Porphyria
Left figure is urine on the first day while the right figure is urine after three days of sun exposures showing the classic change in color to purple.
Pronunciation	/pɔːrˈfɪriə/ or/pɔːrˈfaɪriə/
Specialty	Hematology,dermatology,neurology
Symptoms	Depending on subtype—abdominal pain,chest pain,vomiting, confusion,constipation,fever,seizures,blisters with sunlight[1][2]
Usual onset	Recurrent attacks that last days to weeks[2]
Causes	Usuallygenetic[2]
Diagnostic method	Blood, urine, and stool tests,genetic testing[2]
Differential diagnosis	Lead poisoning,alcoholic liver disease[3]
Treatment	Depends on type and symptoms[2]
Frequency	1 to 100 in 50,000 people[1]

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

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

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

The precise frequency of porphyria is unclear, but it is estimated to affect between 1 and 100 per 50,000 people.^[1] Rates are different around the world.^[2] Porphyria cutanea tarda is believed to be the most common type.^[1] The disease was described as early as 370 BC byHippocrates.^[5] The underlying mechanism was first described by German physiologist and chemistFelix Hoppe-Seyler in 1871.^[5] The nameporphyria is from theGreek πορφύρα,porphyra, meaning "purple", a reference to the color of the urine that may be present during an attack.^[5]

Signs and symptoms

Acute porphyrias

The acute porphyrias areacute intermittent porphyria (AIP),variegate porphyria (VP),aminolevulinic acid dehydratase deficiency porphyria (ALAD) andhereditary coproporphyria (HCP). These diseases primarily affect thenervous system, resulting in episodic crises known as acute attacks. The major symptom of an acute attack isabdominal pain, often accompanied byvomiting,hypertension (elevated blood pressure), andtachycardia (an abnormally rapid heart rate).^[4]

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

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

Chronic porphyrias

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

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

Two distinct patterns of skin disease are seen in porphyria:

• Immediate photosensitivity. This is typical of XLDPP and EPP. Following a variable period ofsun exposure—typically about 30 minutes—patients complain of severe pain, burning, and discomfort in exposed areas. Typically, the effects are not visible, though occasionally there may be some redness and swelling of the skin.
• Vesiculo-erosive skin disease. This—a reference to the characteristicblistering (vesicles) and open sores (erosions) noted in patients—is the pattern seen in CEP, PCT, VP, and HCP. The changes are noted only in sun-exposed areas such as the face and back of the hands. Milder skin disease, such as that seen in VP and HCP, consists of increased skin fragility in exposed areas with a tendency to form blisters and erosions, particularly after minor knocks or scrapes. These heal slowly, often leaving small scars that may be lighter or darker than normal skin. More severe skin disease is sometimes seen in PCT, with prominent lesions, darkening of exposed skin such as the face, andhypertrichosis: abnormal hair growth on the face, particularly the cheeks. The most severe disease is seen in CEP and a rare variant of PCT known ashepatoerythropoietic porphyria (HEP); symptoms include severe shortening of digits, loss of skin appendages such as hair and nails, and severe scarring of the skin with progressive disappearance of ears, lips, and nose. Patients may also show deformed, discolored teeth or gum and eye abnormalities.

Cause

The porphyrias are generally considered genetic in nature.^{[citation needed]}

Genetics

Subtypes of porphyrias depend on which enzyme is deficient.

In the autosomal recessive types, if a person inherits a single gene they may become a carriers. Generally they do not have symptoms, but may pass the gene onto offspring.^[17]

Triggers

Acute porphyria can be triggered by a number of drugs, most of which are believed to trigger it by interacting with enzymes in the liver which are made with heme. Such drugs include:^[18][19][20]

• Sulfonamides, includingsulfadiazine,sulfasalazine andtrimethoprim/sulfamethoxazole.
• Sulfonylureas likeglibenclamide,gliclazide andglimepiride, althoughglipizide is thought to be safe.
• Barbiturates includingthiopental,phenobarbital,primidone, etc.
• Systemic treatment withantifungals includingfluconazole,griseofulvin,ketoconazole andvoriconazole. (Topical use of these agents is thought to be safe due to minimal systemic absorption.)
• Certainantibiotics likerifapentine,rifampicin,rifabutine,isoniazid,nitrofurantoin and, possibly,metronidazole.
• Ergot derivatives includingdihydroergotamine,ergometrine,ergotamine,methysergide, etc.
• Certainantiretroviral medications (e.g.indinavir,nevirapine,ritonavir,saquinavir, etc.)
• Progestogens
• Someanticonvulsants including:carbamazepine,ethosuximide,phenytoin,topiramate,valproate.
• Somepainkillers likedextropropoxyphene,ketorolac,metamizole,pentazocine
• Some cancer treatments likebexarotene,busulfan,chlorambucil,estramustine,etoposide,flutamide,idarubicin,ifosfamide,irinotecan,ixabepilone,letrozole,lomustine,megestrol,mitomycin,mitoxantrone,paclitaxel,procarbazine,tamoxifen,topotecan
• Someantidepressants likeimipramine,phenelzine,trazodone
• Someantipsychotics likerisperidone,ziprasidone
• Someretinoids used for skin conditions likeacitretin andisotretinoin
• Miscellaneous others including:cocaine,methyldopa,fenfluramine,disulfiram,orphenadrine,pentoxifylline, andsodium aurothiomalate.

Pathogenesis

Inhumans,porphyrins are the main precursors ofheme, an essential constituent ofhemoglobin,myoglobin,catalase,peroxidase, and P450 livercytochromes.^{[citation needed]}

The body requires porphyrins to produceheme, which is used to carry oxygen in the blood among other things, but in the porphyrias there is a deficiency (inherited or acquired) of theenzymes that transform the various porphyrins into others, leading to abnormally high levels of one or more of these substances. Porphyrias are classified in two ways, by symptoms and by pathophysiology. Physiologically, porphyrias are classified as liver or erythropoietic based on the sites of accumulation ofheme precursors, either in theliver or in thebone marrow andred blood cells.^[21]

Deficiency in theenzymes of the porphyrin pathway leads to insufficient production ofheme.Heme function plays a central role in cellularmetabolism. This is not the main problem in the porphyrias; mosthemesynthesisenzymes—even dysfunctionalenzymes—have enough residual activity to assist inheme biosynthesis. The principal problem in these deficiencies is the accumulation ofporphyrins, theheme precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine the location of accumulation, whether they inducephotosensitivity, and whether the intermediate is excreted (in theurine orfeces).

There are eightenzymes in theheme biosynthetic pathway, four of which—the first one and the last three—are in themitochondria, while the other four are in thecytosol. Defects in any of these can lead to some form of porphyria.Thehepatic porphyrias are characterized by acute neurological attacks (seizures,psychosis, extremeback andabdominal pain, and an acutepolyneuropathy), while theerythropoietic forms present with skin problems, usually a light-sensitive blistering rash andincreased hair growth.Variegate porphyria (alsoporphyria variegata ormixed porphyria), which results from a partial deficiency inPROTO oxidase, manifests itself with skin lesions similar to those ofporphyria cutanea tarda combined with acute neurologic attacks.Hereditary coproporphyria, which is characterized by a deficiency in coproporphyrinogen oxidase, coded for by the CPOX gene, may also present with both acute neurologic attacks and cutaneous lesions. All other porphyrias are either skin- or nerve-predominant.^{[citation needed]}

Diagnosis

Porphyrin studies

Porphyria is diagnosed through biochemical analysis ofblood,urine, andstool.^[12][22] In general, urine estimation ofporphobilinogen (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.^[23] In nearly all cases of acute porphyria syndromes, urinary PBG is markedly elevated except for the very rareALA dehydratase deficiency or in patients with symptoms due tohereditary tyrosinemia type I.^[24] In cases ofmercury- orarsenic poisoning-induced porphyria, other changes in porphyrin profiles appear, most notably elevations of uroporphyrins I & III, coproporphyrins I & III, and pre-coproporphyrin.^[25]

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 ofacute intermittent porphyria.^{[citation needed]}

Up to 90% of the genetic carriers of the more common, dominantly inherited acute hepatic porphyrias (acute intermittent porphyria, hereditarycoproporphyria, variegate porphyria) have been noted in DNA tests to be latent for classic symptoms and may requireDNA orenzyme testing. The exception to this may be latent post-puberty genetic carriers of hereditarycoproporphyria.^{[citation needed]}

As most porphyrias arerare 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.^[12] All samples to detect porphyrins must be handled properly. Samples should be taken during an acute attack; otherwise afalse negative result may occur. Samples must be protected from light and either refrigerated or preserved.^[12]

If all the porphyrin studies are negative, one must considerpseudoporphyria. A careful medication review often will find the cause of pseudoporphyria.

Additional tests

Further diagnostic tests of affected organs may be required, such asnerve conduction studies forneuropathy or anultrasound of the liver. Basic biochemical tests may assist in identifyingliver disease,hepatocellular carcinoma, and other organ problems.^{[citation needed]}

Management

Acute porphyria

Carbohydrate administration

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, adextrose 10% infusion is commenced, which may aid in recovery by suppressingheme synthesis, which in turn reduces the rate of porphyrin accumulation. However, this can worsen hyponatraemia and should be done with extreme caution as it can prove fatal.^[26]

Heme analogs

Hematin (trade name Panhematin) andheme arginate (trade name NormoSang) are the drugs of choice in acute porphyria, in theUnited States and theUnited 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 fromSt Thomas's Hospital, London.^[27] In the United States,Lundbeck manufactures and supplies Panhematin for infusion.^[28]

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

Any sign of low blood sodium (hyponatremia) or weakness should be treated with the addition of hematin, heme arginate, or eventin 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 tobulbar paresis and respiratory paralysis.^{[citation needed]}

Cimetidine

Cimetidine has also been reported to be effective for acute porphyric crisis and possibly effective for long-term prophylaxis.^[29]

Symptom control

Pain is severe, frequently out of proportion to physical signs, and often requires the use ofopiates to reduce it to tolerable levels. Pain should be treated as early as medically possible.Nausea can be severe; it may respond tophenothiazine drugs but is sometimes intractable. Hot baths and showers may lessen nausea temporarily, though caution should be used to avoid burns or falls.^{[citation needed]}

Early identification

It is recommended that patients with a history of acute porphyria, and even genetic carriers, wear analert 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 absolutelycontraindicated for patients with any form of porphyria.^[30]

Neurologic and psychiatric disorders

Patients who experience frequent attacks can develop chronicneuropathic pain in extremities as well as chronic pain in theabdomen.^[31]Intestinal pseudo-obstruction,ileus,intussusception, hypoganglionosis, andencopresis in children have been associated with porphyrias. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system and vagal nerve dysfunction. Pain treatment with long-actingopioids, such asmorphine, is often indicated, and, in cases where seizure or neuropathy is present,gabapentin is known to improve outcome.^[32]

Seizures often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic:barbiturates especially must be avoided. Somebenzodiazepines are safe and, when used in conjunction with newer anti-seizure medications such as gabapentin, offer a possible regimen for seizure control. Gabapentin has the additional feature of aiding in the treatment of some kinds of neuropathic pain.^[32]Magnesium sulfate and bromides have also been used in porphyria seizures; however, development ofstatus epilepticus in porphyria may not respond to magnesium alone. The addition ofhematin orheme arginate has been used duringstatus epilepticus.^[33]

Depression often accompanies the disease and is best dealt with by treating the offending symptoms and if needed the judicious use ofantidepressants. Some psychotropic drugs are porphyrinogenic, limiting the therapeutic scope. Other psychiatric symptoms such as anxiety, restlessness, insomnia, depression, mania, hallucinations, delusions, confusion, catatonia, and psychosis may occur.^[34]

Underlying liver disease

Some liver diseases may cause porphyria even in the absence of genetic predisposition. These includehemochromatosis andhepatitis C. Treatment of iron overload may be required.^[35]

Patients with the acute porphyrias (AIP,HCP,VP) are at increased risk over their life forhepatocellular carcinoma (primary liver cancer) and may require monitoring. Other typical risk factors for liver cancer need not be present.^[36]

Hormone treatment

Hormonal fluctuations that contribute to cyclical attacks in women have been treated with oral contraceptives andluteinizing hormones to shut down menstrual cycles. However, oral contraceptives have also triggered photosensitivity and withdrawal of oral contraceptives has triggered attacks.Androgens and fertility hormones have also triggered attacks.^{[citation needed]} In 2019,givosiran was approved in the United States for the treatment of acute hepatic porphyria.^[37][38]

Erythropoietic porphyria

These are associated with accumulation of porphyrins in erythrocytes and are rare.

The pain, burning, swelling, and itching that occur in erythropoietic porphyrias generally require avoidance of bright sunlight. Most kinds ofsunscreen 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.^[12]Blood transfusion is occasionally used to suppress innate heme production.

The rarest is congenital erythropoietic porphyria (CEP), otherwise known asGunther's disease. The signs may present from birth and include severe photosensitivity, brown teeth that fluoresce in ultraviolet light due to deposition of Type 1 porphyrins, and laterhypertrichosis. Hemolytic anemia usually develops. Pharmaceutical-gradebeta carotene may be used in its treatment.^[39] A bone marrow transplant has also been successful in curing CEP in a few cases, although long-term results are not yet available.^[40]

In December 2014,afamelanotide received authorization from theEuropean Commission as a treatment for the prevention ofphototoxicity in adult patients with EPP.^[41]

Epidemiology

Rates of all types of porphyria taken together have been estimated to be approximately one in 25,000 in theUnited States.^[42] The worldwide prevalence has been estimated to be between one in 500 and one in 50,000 people.^[43]

Porphyrias have been detected in all races and in multiple ethnic groups on every continent. There are high incidence reports of AIP in areas of India and Scandinavia. More than 200 genetic variants of AIP are known, some of which are specific to families, although some strains have proven to be repeated mutations.

History

The underlying mechanism was first described byFelix Hoppe-Seyler in 1871,^[44] and acute porphyrias were described by the Dutch physicianBarend Stokvis in 1889.^[45][46]

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"^[47]) and severe symptoms of depression or catatonia were treated withelectroshock therapy.

Vampires and werewolves

Porphyria has been suggested as an explanation for the origin ofvampire andwerewolf legends, based upon certain perceived similarities between the condition and thefolklore.

In January 1964, L. Illis's 1963 paper, "On Porphyria and theAetiology of Werewolves," was published inProceedings 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, biochemistDavid Dolphin's paper for theAmerican Association for the Advancement of Science, "Porphyria, Vampires, and Werewolves: The Aetiology of European Metamorphosis Legends," gained widespread media coverage, popularizing the idea.^{[citation needed]}

The theory has been rejected by a few folklorists and researchers as not accurately describing the characteristics of the original werewolf and vampire legends or the disease, and as potentially stigmatizing people with porphyria.^[48][49]

A 1995 article from thePostgraduate Medical Journal (viaNIH) explains:

As it was believed that the folkloric vampire could move about freely in daylight hours, as opposed to the 20th century variant, congenital erythropoietic porphyria cannot readily explain the folkloric vampire but may be an explanation of the vampire as we know it in the 20th century. In addition, the folkloric vampire, when unearthed, was always described as looking quite healthy ("as they were in life"), while due to disfiguring aspects of the disease, sufferers would not have passed the exhumation test. Individuals with congenital erythropoietic porphyria do not crave blood. The enzyme (hematin) necessary to alleviate symptoms is not absorbed intact on oral ingestion, and drinking blood would have no beneficial effect on the sufferer. Finally, and most important, the fact that vampire reports were literally rampant in the 18th century, and that congenital erythropoietic porphyria is an extremely rare manifestation of a rare disease, makes it an unlikely explanation of the folkloric vampire.^[50]

Notable cases

• King George III. The mental illness exhibited by George III in theregency crisis of 1788 has inspired several attempts atretrospective diagnosis. The first, written in 1855, thirty-five years after his death, concluded that he had acutemania. M. Guttmacher, in 1941, suggestedmanic-depressivepsychosis as a more likely diagnosis. The first suggestion that a physical illness was the cause of King George's mental derangement came in 1966, in a paper called "The Insanity of King George III: A Classic Case of Porphyria",^[51] with a follow-up in 1968, "Porphyria in the Royal Houses of Stuart, Hanover and Prussia".^[52] The papers, by a mother/sonpsychiatrist team, were written as though the case for porphyria had been proven, but the response demonstrated that many experts, including those more intimately familiar with the manifestations of porphyria, were unconvinced. Many psychiatrists disagreed with the diagnosis, suggesting bipolar disorder as far more probable. The theory is treated inPurple Secret,^[53] which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to have had it.^[54] In 2005, it was suggested thatarsenic (which is known to be porphyrogenic) given to George III withantimony may have caused his porphyria.^[55] This study found high levels of arsenic in King George's hair. In 2010, one analysis of historical records argued that the porphyria claim was based on spurious and selective interpretation of contemporary medical and historical sources.^[56] The mental illness of George III is the basis of the plot inThe Madness of King George, a 1994 British film based upon the 1991Alan Bennett play,The Madness of George III. The closing credits of the film include the comment that the King's symptoms suggest that he had porphyria and notes that the disease is "periodic, unpredictable, and hereditary".
• Descendants of George III. Among other descendants of George III theorized by the authors ofPurple Secret to have had porphyria (based on analysis of their extensive and detailed medical correspondence) were his great-great-granddaughterPrincess Charlotte of Prussia (Emperor William II's eldest sister) and her daughterPrincess Feodora of Saxe-Meiningen. They uncovered better evidence that George III's great-great-great-grandsonPrince William of Gloucester was reliably diagnosed with variegate porphyria.^[57]
• Mary, Queen of Scots. It is believed that Mary, Queen of Scots,King George III's ancestor, also had acute intermittent porphyria,^[58] although this is subject to much debate. It is assumed she inherited the disorder, if indeed she had it, from her father,James V of Scotland. Both father and daughter endured well-documented attacks that could fall within the constellation of symptoms of porphyria.
• Maria I of Portugal. Maria I—known as "Maria the Pious" or "Maria the Mad" because of both her religious fervor and her acute mental illness, which made her incapable of handling state affairs after 1792 – is also thought to have had porphyria.Francis Willis, the same physician who treated George III, was even summoned by the Portuguese court but returned to England after the court limited the treatments he could oversee. Contemporary sources, such as Secretary of State for Foreign AffairsLuís Pinto de Sousa Coutinho, noted that the queen had ever-worsening stomach pains and abdominal spasms: hallmarks of porphyria.^[59]
• Vlad III. Vlad III was also said to have had acute porphyria, which may have started the notion that vampires were allergic to sunlight.^[60]
• Vincent van Gogh. Other commentators have suggested that Vincent van Gogh may have had acute intermittent porphyria.^[61]
• King Nebuchadnezzar of Babylon. The description of this king inDaniel 4 suggests to some that he had porphyria.^[62]
• PhysicianArchie Cochrane. He was born with porphyria, which caused health problems throughout his life.^[63]
• Paula Frías Allende. The daughter of the Chilean novelistIsabel Allende, she fell into a porphyria-induced coma in 1991,^[64] which inspired Isabel to write the memoirPaula, dedicated to her.

References

External links

• Porphyria atCurlie
• The Drug Database for Acute Porphyria - comprehensive database on drug porphyrinogenicityArchived 23 August 2017 at theWayback Machine
• Orphanet's disease page on PorphyriaArchived 28 June 2020 at theWayback Machine

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