Porphyria

Porphyria
ICD-10	E80.0-E80.2
ICD-9	277.1
MedlinePlus	001208
MeSH	C17.800.849.617

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Overview

Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway (also called porphyrin pathway). They are broadly classified as hepatic porphyrias or erythropoietic porphyrias, based on the site of the overproduction and mainly accumulation of the porphyrins (or their chemical precursors). They manifest with either skin problems or with neurological complications (or occasionally both).

The term derives from the Greek πορφύρα, porphura, meaning "purple pigment". The name is likely to have been a reference to the purple discolouration of some body fluids in patients during an attack. Although original descriptions are attributed to Hippocrates, the disease was first explained biochemically by Felix Hoppe-Seyler in 1874, and acute porphyrias were described by the Dutch physician B.J. Stokvis in 1889.

Epidemiology and Demographics

The acute attack is 5 times more common in females.

Risk Factors

The two most common precipitants are drugs and menstrual cycle. Alcohol, infection, steroid hormones and fasting are also known precipitants.

Pathophysiology & Etiology

Types of Porphyria

The 8 porphyrias are:

1. Acute intermittent Porphyria (AIP)
2. ALA dehydratase deficiency
3. Porphyria cutanea tarda (PCT)
4. Congenital Erythropoetic Porphyria (CEP)
5. Hepatoerythropoetic Porphyria (HEP)
6. Erythopoetic Protoporphyria (EPP)
7. Hereditary coproporphyria (HCP)
8. Variegate Porphyria (VP)

These disorders can also be divided based on the type of precursors that accumulate and the subsequent manifestations that occur. ALA dehydratase deficiency (Plumboporphyria) and AIP are characterized by the accumulation of -aminolevulinic acid (ALA) and Porphobilinogen (PBG). Their manifestations are primarily neuropathic. PCT, CEP, HEP and EEP are characterized by accumulation of porphyrin and have cutaneous manifestations only. HCP and VP have accumulation of porphyrin precursors and porphyrins. They have both neuropathic and cutaneous manifestations.

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

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

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. All other porphyrias are either skin- or nerve-predominant.

Enzyme	Location of enzyme	Associated porphyria	Type of porphyria
δ-aminolevulinate (ALA) synthase	Mitochondrion	X-linked sideroblastic anemia (XLSA)	Erythropoietic
δ-aminolevulinate (ALA) dehydratase	Cytosol	Doss porphyria/ALA dehydratase deficiency	Hepatic
hydroxymethylbilane (HMB) synthase (or PBG deaminase)	Cytosol	acute intermittent porphyria (AIP)	Hepatic
uroporphyrinogen (URO) synthase	Cytosol	Congenital erythropoietic porphyria (CEP)	Erythropoeitic
uroporphyrinogen (URO) decarboxylase	Cytosol	Porphyria cutanea tarda (PCT)	Hepatic
coproporphyrinogen (COPRO) oxidase	Mitochondrion	Hereditary coproporphyria (HCP)	Hepatic
protoporphyrinogen (PROTO) oxidase	Mitochondrion	Variegate porphyria (VP)	Mixed
Ferrochelatase	Mitochondrion	Erythropoietic protoporphyria (EPP)	Erythropoietic

Genetics

Evaluation of family members is necessary to identify latent porphyria. All acute porphyrias are autosomal dominant except for ALA-D which is autosomal recessive.

Diagnosis

Signs and symptoms

Acute porphyria

The cutaneous sensitivity to light is due to excitation of accumulated porphyrins in the skin by UV light. This leads to progressive damage, scarring and deformation.

The “ Acute porphyrias ”: AIP, VP, CP and ALA-dehydratase deficiency are characterized by acute attacks . The acute attack is characterized by:

• Severe abdominal pain (90%), back, buttock and thigh pain.
• Autonomic dysfunction: tachycardia, hypertension, ileus, bladder dysfunction, vomiting, sweating
• Dehydration is common.
• Seizures
• Hyponatremia (thought to be caused by ADH) can be severe.
• Motor neuropathies predominate but almost any neuropathy can be seen. The neuropathic effects can progress and become severe leading to irreversible neurologic damage, a Guillian-Barre type syndrome with paralysis, bulbar dysfunction, respiratory failure and death.

The hepatic porphyrias primarily affect the nervous system, resulting in abdominal pain, vomiting, acute neuropathy, seizures and mental disturbances, including hallucinations, depression, anxiety and paranoia. Cardiac arrhythmias and tachycardia (fast 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 uncommon 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 scenarios. Lupus erythematosus features photosensitivity, 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 signs of their conditions, such as jaundice.

Attacks of the disease can be triggered by drugs (e.g. barbiturates, alcohol, sulfa drugs, hormonal contraception, sedatives and certain antibiotics), other chemicals and certain foods. Fasting can also trigger attacks.

Patients with hepatic porphyrias (PCT, 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, such as hepatitis B or C, iron overload or alcoholic cirrhosis.

Cutaneous porphyria

The erythropoietic porphyrias primarily affect the skin, causing photosensitivity (photodermatitis), blisters, necrosis of the skin and gums, itching, and swelling, and increased hair growth on areas such as the forehead. Often there is no abdominal pain which distinguishes 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 pink urine may be seen. Heme precursors may also accumulate in the teeth and fingernails, giving them a reddish appearance.

Electrolyte and Biomarker Studies

Increased urinary PBG is diagnostic. ALA is somewhat increased. Screening test is Watson-Schwartz test. PBG reacts with Ehrlich’s reagent in acidic solution to form red pigment. ALA-D will only have an elevation of ALA. A negative test rules out porphyria. The results can be confirmed with a quantitative test for fecal and plasma porphyrins and a 24 hour urine sample. The type of acute porphyria is determined based on measurement of fecal and plasma porphyrins. HCP and VP will have coproporphyrin III in feces. VP will also have protoporphyrin and plasma will have an emission peak at 624-26 nm on fluorescence spectroscopy.

Porphyria is diagnosed through spectroscopy 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 lead poisoning or hereditary tyrosinemia type I.

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 postpuberty 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.

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.

Treatment

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 glucose 10% infusion is commenced, which may aid in recovery.

Hematin and heme arginate 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 this drug are maintained at two national centers. In the United States, one company manufactures Panhematin for infusion. The American Porphyria Foundation has information regarding the quick procurement of the drug.

Any sign of low blood sodium (hyponatremia) or weakness should be treated with the addition of hematin or heme arginate 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 extremely severe, frequently out of proportion to physical signs and almost always requires the use of opiates to reduce it to tolerable levels. Pain should be treated early as medically possible due to its severity. Nausea can be severe; it may respond to phenothiazine drugs but is sometimes intractable. Hot water baths/showers may lessen nausea temporarily, though caution should be used to avoid burns or falls.

Early identification

Patients with a history of acute porphyria and even genetic carriers are recommended to wear an alert bracelet or other identification at all times in case they develop severe symptoms or in case of accidents where there is a potential for drug exposure: a result of which may be they cannot explain to healthcare professionals about their condition and the fact that some drugs are absolutely contraindicated.

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 opioids may be indicated. Some cases of chronic pain can be difficult to manage and may require treatment using multiple modalities. Opioid dependence may develop.

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 pharmacotherapeutic scope.

Seizures

Seizure often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: barbiturates especially must be avoided. Some benzodiazepines are safe, and, when used in conjunction with newer anti-seizure medications such as gabapentin offer a possible regime for seizure control.

Magnesium sulfate and bromides have also been used in porphyria seizures, however, development of status epilepticus in porphyria may not respond to magnesium alone. The addition of hematin or heme arginate has been used during status epilepticus.

Underlying liver disease

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.

Erythropoietic porphyrias

These are associated with accumulation of porphyrins in erthrocytes and are rare. The rarest is Congenital erythropoetic porphyria (C.E.P) otherwise known as Gunther's disease. Its rarity is partially due to its autosomal recessive mode of inheritance. 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. Haemolytic anaemia usually develops. Pharmaceutical-grade beta carotene may be used in its treatment.

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.

Culture and history

Porphyrias have been detected in all races, multiple ethnic groups on every continent including Caucasians, Asians, Africans, Peruvian/Mexican Hispanics, Native Americans, Laplanders and Australian aborigines. 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 Scandinavian source of porphyria has been traced to the Sámi ethnic group. Their language, as well as the languages of Finland, Estonia, Hungary, Transylvania, and Bulgaria have ties to languages in small groups of people living in Russia on both sides of the Urals and are branches of Uralic languages and Altaic languages (the Finno-Ugric Languages).

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 uselessly and inappropriately treated with electroshock.

Vampires and werewolves

Porphyria has been suggested as an explanation for the origin of vampire and werewolf legends, based upon a number of similarities between the condition and the folklore that was first speculated upon by biochemist David Dolphin in 1985. His ruminations gave rise to a popular urban legend which accepts this association as factual, though it is historically and factually baseless. Porphyria cutanea tarda presents clinically as a pathological sensitivity of skin exposed to light causing scarring, hair growth and disfiguration. Additionally, it was believed that the patients' missing heme could be absorbed through the stomach, correlating with the legends' hematophagy.

Historical patients

The insanity exhibited by King George III 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. 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. The insanity 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 include the comment that the illness suffered by King George has been attributed to porphyria.

It is suspected that Mary, Queen of Scots--George III's grandmother six times removed--also suffered from acute intermittent porphyria, although this is subject to much debate. It is assumed she inherited the disorder, if 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.

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). The symptoms of the various porphyrias are so wide-ranging that nearly any constellation of symptoms can be attributed to one or more of them.

The poet Robert Browning, also, notoriously wrote a poem called Porphyria's Lover, which aside from a literal interpretation of the word also compares love itself to a form of disorder.

Paula Frias 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.

References

• Kauppinen R. Porphyrias. Lancet 2005;365:241-52. PMID 15652607.

Acknowledgements

Source of Initial Content: Resident report notes prepared by Duane S. Pinto, M.D. and Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]

External links

• American Porphyria Foundation
• European Porphyria Initiative
• Porphynet - site on porphyrins and the porphyrias
• The Drug Database for Acute Porphyria - comprehensive database on drug porphyrinogenicity

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