| Porphyria | |
|---|---|
 | |
| Left figure is urine on the first day while the right figure is urine after three days of sun exposure showing the classic change in color to purple. | |
| Pronunciation | |
| 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 (/pɔːrˈfɪriə/ or/pɔːrˈfaɪriə/) is a group of disorders in which substances calledporphyrins build up in the body, adversely 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 that makeheme.[2] They may be inherited in anautosomal dominant,autosomal recessive, orX-linked dominant manner.[1] One type,porphyria cutanea tarda, may also be due tohemochromatosis (increased 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] Hepatic porphyrias are those in which the enzyme deficiency occurs in the liver. Hepatic porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), aminolevulinic acid dehydratase deficiency porphyria (ALAD), hereditary coproporphyria (HCP), and porphyria cutanea tarda.[5]
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 prevalence 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.[6] The underlying mechanism was first described by German physiologist and chemistFelix Hoppe-Seyler in 1871.[6] The nameporphyria is from theGreek πορφύρα,porphyra, meaning "purple", a reference to the color of the urine that may be present during an attack.[6]
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Acute 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.[citation needed]
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.[7] Elevation of aminolevulinic acid from lead-induced disruption of heme synthesis results in lead poisoning having symptoms similar to acute porphyria.[8][9][10][11][12][13]
The non-acute porphyrias are X-linked dominant protoporphyria (XLDPP), congenitalerythropoietic porphyria (CEP),porphyria cutanea tarda (PCT), anderythropoietic protoporphyria (EPP). None of these is 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:
The porphyrias are generally considered genetic in nature.[citation needed]
Subtypes of porphyrias depend on which enzyme is deficient.
| Porphyria type | Deficientenzyme | Type of porphyria | Inheritance | Symptoms | Prevalence |
|---|---|---|---|---|---|
| Aminolevulinate dehydratase deficiency porphyria (ALADP) | 5-aminolevulinate dehydratase (ALAD) | Hepatic | Autosomal recessive[14] | Abdominal pain, neuropathy[14] | Extremely rare; fewer than 10 cases ever reported.[15] |
| Acute intermittent porphyria (AIP) | Hydroxymethylbilane synthase (HMBS) formerly porphobilinogen deaminase (PBGD) | Hepatic | Autosomal dominant[14] | Periodic abdominal pain,peripheral neuropathy, psychiatric disorders, tachycardia[14] | 1 in 10,000[16]–20,000[16] |
| Congenital erythropoietic porphyria (CEP) | uroporphyrinogen synthase (UROS) | Erythropoietic | Autosomal recessive[14] | Severe photosensitivity with erythema, swelling and blistering. Hemolytic anemia,splenomegaly[14] | 1 in 1,000,000 or less.[17] |
| Porphyria cutanea tarda (PCT) | uroporphyrinogen decarboxylase (UROD) | Hepatic | Approximately 80% sporadic,[18] 20%Autosomal dominant[14] | Photosensitivity withvesicles andbullae[14] | 1 in 10,000[19] |
| Hereditary coproporphyria (HCP) | coproporphyrinogen oxidase (CPOX) | Hepatic | Autosomal dominant[14] | Photosensitivity, neurologic symptoms,colic[14] | 1 in 500,000[19] |
| Harderoporphyria | coproporphyrinogen oxidase (CPOX) | Erythropoietic | Autosomal recessive[14] | Jaundice, anemia, enlarged liver and spleen, often neonatal. Photosensitivity later. | Extremely rare; fewer than 10 cases ever reported. |
| Variegate porphyria (VP) | protoporphyrinogen oxidase (PPOX) | Hepatic | Autosomal dominant[20] | Photosensitivity, neurologic symptoms, developmental delay | 1 in 300 in South Africa[19] 1 in 75,000 in Finland[21] |
| Erythropoietic protoporphyria (EPP) | ferrochelatase (FECH) | Erythropoietic | Autosomal recessive[14] | Photosensitivity with skin lesions. Gallstones, mild liver dysfunction[14] | 1 in 75,000[19]–200,000[19] |
X-linked dominant protoporphyria is a rare form oferythropoietic protoporphyria caused by a gain-of-functionmutation inALAS2 characterized by severephotosensitivity.[22][23]
In the autosomal recessive types, anyone who inherit a single gene may become a carrier. Generally they do not have symptoms but may pass the gene on to offspring.[24]
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 that are made with heme. Such drugs include:[25][26][27]
Inhumans,porphyrins are the main precursors ofheme, an essential constituent ofhemoglobin,myoglobin,catalase,peroxidase, and P450 livercytochromes.[28]
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.[29]
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).[citation needed]
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.[30]
Porphyria is diagnosed through biochemical analysis ofblood,urine, andstool.[17][31] 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.[32] 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.[33] 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.[34]
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.[17] 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.[17]
If all the porphyrin studies are negative, one must considerpseudoporphyria. A careful medication review often will find the cause of pseudoporphyria.[citation needed]
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.[35]
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 cases of low blood sodium levels (hyponatraemia) and should be done with extreme caution as it can prove fatal.[36]
Hematin (trade name Panhematin) andheme 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 fromSt Thomas's Hospital, London.[37] In the United States,Lundbeck manufactures and supplies Panhematin for infusion.[38]
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 has also been reported to be effective for acute porphyric crisis and possibly effective for long-term prophylaxis.[39]
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 scalds or falls.[citation needed]
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.[40]
Patients who experience frequent attacks can develop chronicneuropathic pain in extremities as well as chronic pain in theabdomen.[41]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.[42]
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.[42]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.[43]
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.[44]
Some liver diseases may cause porphyria even in the absence of genetic predisposition. These includehemochromatosis andhepatitis C. Treatment of iron overload may be required.[2]
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.[2]
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.[45] In 2019,givosiran was approved in the United States for the treatment of acute hepatic porphyria.[46][47]
These are associated with accumulation of porphyrins in erythrocytes and are rare.
The pain, burning, swelling, and itching that occur in erythropoietic porphyrias (EP) 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.[17]Blood transfusion is occasionally used to suppress innate heme production.[citation needed]
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.[48] A bone marrow transplant has also been successful in curing CEP in a few cases, although long-term results are not yet available.[49]
In December 2014,afamelanotide received authorization from theEuropean Commission as a treatment for the prevention ofphototoxicity in adult patients with EPP.[50] In a 2023 industry-funded phase 2 trial, dersimelagon, an orally administered, selective melanocortin 1 receptor agonist that increases levels of skin eumelanin, was reported to have increased the duration of symptom-free sunlight exposure and quality of life compared to placebo in patients with erythropoietic protoporphyria.[51]
Rates of all types of porphyria taken together have been estimated to be approximately one in 25,000 in the United States.[52] The worldwide prevalence has been estimated to be between one in 500 and one in 50,000 people.[53]
Porphyrias have been detected in all races and in many 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.[citation needed]
The underlying mechanism was first described by the German physiologistFelix Hoppe-Seyler in 1871,[54] and acute porphyrias were described by the Dutch physicianBarend Stokvis in 1889.[55][56]
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"[57]) and severe symptoms of depression or catatonia were treated withelectroshock therapy.
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 bookVampires. 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 nor the disease and as potentially stigmatizing people with porphyria.[58][59]
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"), whereas owing 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 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.[60]
Stated or implied references to porphyria are included in some literature, particularly gothic literature. These include the following:
Indeed, lead poisoning, like all porphyrin diseases, is accompanied by obstinate constipation, nervous lesions, hyperpigmentation and abdominal attacks.
the symptoms in lead poisoning closely mimic those of acute porphyria
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