groups and carry out electron transport.They are found either as monomeric proteins or as subunits of bigger enzymatic complexes that catalyze redox reactions....
s.
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
. Heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
function plays a central role in cellular metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
. This is not the main problem in the porphyrias; most heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
synthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
enzymes—even dysfunctional enzymes—have enough residual activity to assist in heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
biosynthesis. The principal problem in these deficiencies is the accumulation of porphyrins, the heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine the location of accumulation, whether they induce photosensitivity
Photosensitivity
Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.- Human medicine :Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...
, and whether the intermediate is excreted (in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
or feces
Feces
Feces, faeces, or fæces is a waste product from an animal's digestive tract expelled through the anus or cloaca during defecation.-Etymology:...
).
There are eight enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s in the heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
biosynthetic pathway, four of which—the first one and the last three—are in the mitochondria, while the other four are in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
. Defects in any of these can lead to some form of porphyria.
The hepatic porphyria
Hepatic porphyria
Hepatic porphyrias is a form of porphyria in which the enzyme deficiency occurs in the liver.Examples include :* Acute intermittent porphyria* Porphyria cutanea tarda and Hepatoerythropoietic porphyria...
s are characterized by acute neurological attacks (seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
, extreme back
Back pain
Back pain is pain felt in the back that usually originates from the muscles, nerves, bones, joints or other structures in the spine.The pain can often be divided into neck pain, upper back pain, lower back pain or tailbone pain...
and abdominal pain
Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
and an acute polyneuropathy
Polyneuropathy
Polyneuropathy is a neurological disorder that occurs when many peripheral nerves throughout the body malfunction simultaneously. It may be acute and appear without warning, or chronic and develop gradually over a longer period of time. Many polyneuropathies have both motor and sensory...
), while the erythropoietic forms
Erythropoietic porphyria
Erythropoietic porphyria is a type of porphyria associated with erythropoietic cells. In erythropoietic porphyrias, the enzyme deficiency occurs in the red blood cells.There are three types:...
present with skin problems, usually a light-sensitive blistering rash and increased hair growth
Hypertrichosis
Hypertrichosis is an abnormal amount of hair growth on the body; extensive cases of hypertrichosis have informally been called werewolf syndrome. There are two distinct types of hypertrichosis: generalized hypertrichosis, which occurs over the entire body, and localized hypertrichosis, which is...
.
Variegate porphyria
Variegate porphyria
Variegate porphyria is an autosomal dominant porphyria that can have acute symptoms along with symptoms that affect the skin...
(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
Porphyria cutanea tarda
Porphyria cutanea tarda is the most common subtype of porphyria. 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...
combined with acute neurologic attacks. All other porphyrias are either skin- or nerve-predominant.
Subtypes
Subtypes of porphyrias depend on what enzyme is deficient.| Enzyme Enzyme Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates... |
Associated porphyria | Type of porphyria | Inheritance | Symptoms | Prevalence Prevalence In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population... |
|---|---|---|---|---|---|
| δ-aminolevulinate (ALA) synthase | X-linked sideroblastic anemia Sideroblastic anemia Sideroblastic anemia or sideroachrestic anemia is a disease in which the bone marrow produces ringed sideroblasts rather than healthy red blood cells . It may be caused either by a genetic disorder or indirectly as part of myelodysplastic syndrome, which can evolve into hematological malignancies... (XLSA) |
Erythropoietic | X-linked | ||
| δ-aminolevulinate dehydratase (ALAD) | Doss porphyria/ALA dehydratase deficiency Aminolevulinic acid dehydratase deficiency porphyria Aminolevulinic acid dehydratase deficiency porphyria is a cutaneous condition, disease can present during early childhood with acute neurologic symptoms that resemble those encountered in acute intermittent porphyria... |
Hepatic | Autosomal recessive | Abdominal pain, neuropathy | Extremely rare (less than 10 cases ever reported) |
| hydroxymethylbilane (HMB) synthase Porphobilinogen deaminase Porphobilinogen deaminase is an enzyme involved in the third step of the metabolism of porphyrin, converting porphobilinogen into hydroxymethylbilane. The enzyme has the unique cofactor dipyrromethane... (or PBG Porphobilinogen Porphobilinogen is a pyrrole involved in porphyrin metabolism.It is generated by aminolevulinate and the enzyme ALA dehydratase. PBG is then converted into hydroxymethyl bilane by the enzyme porphobilinogen deaminase, also known as hydroxymethylbilane synthase.Acute intermittent porphyria causes... deaminase) |
acute intermittent porphyria Acute intermittent porphyria Acute intermittent porphyria is a rare autosomal dominant metabolic disorder affecting the production of heme, the oxygen-binding prosthetic group of hemoglobin. It is characterized by a deficiency of the enzyme porphobilinogen deaminase. Acute intermittent porphyria is the second most common... (AIP) |
Hepatic | Autosomal dominant | Periodic abdominal pain, peripheral neuropathy Peripheral neuropathy Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness.... , psychiatric disorders, tachycardia |
1 in 10,000-20,000 |
| uroporphyrinogen (URO) synthase Uroporphyrinogen III synthase Uroporphyrinogen III synthase is an enzyme involved in the metabolism of the cyclic tetrapyrrole compound porphyrin. It is involved in the conversion of hydroxymethyl bilane into uroporphyrinogen III... |
Congenital erythropoietic porphyria (CEP) | Erythropoietic | Autosomal recessive | Severe photosensitivity with erythema, swelling and blistering. Hemolytic anemia, splenomegaly Splenomegaly Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any... |
1 in 1,000,000 or less. |
| uroporphyrinogen (URO) decarboxylase Uroporphyrinogen III decarboxylase Uroporphyrinogen decarboxylase, also known as UROD, is an enzyme that in humans is encoded by the UROD gene.- Function :This gene encodes the fifth enzyme of the heme biosynthetic pathway... |
Porphyria cutanea tarda Porphyria cutanea tarda Porphyria cutanea tarda is the most common subtype of porphyria. 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... (PCT) |
Hepatic | Autosomal dominant | Photosensitivity with vesicles and bullae | 1 in 10,000 |
| coproporphyrinogen (COPRO) oxidase Coproporphyrinogen III oxidase Coproporphyrinogen-III oxidase, mitochondrial is an enzyme that in humans is encoded by the CPOX gene. A genetic defect in the enzyme results in a reduced production of heme in animals. The medical condition associated with this enzyme defect is called hereditary coproporphyria... |
Hereditary coproporphyria Hereditary coproporphyria Hereditary coproporphyria is a type of acute porphyria that is associated with a deficiency of the enzyme coproporphyrinogen III oxidase.... (HCP) |
Hepatic | Autosomal dominant | Photosensitivity, neurologic symptoms, colic Colic Colic is a form of pain which starts and stops abruptly. Types include:*Baby colic, a condition, usually in infants, characterized by incessant crying*Renal colic, a pain in the flank, characteristic of kidney stones... |
1 in 500,000 |
| protoporphyrinogen (PROTO) oxidase Protoporphyrinogen oxidase Protoporphyrinogen oxidase is an enzyme that is responsible for the seventh step in heme production.... |
Variegate porphyria Variegate porphyria Variegate porphyria is an autosomal dominant porphyria that can have acute symptoms along with symptoms that affect the skin... (VP) |
Mixed | Autosomal dominant | Photosensitivity, neurologic symptoms, developmental delay | 1 in 300 in South Africa 1 in 75.000 in Finland |
| Ferrochelatase Ferrochelatase Ferrochelatase is an enzyme that catalyses the terminal step in the biosynthesis of heme, converting protoporphyrin IX into heme. It catalyses the reaction:A ferrochelatase enzyme consists of 497 amino acid residues with a m.w... |
Erythropoietic protoporphyria Erythropoietic protoporphyria Erythropoietic protoporphyria is a relatively mild form of porphyria, although very painful, which arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the tissue... (EPP) |
Erythropoietic | Autosomal dominant | Photosensitivity with skin lesions. Gallstones, mild liver dysfunction | 1 in 75,000-200,000 |
| Transient erythroporphyria of infancy Transient erythroporphyria of infancy Transient erythroporphyria of infancy is a cutaneous condition reported in infants exposed to blue lights for the treatment of indirect hyperbilirubinemia characterized by marked purpura in skin exposed to the UV light.... |
Purpuric skin lesions |
Acute porphyria
Carbohydrates and hemeOften, 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
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
10% infusion is commenced, which may aid in recovery.
Hematin (trade name Panhematin) and heme arginate
Heme arginate
Heme arginate is a compound of heme and arginine used in the treatment of acute porphyrias. This heme product is only available outside the United States, where the equivalent is hematin....
(trade name NormoSang) are the drugs of choice in acute porphyria, in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
and the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
, 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
St Thomas' Hospital
St Thomas' Hospital is a large NHS hospital in London, England. It is administratively a part of Guy's & St Thomas' NHS Foundation Trust. It has provided health care freely or under charitable auspices since the 12th century and was originally located in Southwark.St Thomas' Hospital is accessible...
, London. In the United States, Lundbeck
Lundbeck
H. Lundbeck A/S is a Danish international pharmaceutical company engaged in the research and development, production, marketing, and sale of drugs for the treatment of disorders in the central nervous system , including depression, schizophrenia, Alzheimer’s disease, Parkinson’s disease,...
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
Heme arginate
Heme arginate is a compound of heme and arginine used in the treatment of acute porphyrias. This heme product is only available outside the United States, where the equivalent is hematin....
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.
Precipitating factors
If drugs or hormones have caused the attack, discontinuing the offending substances is essential. Infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
is one of the top causes of attacks and requires vigorous treatment.
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, due to its severity. Nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
can be severe; it may respond to phenothiazine
Phenothiazine
Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
drugs but is sometimes intractable. Hot water baths/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
Medical identification tag
A medical identification tag is a small emblem or tag worn on a bracelet, neck chain, or on the clothing bearing a message that the wearer has an important medical condition that might require immediate attention...
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
Contraindication
In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...
for any patients with any porphyria.
Neurologic and psychiatric issues
Patients who experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the gut. Gut dysmotility, ileus
Ileus
Ileus is a disruption of the normal propulsive ability of the gastrointestinal tract.Ileus is commonly defined simply as bowel obstruction. However, authoritative sources define it as decreased motor activity of the GI tract due to non-mechanical causes...
, intussusception
Intussusception (medical disorder)
An intussusception is a medical condition in which a part of the intestine has invaginated into another section of intestine, similar to the way in which the parts of a collapsible telescope slide into one another. This can often result in an obstruction...
, hypoganglionosis, encopresis
Encopresis
Encopresis is involuntary fecal soiling in adults and children who have usually already been toilet trained. Persons with encopresis often leak stool into their undergarments.-Prevalence:The estimated prevalence of encopresis in four-year-olds is between one and three percent...
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 opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
s may be indicated. Some cases of chronic pain can be difficult to manage and may require treatment using multiple modalities. Opioid dependence may develop.
Depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
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 are porphyrinogenic, limiting the therapeutic scope.
Seizures
Seizures often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: barbiturate
Barbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
s especially must be avoided. Some benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s are safe and, when used in conjunction with newer anti-seizure medications such as gabapentin
Gabapentin
Gabapentin is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain...
, 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
Heme arginate
Heme arginate is a compound of heme and arginine used in the treatment of acute porphyrias. This heme product is only available outside the United States, where the equivalent is hematin....
has been used during status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
.
Underlying liver disease
Some liver diseases may cause porphyria even in the absence of genetic predisposition. These include hemochromatosis and hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
. Treatment of iron overload may be required.
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.
Erythropoietic porphyrias
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 diseaseGunther's disease
Gunther disease, also known as congenital erythropoietic porphyria , uroporphyrinogen III synthase deficiency and UROS deficiency, is a congenital form of erythropoietic porphyria. It is a rare, autosomal recessive metabolic disorder affecting heme, caused by deficiency of the enzyme...
. 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
Hypertrichosis
Hypertrichosis is an abnormal amount of hair growth on the body; extensive cases of hypertrichosis have informally been called werewolf syndrome. There are two distinct types of hypertrichosis: generalized hypertrichosis, which occurs over the entire body, and localized hypertrichosis, which is...
. 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
Sunscreen
Sunblock is a lotion, spray, gel or other topical product that absorbs or reflects some of the sun's ultraviolet radiation on the skin exposed to sunlight and thus helps protect against sunburn...
are not effective, but SPF-rated long-sleeve shirts, hats, bandanas and gloves can help. Chloroquine
Chloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
may be used to increase porphyrin secretion in some EPs. Blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
is occasionally used to suppress innate heme production.
Culture and history
Porphyrias have been detected in all races, multiple ethnic groups on every continent including AfricansAfrican people
African people refers to natives, inhabitants, or citizen of Africa and to people of African descent.-Etymology:Many etymological hypotheses that have been postulated for the ancient name "Africa":...
, Asians
Asian people
Asian people or Asiatic people is a term with multiple meanings that refers to people who descend from a portion of Asia's population.- Central Asia :...
, Australian aborigines
Australian Aborigines
Australian Aborigines , also called Aboriginal Australians, from the latin ab originem , are people who are indigenous to most of the Australian continentthat is, to mainland Australia and the island of Tasmania...
, Caucasians
Caucasian race
The term Caucasian race has been used to denote the general physical type of some or all of the populations of Europe, North Africa, the Horn of Africa, Western Asia , Central Asia and South Asia...
, Peru
Peru
Peru , officially the Republic of Peru , is a country in western South America. It is bordered on the north by Ecuador and Colombia, on the east by Brazil, on the southeast by Bolivia, on the south by Chile, and on the west by the Pacific Ocean....
vian, Mexican
Mexico
The United Mexican States , commonly known as Mexico , is a federal constitutional republic in North America. It is bordered on the north by the United States; on the south and west by the Pacific Ocean; on the southeast by Guatemala, Belize, and the Caribbean Sea; and on the east by the Gulf of...
, Native Americans
Indigenous peoples of the Americas
The indigenous peoples of the Americas are the pre-Columbian inhabitants of North and South America, their descendants and other ethnic groups who are identified with those peoples. Indigenous peoples are known in Canada as Aboriginal peoples, and in the United States as Native Americans...
, and Sami
Sami people
The Sami people, also spelled Sámi, or Saami, are the arctic indigenous people inhabiting Sápmi, which today encompasses parts of far northern Sweden, Norway, Finland, the Kola Peninsula of Russia, and the border area between south and middle Sweden and Norway. The Sámi are Europe’s northernmost...
. 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.
Vampires and werewolves
Porphyria has been suggested as an explanation for the origin of vampireVampire
Vampires are mythological or folkloric beings who subsist by feeding on the life essence of living creatures, regardless of whether they are undead or a living person...
and werewolf
Werewolf
A werewolf, also known as a lycanthrope , is a mythological or folkloric human with the ability to shapeshift into a wolf or an anthropomorphic wolf-like creature, either purposely or after being placed under a curse...
legends, based upon certain perceived similarities between the condition and the folklore
Folklore
Folklore consists of legends, music, oral history, proverbs, jokes, popular beliefs, fairy tales and customs that are the traditions of a culture, subculture, or group. It is also the set of practices through which those expressive genres are shared. The study of folklore is sometimes called...
.
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
Nancy Garden
Nancy Garden is an American author of children's and young adult literature.- Biography :She is best known for her novel, Annie on My Mind , which was critically acclaimed but attracted controversy because of its lesbian characters, Annie and Liza who fall in love...
argued for a connection between porphyria and the vampire belief in her 1973 book, Vampires. In 1985, biochemist David Dolphin
David Dolphin
David H. Dolphin, OC, FRS, FRSC is a Canadian biochemist.He is an internationally recognized expert in porphyrin chemistry and biochemistry...
's paper for the American Association for the Advancement of Science
American Association for the Advancement of Science
The American Association for the Advancement of Science is an international non-profit organization with the stated goals of promoting cooperation among scientists, defending scientific freedom, encouraging scientific responsibility, and supporting scientific education and science outreach for the...
, "Porphyria, Vampires, and Werewolves: The Aetiology of European Metamorphosis Legends", gained widespread media coverage, thus popularizing the connection.
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.
Notable cases
The mental illness exhibited by King George IIIGeorge III of the United Kingdom
George III was King of Great Britain and King of Ireland from 25 October 1760 until the union of these two countries on 1 January 1801, after which he was King of the United Kingdom of Great Britain and Ireland until his death...
evidenced in the regency crisis of 1788 has inspired several attempts at retrospective diagnosis
Retrospective diagnosis
A retrospective diagnosis is the practice of identifying an illness in a historical figure using modern knowledge, methods and disease classifications...
. The first, written in 1855, thirty-five years after his death, concluded he suffered from acute mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
. M. Guttmacher, in 1941, suggested manic-depressive psychosis as a more likely diagnosis. The first suggestion that a physical illness was the cause of King George's mental derangements came in 1966, in a paper "The Insanity of King George III: A Classic Case of Porphyria", 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. In 2005 it was suggested that arsenic
Arsenic
Arsenic is a chemical element with the symbol As, atomic number 33 and relative atomic mass 74.92. Arsenic occurs in many minerals, usually in conjunction with sulfur and metals, and also as a pure elemental crystal. It was first documented by Albertus Magnus in 1250.Arsenic is a metalloid...
(which is known to be porphyrogenic) given to George III with antimony
Antimony
Antimony is a toxic chemical element with the symbol Sb and an atomic number of 51. A lustrous grey metalloid, it is found in nature mainly as the sulfide mineral stibnite...
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
The Madness of King George
The Madness of King George is a 1994 film directed by Nicholas Hytner and adapted by Alan Bennett from his own play, The Madness of George III. It tells the true story of George III's deteriorating mental health, and his equally declining relationship with his son, the Prince of Wales, particularly...
, a 1994 British film based upon the 1991 Alan Bennett
Alan Bennett
Alan Bennett is a British playwright, screenwriter, actor and author. Born in Leeds, he attended Oxford University where he studied history and performed with The Oxford Revue. He stayed to teach and research mediaeval history at the university for several years...
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
Princess Charlotte of Prussia
Princess Charlotte of Prussia , Duchess of Saxe-Meiningen was the second child born to Prince Friedrich of Prussia and Princess Victoria...
(Emperor William II
William II, German Emperor
Wilhelm II was the last German Emperor and King of Prussia, ruling the German Empire and the Kingdom of Prussia from 15 June 1888 to 9 November 1918. He was a grandson of the British Queen Victoria and related to many monarchs and princes of Europe...
's eldest sister) and her daughter Princess Feodora of Saxe-Meiningen
Princess Feodora of Saxe-Meiningen
Princess Feodora of Saxe-Meiningen was born at Potsdam, was the only child of Bernhard III, Duke of Saxe-Meiningen and his wife Charlotte of Prussia...
. They had more success in being able to uncover reliable evidence that George III's great-great-great-grandson Prince William of Gloucester
Prince William of Gloucester
Prince William of Gloucester was a member of the British Royal Family, a grandson of George V.-Early life:...
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
James V of Scotland
James V was King of Scots from 9 September 1513 until his death, which followed the Scottish defeat at the Battle of Solway Moss...
; both father and daughter endured well-documented attacks that some believe fall within the constellation of symptoms of porphyria.
Vlad III the Impaler
Vlad III the Impaler
Vlad III, Prince of Wallachia , also known by his patronymic Dracula , and posthumously dubbed Vlad the Impaler , was a three-time Voivode of Wallachia, ruling mainly from 1456 to 1462, the period of the incipient Ottoman conquest of the Balkans...
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
Vincent van Gogh
Vincent Willem van Gogh , and used Brabant dialect in his writing; it is therefore likely that he himself pronounced his name with a Brabant accent: , with a voiced V and palatalized G and gh. In France, where much of his work was produced, it is...
may have suffered from acute intermittent porphyria. It has also been imagined that King Nebuchadnezzar of Babylon suffered from some form of porphyria (cf. Daniel 4). 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
Isabel Allende
Isabel Allende Llona is a Chilean writer with American citizenship. Allende, whose works sometimes contain aspects of the "magic realist" tradition, is famous for novels such as The House of the Spirits and City of the Beasts , which have been commercially successful...
, fell into a porphyria-induced coma in 1991 which inspired Isabel Allende to write the autobiographical book Paula
Paula (novel)
Paula is a 1995 memoir written by Isabel Allende. She intended to write a straightforward narrative about the darkest experience of her life...
, dedicated to her daughter.