Editing Porphyria

{{short description|Metabolic disorders in which porphyrins build up in the body}}
{{about|the medical condition||Porphyry (disambiguation)}}
{{distinguish|Porphyra|Porphyrio}}
{{Use dmy dates|date=April 2014}}
{{Infobox medical condition (new)
| name            = Porphyria
| image           = Urine of patient with porphyria.png
| caption         = 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.
| field           = [[Hematology]], [[dermatology]], [[neurology]]
| pronounce       = {{IPAc-en|p|ɔːr|ˈ|f|ɪr|i|ə}} or {{IPAc-en|p|ɔːr|ˈ|f|aɪ|r|i|ə}}
| symptoms        = Depending on subtype—[[abdominal pain]], [[chest pain]], [[vomiting]], confusion, [[constipation]], [[fever]], [[seizure]]s, [[blister]]s with sunlight<ref name=NIH2009GHR/><ref name=NIDDK/>
| complications   =
| onset           = Recurrent attacks that last days to weeks<ref name=NIDDK/>
| duration        =
| causes          = Usually [[genetics|genetic]]<ref name=NIDDK/>
| risks           =
| diagnosis       = Blood, urine, and stool tests, [[genetic testing]]<ref name=NIDDK/>
| differential    = [[Lead poisoning]], [[alcoholic liver disease]]<ref>{{cite book |last1=Dancygier |first1=Henryk |title=Clinical Hepatology: Principles and Practice of Hepatobiliary Diseases |date=2009 |publisher=Springer Science & Business Media |isbn=9783642045196 |page=1088 |url=https://books.google.com/books?id=lrPX8C4p90QC&pg=PA1088 |url-status=live |archive-url=https://web.archive.org/web/20170908185104/https://books.google.com/books?id=lrPX8C4p90QC&pg=PA1088 |archive-date=8 September 2017 |df=dmy-all}}</ref>
| prevention      =
| treatment       = Depends on type and symptoms<ref name=NIDDK/>
| medication      =
| prognosis       =
| frequency       = 1 to 100 in 50,000 people<ref name=NIH2009GHR/>
| deaths          =
}}
<!-- Definition and symptoms -->
'''Porphyria''' ({{IPAc-en|p|ɔːr|ˈ|f|ɪr|i|ə}} or {{IPAc-en|p|ɔːr|ˈ|f|aɪ|r|i|ə}}) is a group of disorders in which substances called [[porphyrin]]s build up in the body, adversely affecting the skin or [[nervous system]].<ref name=NIH2009GHR/> The types that affect the nervous system are also known as [[Porphyria#Acute porphyrias|acute porphyria]], as symptoms are rapid in onset and short in duration.<ref name=NIH2009GHR/> Symptoms of an attack include [[abdominal pain]], [[chest pain]], [[vomiting]], confusion, [[constipation]], [[fever]], [[hypertension|high blood pressure]], and [[tachycardia|high heart rate]].<ref name=NIH2009GHR/><ref name=NIDDK/><ref name=Stein2017/> The attacks usually last for days to weeks.<ref name=NIDDK/> Complications may include [[paralysis]], [[hyponatraemia|low blood sodium levels]], and [[seizure]]s.<ref name=Stein2017>{{cite journal |last1=Stein |first1=PE |last2=Badminton |first2=MN |last3=Rees |first3=DC |title=Update review of the acute porphyrias |journal=British Journal of Haematology|date=February 2017|volume=176|issue=4|pages=527–538|doi=10.1111/bjh.14459|pmid=27982422|s2cid=19970176 |doi-access=free }}</ref> Attacks may be triggered by [[Alcohol (drug)|alcohol]], [[smoking]], hormonal changes, fasting, stress, or certain medications.<ref name=NIDDK/><ref name="Stein2017"/> If the skin is affected, [[blister]]s or itching may occur with sunlight exposure.<ref name=NIDDK/>

<!-- Cause -->
Most types of porphyria are inherited from one or both of a person's parents and are due to a [[mutation]] in one of the [[gene]]s that make [[heme]].<ref name=NIDDK/> They may be inherited in an [[autosomal dominant]], [[autosomal recessive]], or [[X-linked dominant]] manner.<ref name=NIH2009GHR/> One type, ''[[porphyria cutanea tarda]]'', may also be due to [[hemochromatosis]] (increased iron in the liver), [[hepatitis C]], alcohol, or [[HIV/AIDS]].<ref name=NIH2009GHR/> The underlying mechanism results in a decrease in the amount of [[heme]] produced and a build-up of substances involved in making heme.<ref name=NIH2009GHR /> Porphyrias may also be classified by whether the liver or [[bone marrow]] is affected.<ref name=NIH2009GHR/> Diagnosis is typically made by blood, urine, and stool tests.<ref name=NIDDK/> [[Genetic testing]] may be done to determine the specific mutation.<ref name=NIDDK/> 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.<ref>{{Citation |last=Kothadia |first=Jiten P. |title=Acute Hepatic Porphyria |date=2024 |work=StatPearls |url=http://www.ncbi.nlm.nih.gov/books/NBK537178/ |access-date=2024-03-31 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30725863 |last2=LaFreniere |first2=Kilian |last3=Shah |first3=Jamil M.}}</ref>

<!-- Treatment -->
Treatment depends on the type of porphyria and the person's symptoms.<ref name=NIDDK/> Treatment of porphyria of the skin generally involves the avoidance of sunlight, while treatment for acute porphyria may involve giving intravenous heme or a [[glucose]] solution.<ref name=NIDDK/> Rarely, a [[liver transplant]] may be carried out.<ref name=NIDDK/>

<!-- Epidemiology, history, and culture -->
The precise prevalence of porphyria is unclear, but it is estimated to affect between 1 and 100 per 50,000 people.<ref name=NIH2009GHR/> Rates are different around the world.<ref name=NIDDK/> Porphyria cutanea tarda is believed to be the most common type.<ref name=NIH2009GHR>{{cite web|title=porphyria|url=https://medlineplus.gov/genetics/condition/porphyria/|website=[[MedlinePlus]]|access-date=31 March 2021|date=July 2009}}</ref> The disease was described as early as 370 BC by [[Hippocrates]].<ref name=McM2014/> The underlying mechanism was first described by German physiologist and chemist [[Felix Hoppe-Seyler]] in 1871.<ref name=McM2014/> The name ''porphyria'' is from the [[Greek language|Greek]] πορφύρα, ''porphyra'', meaning "[[purple]]", a reference to the color of the urine that may be present during an attack.<ref name=McM2014>{{cite book|last1=McManus|first1=Linda|title=Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease Mechanisms|date=2014|publisher=Elsevier|isbn=9780123864574|page=1488|url=https://books.google.com/books?id=uQB0AwAAQBAJ&pg=PA1488|url-status=live|archive-url=https://web.archive.org/web/20170908185105/https://books.google.com/books?id=uQB0AwAAQBAJ&pg=PA1488|archive-date=8 September 2017|df=dmy-all}}</ref>
{{TOC limit|3}}

==Signs and symptoms==
{{More citations needed section|date = January 2016}}
[[File:Prfr1.jpg|thumb|A skin rash in a person with porphyria]]

===Acute porphyrias===
[[Acute intermittent porphyria]] (AIP), [[variegate porphyria]] (VP), [[aminolevulinic acid dehydratase deficiency porphyria]] (ALAD) and [[hereditary coproporphyria]] (HCP). These diseases primarily affect the [[nervous system]], resulting in episodic crises known as acute attacks. The major symptom of an acute attack is [[abdominal pain]], often accompanied by [[vomiting]], [[hypertension]] (elevated blood pressure), and [[tachycardia]] (an abnormally rapid heart rate).<ref name=Stein2017/>

The most severe episodes may involve neurological complications: typically motor neuropathy (severe dysfunction of the peripheral nerves that innervate muscle), which leads to muscle weakness and potentially to [[Tetraplegia|quadriplegia]] (paralysis of all four limbs) and [[central nervous system]] symptoms such as [[seizure]]s and [[coma]]. Occasionally, there may be short-lived psychiatric symptoms such as anxiety, confusion, [[hallucination]]s, and, very rarely, overt psychosis. All these symptoms resolve once the acute attack passes.{{citation needed|date=March 2021}}

Given the many presentations and the relatively low occurrence of porphyria, patients may initially be suspected to have other, unrelated conditions. For instance, the polyneuropathy of acute porphyria may be mistaken for [[Guillain–Barré syndrome]], and porphyria testing is commonly recommended in those situations.<ref>{{cite journal |vauthors=Albers JW, Fink JK |title = Porphyric neuropathy |journal = Muscle Nerve |volume = 30 |issue = 4 |pages = 410–422 |year = 2004 |pmid = 15372536 |doi = 10.1002/mus.20137 |hdl = 2027.42/34640 |s2cid = 68067335 |url = https://deepblue.lib.umich.edu/bitstream/2027.42/34640/1/20137_ftp.pdf |hdl-access = free }}</ref> Elevation of aminolevulinic acid from lead-induced disruption of heme synthesis results in lead poisoning having symptoms similar to acute porphyria.<ref>{{cite book |last=Vannotti |first=Alfred |name-list-style = vanc |date=1954 |title=Porphyrins: Their Biological and Chemical Importance |url=https://books.google.com/books?id=-bzoAAAAIAAJ |publisher=Hilger & Watts, Hilger Division |page=126 |quote=Indeed, lead poisoning, like all porphyrin diseases, is accompanied by obstinate constipation, nervous lesions, hyperpigmentation and abdominal attacks.}}</ref><ref>{{cite book|last1=Dancygier|first1=Henryk |name-list-style = vanc |title=Clinical Hepatology: Principles and Practice of Hepatobiliary Diseases|date=2009|publisher=Springer Science & Business Media|isbn=9783642045196|page=1088|url=https://books.google.com/books?id=lrPX8C4p90QC&pg=PA1088|url-status=live|archive-url=https://web.archive.org/web/20170908185104/https://books.google.com/books?id=lrPX8C4p90QC&pg=PA1088|archive-date=8 September 2017|df=dmy-all}}</ref><ref>{{cite journal | vauthors = Akshatha LN, Rukmini MS, Mamatha TS, Sadashiva Rao P, Prashanth B | title = Lead poisoning mimicking acute porphyria! | journal = Journal of Clinical and Diagnostic Research | volume = 8 | issue = 12 | pages = CD01-2 | date = December 2014 | pmid = 25653942 | pmc = 4316248 | doi = 10.7860/JCDR/2014/10597.5315}}</ref><ref>{{cite journal | vauthors = Tsai MT, Huang SY, Cheng SY | title = Lead Poisoning Can Be Easily Misdiagnosed as Acute Porphyria and Nonspecific Abdominal Pain | journal = Case Reports in Emergency Medicine | volume = 2017 | pages = 9050713 | date = 2017 | pmid = 28630774 | pmc = 5467293 | doi = 10.1155/2017/9050713| doi-access = free }}</ref><ref>{{cite journal | title = Hereditary Coproporphyria | journal = GeneReviews | date = 2018 | pmid = 23236641 | url = https://www.ncbi.nlm.nih.gov/books/NBK114807/ | access-date = 28 February 2020 | quote = the symptoms in lead poisoning closely mimic those of acute porphyria | last1 = Wang | first1 = B. | last2 = Bissell | first2 = D. M. | last3 = Adam | first3 = M. P. | last4 = Ardinger | first4 = H. H. | last5 = Pagon | first5 = R. A. | last6 = Wallace | first6 = S. E. | author7 = Bean LJH | last8 = Stephens | first8 = K. | last9 = Amemiya | first9 = A.}}</ref><ref>{{cite news |last=Murphy |first=Brian |date=3 November 2020 |title=What Tests Can Help Diagnose Porphyria? |url=https://porphyrianews.com/2020/11/03/what-tests-can-help-diagnose-porphyria/ |work= |access-date=22 May 2021}}</ref>

===Chronic porphyrias===
The non-acute porphyrias are X-linked dominant protoporphyria (XLDPP), congenital [[erythropoietic porphyria]] (CEP), [[porphyria cutanea tarda]] (PCT), and [[erythropoietic protoporphyria]] (EPP). None of these 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:
* '''Immediate photosensitivity.''' This is typical of XLDPP and EPP. Following a variable period of [[Health effects of sunlight exposure|sun 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 characteristic [[blister]]ing (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, and [[hypertrichosis]]: abnormal hair growth on the face, particularly the cheeks. The most severe disease is seen in CEP and a rare variant of PCT known as [[hepatoerythropoietic 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.

===Congenital porphyrias===
* Congenital porphyrias are genetic disorders caused by mutations in enzymes involved in the heme biosynthesis pathway. There are several types of congenital porphyrias, including erythropoietic protoporphyria (EPP), congenital erythropoietic porphyria (CEP), and porphyria cutanea tarda (PCT). Each type is characterized by specific enzyme deficiencies leading to the accumulation of different porphyrins.
* Erythropoietic protoporphyria (EPP) is caused by a deficiency in ferrochelatase, leading to the accumulation of protoporphyrin IX in red blood cells, plasma, and tissues. Patients with EPP experience severe photosensitivity, with exposure to sunlight causing painful skin reactions.
* Congenital erythropoietic porphyria (CEP), also known as Günther's disease, results from a deficiency in uroporphyrinogen III synthase. This leads to the accumulation of uroporphyrin I and coproporphyrin I in the bone marrow, blood, and urine. Symptoms of CEP include severe photosensitivity, anemia, splenomegaly, and often disfiguring cutaneous lesions.
* Diagnosis of congenital porphyrias involves clinical evaluation, biochemical testing, and genetic analysis. Treatment aims to manage symptoms and prevent acute attacks by avoiding triggers, such as sunlight exposure, certain medications, and alcohol. Additionally, treatments may include phlebotomy to reduce iron levels in PCT, administration of heme preparations to alleviate symptoms, and liver transplantation in severe cases. Early diagnosis and appropriate management are crucial in improving the quality of life for individuals with congenital porphyrias.

==Cause==
The porphyrias are generally considered genetic in nature.{{citation needed|date=July 2020}}

===Genetics===
Subtypes of porphyrias depend on which enzyme is deficient.

{| class="wikitable"
!Porphyria type
!Deficient [[enzyme]]
!Type of porphyria
!Inheritance
!Symptoms
![[Prevalence]]
|-
| [[Aminolevulinate dehydratase deficiency porphyria]] (ALADP)
| [[5-aminolevulinate dehydratase]] (ALAD)
| Hepatic
| [[Autosomal recessive]]<ref name=brschemi18-1>Table 18-1 in: {{Cite book |author1=Marks, Dawn B. |author2=Swanson, Todd |author3=Sandra I Kim |author4=Marc Glucksman |title=Biochemistry and molecular biology |publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins |location=Philadelphia |year=2007 |isbn=978-0-7817-8624-9 |url-access=registration |url=https://archive.org/details/biochemistrymole0000swan_f9p0 }}</ref>
| Abdominal pain, neuropathy<ref name=brschemi18-1/>
| Extremely rare; fewer than 10 cases ever reported.<ref name=RD>[http://rarediseasesnetwork.epi.usf.edu/porphyrias/patients/ADP/ Overview of the Porphyrias] {{webarchive|url=https://web.archive.org/web/20110722233132/http://rarediseasesnetwork.epi.usf.edu/porphyrias/patients/ADP/ |date=22 July 2011 }} at The Porphyrias Consortium (a part of NIH Rare Diseases Clinical Research Network (RDCRN)) Retrieved June 2011</ref>
|-
| [[Acute intermittent porphyria]] (AIP)
| [[Hydroxymethylbilane synthase]] (HMBS) formerly porphobilinogen deaminase (PBGD)
| Hepatic
| [[Autosomal dominant]]<ref name=brschemi18-1/>
| Periodic abdominal pain, [[peripheral neuropathy]], psychiatric disorders, tachycardia<ref name=brschemi18-1/>
| 1 in 10,000<ref name=medscape/>–20,000<ref name=medscape>[http://emedicine.medscape.com/article/1148341-overview#a0199 Medscape - Diseases of Tetrapyrrole Metabolism - Refsum Disease and the Hepatic Porphyrias ] {{webarchive|url=https://web.archive.org/web/20110604065657/http://emedicine.medscape.com/article/1148341-overview |date=4 June 2011 }} Author: Norman C Reynolds. Chief Editor: Stephen A Berman. Updated: 23 March 2009</ref>
|-
| [[Congenital erythropoietic porphyria]] (CEP)
| [[Uroporphyrinogen III synthase|uroporphyrinogen synthase (UROS)]]
| Erythropoietic
| [[Autosomal recessive]]<ref name=brschemi18-1/>
| Severe photosensitivity with erythema, swelling and blistering. Hemolytic anemia, [[splenomegaly]]<ref name=brschemi18-1/>
| 1 in 1,000,000 or less.<ref name="Thadani"/>
|-
| [[Porphyria cutanea tarda]] (PCT)
| [[Uroporphyrinogen III decarboxylase|uroporphyrinogen decarboxylase (UROD)]]
| Hepatic
| Approximately 80% sporadic,<ref>{{cite web |title=OMIM Entry - 176090 - PORPHYRIA CUTANEA TARDA, TYPE I |url=https://omim.org/entry/176090 |website=omim.org |access-date=24 February 2021 |language=en-us}}</ref> 20% [[Autosomal dominant]]<ref name=brschemi18-1/>
| Photosensitivity with [[Vesicle (dermatology)|vesicles]] and [[Bulla (dermatology)|bullae]]<ref name=brschemi18-1/>
| 1 in 10,000<ref name=Hann2006/>
|-
| [[Hereditary coproporphyria]] (HCP)
| [[Coproporphyrinogen III oxidase|coproporphyrinogen oxidase (CPOX)]]
| Hepatic
| [[Autosomal dominant]]<ref name=brschemi18-1/>
| Photosensitivity, neurologic symptoms, [[colic]]<ref name=brschemi18-1/>
| 1 in 500,000<ref name=Hann2006/>
|-
| [[Harderoporphyria]]
| [[Coproporphyrinogen III oxidase|coproporphyrinogen oxidase (CPOX)]]
| Erythropoietic
| [[Autosomal recessive]]<ref name=brschemi18-1/>
| Jaundice, anemia, enlarged liver and spleen, often neonatal. Photosensitivity later.
| Extremely rare; fewer than 10 cases ever reported.
|-
| [[Variegate porphyria]] (VP)
| [[Protoporphyrinogen oxidase|protoporphyrinogen oxidase (PPOX)]]
| Hepatic
| [[Autosomal dominant]]<ref name=VPNBK>{{cite journal|last1=Singal|first1=AK|last2=Anderson|first2=KE|last3=Pagon|first3=RA|last4=Adam|first4=MP|last5=Ardinger|first5=HH|last6=Wallace|first6=SE|last7=Amemiya|first7=A|last8=Bean|first8=LJH|last9=Bird|first9=TD|last10=Dolan|first10=CR|last11=Fong|first11=CT|last12=Smith|first12=RJH|last13=Stephens|first13=K|title=Variegate Porphyria|journal=GeneReviews|date=2013|pmid=23409300|url=https://www.ncbi.nlm.nih.gov/books/NBK121283/|access-date=18 April 2015|publisher=University of Washington|location=Seattle, USA|url-status=live|archive-url=https://web.archive.org/web/20170118123846/https://www.ncbi.nlm.nih.gov/books/NBK121283/|archive-date=18 January 2017|df=dmy-all}}</ref>
| Photosensitivity, neurologic symptoms, developmental delay
| 1 in 300 in South Africa<ref name=Hann2006/><br />1 in 75,000 in Finland<ref>{{cite journal | author = Mustajoki P | title = Variegate porphyria. Twelve years' experience in Finland | journal = The Quarterly Journal of Medicine | volume = 49 | issue = 194 | pages = 191–203 | year = 1980 | pmid = 7433635 }}</ref>
|-
| [[Erythropoietic protoporphyria]] (EPP)
| [[ferrochelatase]] (FECH)
| Erythropoietic
| [[Autosomal recessive]]<ref name=brschemi18-1/>
| Photosensitivity with skin lesions. Gallstones, mild liver dysfunction<ref name=brschemi18-1/>
| 1 in 75,000<ref name=Hann2006>{{Cite book |last1 = Arceci | first1 = Robert. | last2 = Hann | first2 = Ian M. | last3 = Smith | first3 = Owen P. | title = Pediatric hematolog | year = 2006 | publisher = Blackwell Pub. | location = Malden, Mass. | isbn = 978-1-4051-3400-2 }}</ref>–200,000<ref name=Hann2006/>
|-
|}

[[X-linked dominant inheritance|X-linked dominant]] protoporphyria is a rare form of [[erythropoietic protoporphyria]] caused by a gain-of-function [[mutation]] in [[ALAS2]] characterized by severe [[photosensitivity in humans|photosensitivity]].<ref>{{cite web |title=OMIM Entry - # 300752 - PROTOPORPHYRIA, ERYTHROPOIETIC, X-LINKED; XLEPP |url=https://omim.org/entry/300752 |website=omim.org |language=en-us}}</ref><ref>{{cite web |title=Orphanet: X linked erythropoietic protoporphyria |url=https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=443197 |website=www.orpha.net}}</ref>

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.<ref>{{Cite web|url=https://www.mayoclinic.org/diseases-conditions/porphyria/symptoms-causes/syc-20356066|title=Porphyria - Symptoms and causes|website=Mayo Clinic|language=en|access-date=2020-03-05}}</ref>

===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 that are made with heme. Such drugs include:<ref name=APF>{{cite web|title=About Porphyria: Safety database|work=Porphyria Drug Safety Database|publisher=American Porphyria Foundation|access-date=27 August 2017|author=Tishler, PV|url=http://www.porphyriafoundation.com/drug_database/|url-status=dead|archive-url=https://web.archive.org/web/20170712121843/http://www.porphyriafoundation.com/drug_database/|archive-date=12 July 2017|df=dmy-all}}</ref><ref name=EPN>{{cite web|title=napos|work=The Drug Database for Acute Porphyria|publisher=European Porphyria Network|access-date=27 August 2017|author=Brun, A|url=http://www.drugs-porphyria.org|url-status=dead|archive-url=https://web.archive.org/web/20170823070041/http://www.drugs-porphyria.org/|archive-date=23 August 2017|df=dmy-all}}</ref><ref name=BNF>{{cite book | author = Joint Formulary Committee | title = British National Formulary (BNF) | year = 2013 | url = https://archive.org/details/bnf65britishnati0000unse/page/663 | isbn = 978-0-85711-084-8 | edition = 65 | location = London, UK | publisher = Pharmaceutical Press | page = [https://archive.org/details/bnf65britishnati0000unse/page/663 663] }}</ref>
* [[Sulfonamide]]s, including [[sulfadiazine]], [[sulfasalazine]] and [[trimethoprim/sulfamethoxazole]].
* [[Sulfonylurea]]s like [[glibenclamide]], [[gliclazide]] and [[glimepiride]], although [[glipizide]] is thought to be safe.
* [[Barbiturates]] including [[thiopental]], [[phenobarbital]], [[primidone]], etc.
* Systemic treatment with [[antifungals]] including [[fluconazole]], [[griseofulvin]], [[ketoconazole]] and [[voriconazole]]. (Topical use of these agents is thought to be safe due to minimal systemic absorption.)
* Certain [[antibiotics]] like [[rifapentine]], [[rifampicin]], [[rifabutine]], [[isoniazid]], [[nitrofurantoin]] and, possibly, [[metronidazole]].
* [[Ergot]] derivatives including [[dihydroergotamine]], [[ergometrine]], [[ergotamine]], [[methysergide]], etc.
* Certain [[antiretroviral]] medications ( [[indinavir]], [[nevirapine]], [[ritonavir]], [[saquinavir]], etc.)
* [[Progestogen]]s
* Some [[anticonvulsants]] including: [[carbamazepine]], [[ethosuximide]], [[phenytoin]], [[topiramate]], [[valproate]].
* Some [[analgesics|painkillers]] like [[dextropropoxyphene]], [[ketorolac]], [[metamizole]], [[pentazocine]]
* Some cancer treatments like [[bexarotene]], [[busulfan]], [[chlorambucil]], [[estramustine]], [[etoposide]], [[flutamide]], [[idarubicin]], [[ifosfamide]], [[irinotecan]], [[ixabepilone]], [[letrozole]], [[lomustine]], [[megestrol]], [[mitomycin]], [[mitoxantrone]], [[paclitaxel]], [[procarbazine]], [[tamoxifen]], [[topotecan]]
* Some [[antidepressants]] like [[imipramine]], [[phenelzine]], [[trazodone]]
* Some [[antipsychotics]] like [[risperidone]], [[ziprasidone]]
* Some [[retinoids]] used for skin conditions like [[acitretin]] and [[isotretinoin]]
* Miscellaneous others including: [[cocaine]], [[methyldopa]], [[fenfluramine]], [[disulfiram]], [[orphenadrine]], [[pentoxifylline]], and [[sodium aurothiomalate]].

==Pathogenesis==
[[File:Heme synthesis.svg|thumb|right|350px|Heme synthesis. Note that some reactions occur in the [[cytoplasm]] and some in the [[mitochondrion]] (yellow).]]

In [[human]]s, [[porphyrin]]s are the main precursors of [[heme]], an essential constituent of [[hemoglobin]], [[myoglobin]], [[catalase]], [[peroxidase]], and P450 liver [[cytochrome]]s.<ref>{{Cite book |title=Sweet Biochemistry |url=https://www.sciencedirect.com/book/9780128144534/sweet-biochemistry |access-date=2022-10-30 |isbn=9780128144534 |language=en |last1=Kumari |first1=Asha |date=12 October 2017 |publisher=Elsevier Science }}</ref>

The body requires porphyrins to produce [[heme]], which is used to carry oxygen in the blood among other things, but in the porphyrias there is a deficiency (inherited or acquired) of the [[enzyme]]s that transform the various porphyrins into others, leading to abnormally high levels of one or more of these substances. Porphyrias are classified in two ways, by symptoms and by pathophysiology. Physiologically, porphyrias are classified as liver or erythropoietic based on the sites of accumulation of [[heme]] precursors, either in the [[liver]] or in the [[bone marrow]] and [[red blood cells]].<ref name=saudubray>{{cite book |last1=Lourenço|first1=Charles Marquez|last2=Lee|first2=Chul|last3=Anderson|first3=Karl E.|editor1-first=Jean-Marie|editor1-last=Saudubray|editor2-first=Georges|editor2-last=van den Berghe|editor3-first=John H.|editor3-last=Walter|title=Inborn Metabolic Diseases: Diagnosis and Treatment |url=https://archive.org/details/inbornmetabolicd00saud|url-access=limited|edition=5th |year=2012 |publisher=Springer |location=New York |isbn= 978-3-642-15719-6 | pages=[https://archive.org/details/inbornmetabolicd00saud/page/n525 521]–532 |chapter=Disorders of Haem Biosynthesis}}</ref>

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]] [[Biosynthesis|synthesis]] [[enzymes]]—even dysfunctional [[enzymes]]—have enough residual activity to assist in [[heme]] biosynthesis. The principal problem in these deficiencies is the accumulation of [[porphyrin]]s, 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]]).{{citation needed|date=November 2021}}

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 pain|back]] and [[abdominal pain]], and an acute [[polyneuropathy]]), while the [[Erythropoietic porphyria|erythropoietic forms]] present with skin problems, usually a light-sensitive blistering rash and [[hypertrichosis|increased hair growth]]. ''[[Variegate porphyria]]'' (also ''porphyria variegata'' or ''mixed porphyria''), which results from a partial deficiency in [[PROTO oxidase]], manifests itself with skin lesions similar to those of [[porphyria cutanea tarda]] combined with acute neurologic attacks. [[Hereditary coproporphyria]], which is characterized by a deficiency in coproporphyrinogen oxidase, coded for by the CPOX gene, may also present with both acute neurologic attacks and cutaneous lesions. All other porphyrias are either skin- or nerve-predominant.<ref>{{Citation |last1=Ogun |first1=Aminat S. |title=Biochemistry, Heme Synthesis |date=2022 |url=http://www.ncbi.nlm.nih.gov/books/NBK537329/ |work=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30726014 |access-date=2022-10-30 |last2=Joy |first2=Neena V. |last3=Valentine |first3=Menogh}}</ref>

==Diagnosis==

===Porphyrin studies===
Porphyria is diagnosed through biochemical analysis of [[blood]], [[urine]], and [[feces|stool]].<ref name=Thadani>{{cite journal |vauthors=Thadani H, Deacon A, Peters T | title = Diagnosis and management of porphyria | journal = BMJ | volume = 320 | issue = 7250 | pages = 1647–1651 | year = 2000 | pmid = 10856069 | pmc = 1127427 | doi = 10.1136/bmj.320.7250.1647 }}</ref><ref>{{cite web|title=Tests for Porphyria diagnosis|url=http://www.porphyriafoundation.com/testing-and-treatment/testing-for-porphyria/tests-for-porphyria-diagnosis|publisher=American Porphyria Foundation|access-date=17 May 2014|url-status=dead|archive-url=https://web.archive.org/web/20140320095019/http://www.porphyriafoundation.com/testing-and-treatment/testing-for-porphyria/tests-for-porphyria-diagnosis|archive-date=20 March 2014|df=dmy-all}}</ref> 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.<ref name=Anderson>{{cite journal |vauthors=Anderson KE, Bloomer JR, Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR, Desnick RJ | title = Recommendations for the diagnosis and treatment of the acute porphyrias | journal = Ann. Intern. Med. | volume = 142 | issue = 6 | pages = 439–50 | year = 2005 | pmid = 15767622 | doi = 10.7326/0003-4819-142-6-200503150-00010 | s2cid = 36122555 }}</ref> 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 [[tyrosinemia|hereditary tyrosinemia type I]].<ref>{{cite journal |vauthors=Berkó G, Durkó I | title = [Modification of the Mauzerall-Granick method for the determination of urinary aminolevulinic acid]. | language = hu | journal = Orvosi Hetilap | volume = 112 | issue = 51 | pages = 3085–6 | date = 19 December 1971 | pmid = 5136653 }}</ref> In cases of
[[mercury poisoning|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.<ref name=Woods1995>{{Cite book| last = Woods| first = J.S.| contribution = Porphyrin metabolism as indicator of metal exposure and toxicity| editor-last = Goyer| editor-first = R.A. |editor2=Cherian, M.G.| title = Toxicology of metals, biochemical aspects| volume = 115| pages = 19–52, Chapter 2| publisher = Springer| place = Berlin| year = 1995 }}</ref>

As most porphyrias are [[rare disease|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.<ref name=Thadani/> 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.<ref name=Thadani/>

If all the porphyrin studies are negative, one must consider [[pseudoporphyria]]. A careful medication review often will find the cause of pseudoporphyria.{{citation needed|date=March 2022}}

===Additional tests===
Further diagnostic tests of affected organs may be required, such as [[nerve conduction studies]] for [[neuropathy]] or an [[medical ultrasonography|ultrasound]] of the liver. Basic biochemical tests may assist in identifying [[liver disease]], [[hepatocellular carcinoma]], and other organ problems.<ref>{{Cite journal|last1=Di Pierro|first1=Elena|last2=De Canio|first2=Michele|last3=Mercadante|first3=Rosa|last4=Savino|first4=Maria|last5=Granata|first5=Francesca|last6=Tavazzi|first6=Dario|last7=Nicolli|first7=Anna Maria|last8=Trevisan|first8=Andrea|last9=Marchini|first9=Stefano|last10=Fustinoni|first10=Silvia|date=2021-07-26|title=Laboratory Diagnosis of Porphyria|journal=Diagnostics|volume=11|issue=8|pages=1343|doi=10.3390/diagnostics11081343|issn=2075-4418|pmc=8391404|pmid=34441276|doi-access=free}}</ref>

•Other Diagnosis{{cn|date=December 2024}}

Clinical Evaluation: A thorough medical history and physical examination focusing on symptoms related to photosensitivity, skin lesions, abdominal pain, and neurological manifestations.

Genetic Testing: Molecular genetic testing to identify specific gene mutations associated with congenital porphyrias.

Other Tests: Liver function tests, iron studies, and imaging studies such as ultrasound or MRI may be conducted to evaluate liver and spleen involvement.

==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, a [[dextrose]] 10% infusion is commenced, which may aid in recovery by suppressing [[heme]] synthesis, which in turn reduces the rate of porphyrin accumulation.  However, this can worsen cases of low blood sodium levels ([[hyponatraemia]]) and should be done with extreme caution as it can prove fatal.<ref>{{Cite web|url=http://patient.info/doctor/porphyrias#nav-8|title=Porphyrias - immediate management|author=patient.co.uk|access-date=19 October 2016|url-status=dead|archive-url=https://web.archive.org/web/20161020045301/http://patient.info/doctor/porphyrias#nav-8|archive-date=20 October 2016|df=dmy-all}}</ref>

====Heme analogs====
[[Hematin]] (trade name Panhematin) and [[heme arginate]] (trade name NormoSang) are the drugs of choice in acute porphyria in the United States and the United Kingdom respectively. These drugs need to be given very early in an attack to be effective; effectiveness varies amongst individuals. They are not curative drugs but can shorten attacks and reduce the intensity of an attack. Side effects are rare but can be serious. These heme-like substances theoretically inhibit ALA synthase and hence the accumulation of toxic precursors. In the United Kingdom, supplies of NormoSang are kept at two national centers; emergency supply is available from [[St Thomas's Hospital]], London.<ref>{{Cite book|title=British National Formulary (BNF 57) |date=March 2009 |publisher=[[BMJ Group]] and RPS Publishing |location=United Kingdom |isbn=978-0-85369-845-6 |page=549 |chapter=9.8.2: Acute porphyrias |author=[[British Medical Association]], [[Royal Pharmaceutical Society of Great Britain]]}}</ref> In the United States, [[Lundbeck]] manufactures and supplies Panhematin for infusion.<ref>{{Cite web |url=http://www.porphyriafoundation.com/testing-and-treatment/medications-for-porphyria/panhematin |title=Panhematin for Acute Porphyria |year=2010 |author=American Porphyria Foundation |access-date=5 August 2010 |url-status=dead |archive-url=https://web.archive.org/web/20100825015445/http://www.porphyriafoundation.com/testing-and-treatment/medications-for-porphyria/panhematin |archive-date=25 August 2010 |df=dmy-all }}</ref>

Heme arginate (NormoSang) is used during crises but also in preventive treatment to avoid crises, one treatment every 10 days.{{citation needed|date=December 2014}}

Any sign of low blood sodium ([[hyponatremia]]) or weakness should be treated with the addition of hematin, heme arginate, or even [[tin mesoporphyrin]], as these are signs of impending syndrome of inappropriate antidiuretic hormone (SIADH) or peripheral nervous system involvement that may be localized or severe, progressing to [[bulbar palsy|bulbar paresis]] and respiratory paralysis.{{Citation needed|date=February 2007}}

====Cimetidine====
[[Cimetidine]] has also been reported to be effective for acute porphyric crisis and possibly effective for long-term prophylaxis.<ref name="pmid16263899">{{cite journal |vauthors=Cherem JH, Malagon J, Nellen H | title = Cimetidine and acute intermittent porphyria | journal = Ann. Intern. Med. | volume = 143 | issue = 9 | pages = 694–5 | year = 2005 | pmid = 16263899 | doi = 10.7326/0003-4819-143-9-200511010-00023| doi-access = free }}</ref>

====Symptom control====
Pain is severe, frequently out of proportion to physical signs, and often requires the use of [[opiates]] to reduce it to tolerable levels. Pain should be treated as early as medically possible. [[Nausea]] can be severe; it may respond to [[phenothiazine]] drugs but is sometimes intractable. Hot baths and showers may lessen nausea temporarily, though caution should be used to avoid scalds or falls.{{citation needed|date=July 2020}}

====Early identification====
It is recommended that patients with a history of acute porphyria, and even genetic carriers, wear an [[Medical identification tag|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 [[Contraindication|contraindicated]] for patients with any form of porphyria.<ref>{{Cite web|url=https://www.mayoclinic.org/diseases-conditions/porphyria/diagnosis-treatment/drc-20356072|title=Porphyria - Diagnosis and treatment - Mayo Clinic|website=www.mayoclinic.org|access-date=2018-12-06}}</ref>

====Neurologic and psychiatric disorders====
Patients who experience frequent attacks can develop chronic [[neuropathic]] pain in extremities as well as chronic pain in the [[abdomen]].<ref name="pmid20519771">{{cite journal |vauthors=Birgisdottir BT, Asgeirsson H, Arnardottir S, Jonsson JJ, Vidarsson B | title = [Acute abdominal pain caused by acute intermittent porphyria - case report and review of the literature] | language = is | journal = Laeknabladid | volume = 96 | issue = 6 | pages = 413–18 | year = 2010 | pmid = 20519771 }}</ref> [[Intestinal pseudo-obstruction]], [[ileus]], [[Intussusception (medical disorder)|intussusception]], hypoganglionosis, and [[encopresis]] in children have been associated with porphyrias. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system and vagal nerve dysfunction. Pain treatment with long-acting [[opioid]]s, such as [[morphine]], is often indicated, and, in cases where seizure or neuropathy is present, [[gabapentin]] is known to improve outcome.<ref name="Tsao 2010 112–115">{{cite journal |vauthors=Tsao YC, Niu DM, Chen JT, Lin CY, Lin YY, Liao KK | title = Gabapentin reduces neurovisceral pain of porphyria | journal = Acta Neurol Taiwan | volume = 19 | issue = 2 | pages = 112–5 | year = 2010 | pmid = 20714961 }}</ref>

[[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 regimen for seizure control. Gabapentin has the additional feature of aiding in the treatment of some kinds of neuropathic pain.<ref name="Tsao 2010 112–115"/> [[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]].<ref>{{cite journal |vauthors=Cherian A, Thomas SV |title=Status epilepticus |journal=Ann Indian Acad Neurol |volume=12 |issue=3 |pages=140–53 |year=2009 |pmid=20174493 |pmc=2824929 |doi=10.4103/0972-2327.56312 |doi-access=free }}</ref>

[[Clinical depression|Depression]] often accompanies the disease and is best dealt with by treating the offending symptoms and if needed the judicious use of [[antidepressant]]s. 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.<ref>Murray ED, Buttner N, Price BH. (2012) Depression and Psychosis in Neurological Practice. In: Neurology in Clinical Practice, 6th Edition. Bradley WG, Daroff RB, Fenichel GM, Jankovic J (eds.) Butterworth Heinemann. 12 April 2012. {{ISBN|978-1437704341}}</ref>

====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.<ref name=NIDDK>{{Cite web|url=https://www.niddk.nih.gov/health-information/liver-disease/porphyria|title=Porphyria {{!}} NIDDK|website=National Institute of Diabetes and Digestive and Kidney Diseases|access-date=2018-12-06}}</ref>

Patients with the acute porphyrias ([[acute intermittent porphyria|AIP]], [[hereditary coproporphyria|HCP]], [[variegate porphyria|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.<ref name=NIDDK/>

====Hormone treatment====
Hormonal fluctuations that contribute to cyclical attacks in women have been treated with oral contraceptives and [[luteinizing hormone]]s to shut down menstrual cycles. However, oral contraceptives have also triggered photosensitivity and withdrawal of oral contraceptives has triggered attacks. [[Androgen]]s and fertility hormones have also triggered attacks.<ref>{{cite web |title=Hormonal Contraceptives and Porphyria |url=https://porphyrianews.com/health-insights/hormonal-contraceptives-and-porphyria/ |website=Porphyria news|date=September 2020 }}</ref> In 2019, [[givosiran]] was approved in the United States for the treatment of acute hepatic porphyria.<ref name="FDA PR">{{cite press release | title=FDA approves first treatment for inherited rare disease | website=U.S. [[Food and Drug Administration]] (FDA) | date=20 November 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-inherited-rare-disease | archive-url=https://web.archive.org/web/20191121062641/https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-inherited-rare-disease | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}}{{PD-notice}}</ref><ref name="FDA PR 2">{{cite press release | title=FDA approves givosiran for acute hepatic porphyria | website=U.S. [[Food and Drug Administration]] (FDA) | date=20 November 2019 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-givosiran-acute-hepatic-porphyria | archive-url=https://web.archive.org/web/20191121071000/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-givosiran-acute-hepatic-porphyria | archive-date=21 November 2019 | url-status=live | access-date=20 November 2019}}{{PD-notice}}</ref>

===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 (EP) 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.<ref name=Thadani/> [[Blood transfusion]] is occasionally used to suppress innate heme production.{{citation needed|date=November 2021}}

The rarest is congenital erythropoietic porphyria (CEP), otherwise known as [[Gunther's disease]]. The signs may present from birth and include severe photosensitivity, brown teeth that fluoresce in ultraviolet light due to deposition of Type 1 porphyrins, and later [[hypertrichosis]]. Hemolytic anemia usually develops. Pharmaceutical-grade [[beta carotene]] may be used in its treatment.<ref>Martin A Crook.2006. Clinical chemistry and Metabolic Medicine. seventh edition. Hodder Arnold. {{ISBN|0-340-90616-2}}</ref> A bone marrow transplant has also been successful in curing CEP in a few cases, although long-term results are not yet available.<ref name="pmid18186900">{{cite journal |vauthors=Faraci M, Morreale G, Boeri E, Lanino E, Dallorso S, Dini G, Scuderi F, Cohen A, Cappelli B | title = Unrelated HSCT in an adolescent affected by congenital erythropoietic porphyria | journal = Pediatr Transplant | volume = 12 | issue = 1 | pages = 117–120 | year = 2008 | pmid = 18186900 | doi = 10.1111/j.1399-3046.2007.00842.x | s2cid = 20789520 | doi-access = free }}</ref>

In December 2014, [[afamelanotide]] received authorization from the [[European Commission]] as a treatment for the prevention of [[phototoxicity]] in adult patients with EPP.<ref>{{cite web|title=Community register of medicinal products for human use|url=http://ec.europa.eu/health/documents/community-register/html/h969.htm#EndOfPage|website=ec.europa.eu|publisher=European Commission|access-date=24 December 2014|url-status=live|archive-url=https://web.archive.org/web/20141224180750/http://ec.europa.eu/health/documents/community-register/html/h969.htm#EndOfPage|archive-date=24 December 2014|df=dmy-all}}</ref> 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.<ref>{{Cite journal |last1=Balwani |first1=Manisha |last2=Bonkovsky |first2=Herbert L. |last3=Levy |first3=Cynthia |last4=Anderson |first4=Karl E. |last5=Bissell |first5=D. Montgomery |last6=Parker |first6=Charles |last7=Takahashi |first7=Fumihiro |last8=Desnick |first8=Robert J. |last9=Belongie |first9=Kirstine |date=2023-04-13 |title=Dersimelagon in Erythropoietic Protoporphyrias |url=http://www.nejm.org/doi/10.1056/NEJMoa2208754 |journal=New England Journal of Medicine |language=en |volume=388 |issue=15 |pages=1376–1385 |doi=10.1056/NEJMoa2208754 |pmid=37043653 |s2cid=258110676 |issn=0028-4793}}</ref>

==Epidemiology==
Rates of all types of porphyria taken together have been estimated to be approximately one in 25,000 in the United States.<ref>[http://emedicine.medscape.com/article/957765-overview#target2 eMedicine > Porphyria, Cutaneous] {{webarchive|url=https://web.archive.org/web/20101205041014/http://emedicine.medscape.com/article/957765-overview |date=5 December 2010 }} Authors: Vikramjit S Kanwar, Thomas G DeLoughery, Richard E Frye and Darius J Adams. Updated: 27 July 2010.</ref> The worldwide prevalence has been estimated to be between one in 500 and one in 50,000 people.<ref>[http://ghr.nlm.nih.gov/condition=porphyria Genetics Home Reference > Porphyria] {{webarchive|url=https://web.archive.org/web/20100805111912/http://ghr.nlm.nih.gov/condition%3Dporphyria |date=5 August 2010 }} Reviewed July 2009</ref>

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|date=November 2021}}

===Other Information===

The epidemiology of congenital porphyrias varies depending on the specific type of porphyria. Here's a general overview:

1. '''Erythropoietic Protoporphyria (EPP):''' EPP is relatively rare, with an estimated prevalence of 1 to 9 cases per 100,000 individuals worldwide. It affects both males and females, typically presenting in childhood or early adulthood.{{cn|date=December 2024}}

2. '''Congenital Erythropoietic Porphyria (CEP):''' CEP is extremely rare, with fewer than 200 cases reported worldwide. It is inherited in an autosomal recessive manner, meaning both parents must carry a mutated gene for a child to develop the condition. CEP occurs with higher frequency in certain populations, including individuals of Northern European descent.{{cn|date=December 2024}}

3. '''Porphyria Cutanea Tarda (PCT):''' PCT is the most common form of porphyria, with an estimated prevalence of 1 to 2 cases per 10,000 individuals in the general population. It predominantly affects adults, with a higher prevalence in men than in women. PCT can be sporadic or familial and is often associated with underlying liver disease, alcohol abuse, hepatitis C infection, or certain medications.{{cn|date=December 2024}}

These prevalence estimates may vary across different regions and populations, and the actual prevalence of congenital porphyrias may be underreported due to challenges in diagnosis and awareness. Additionally, advances in genetic testing and increased awareness of porphyria may lead to more accurate epidemiological data in the future.{{cn|date=December 2024}}

==History==
The underlying mechanism was first described by the German physiologist [[Felix Hoppe-Seyler]] in 1871,<ref>{{Cite journal |author=Hoppe-Seyler F |title=Das Hämatin |journal=Tubinger Med-Chem Untersuch |year=1871| volume=4 | pages=523–33}}</ref> and acute porphyrias were described by the Dutch physician [[Barend Joseph Stokvis|Barend Stokvis]] in 1889.<ref name=Lane>{{Cite web |author=Nick Lane |title=Born to the purple: the story of porphyria |work=Scientific American |url=http://www.sciam.com/article.cfm?articleID=000B1BEF-C051-1DF8-9733809EC588EEDF |date=2002-12-16 |access-date=5 August 2008 |url-status=dead |archive-url=https://web.archive.org/web/20071011105238/http://www.sciam.com/article.cfm?articleID=000B1BEF-C051-1DF8-9733809EC588EEDF |archive-date=11 October 2007 |df=dmy-all }}</ref><ref>{{Cite journal |author=Stokvis BJ |title=Over twee zeldzame kleurstoffen in urine van zieken |journal=Nederl Tijdschr Geneeskd | volume=2 | pages=409–417 |language=nl}} Reprinted in {{cite journal | author = Stokvis BJ | title = Over twee zeldzame kleurstoffen in urine van zieken | language = nl | journal = Ned Tijdschr Geneeskd | volume = 133 | issue = 51 | pages = 2562–70 | date = December 1989 | pmid = 2689889 }}</ref>

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"<ref>Denver, Joness. "An Encyclopaedia of Obscure Medicine". Published by University Books, Inc., 1959.</ref>) and severe symptoms of depression or catatonia were treated with [[Electroshock therapy|electroshock]] therapy.

===Vampires and werewolves===
Porphyria has been suggested as an explanation for the origin of [[vampire]] and [[werewolf]] legends, based upon certain perceived similarities between the condition and the [[folklore]].

In January 1964, L. Illis's 1963 paper 'On Porphyria and the [[Aetiology]] of Werewolves' was published in ''[[Proceedings of the Royal Society of Medicine]]. ''Later, [[Nancy Garden]] argued for a connection between porphyria and the vampire belief in her 1973 book ''Vampires''. In 1985, biochemist [[David Dolphin]]'s paper for the [[American Association for the Advancement of Science]], 'Porphyria, Vampires, and Werewolves: The Aetiology of European Metamorphosis Legends', gained widespread media coverage, popularizing the idea.{{citation needed|date=August 2019}}

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.<ref>''American Vampires: Fans, Victims, Practitioners'', Norine Dresser, W. W. Norton & Company, 1989.</ref><ref>[http://www.straightdope.com/columns/read/1321/did-vampires-suffer-from-the-disease-porphyria-or-not "Did vampires suffer from the disease porphyria — or not?"] {{webarchive|url=https://web.archive.org/web/20130205152541/http://www.straightdope.com/columns/read/1321/did-vampires-suffer-from-the-disease-porphyria-or-not |date=5 February 2013 }} [[The Straight Dope]], 7 May 1999.</ref>

A 1995 article from the ''[[Postgraduate Medical Journal]]'' (via [[National Institutes of Health|NIH]]) explains:
<blockquote>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.<ref>{{cite journal |last=Cox|first=Ann M.|date=1995|title=Porphyria and vampirism: another myth in the making|journal=Postgraduate Medical Journal|volume=71|issue=841|pages=643–644|doi=10.1136/pgmj.71.841.643-a|pmid=7494765|pmc=2398345}}</ref></blockquote>

===Notable cases===
* [[George III of the United Kingdom]]. The mental illness exhibited by George III in the [[Regency Crisis of 1788|regency crisis of 1788]] has inspired several attempts at [[retrospective diagnosis]]. The first, written in 1855, thirty-five years after his death, concluded that he had acute [[mania]]. M. Guttmacher, in 1941, suggested [[Bipolar disorder|manic-depressive]] [[psychosis]] as a more likely diagnosis. The first suggestion that a physical illness was the cause of King George's mental derangement came in 1966, in a paper called "The Insanity of King George III: A Classic Case of Porphyria",<ref>{{cite journal |vauthors=Macalpine I, Hunter R | title = The 'insanity' of King George 3d: a classic case of porphyria | journal = [[Br Med J]] | volume = 1 | issue = 5479 | pages = 65–71 | date = January 1966 | pmid = 5323262 | pmc = 1843211 | doi = 10.1136/bmj.1.5479.65 }}</ref> with a follow-up in 1968, "Porphyria in the Royal Houses of Stuart, Hanover and Prussia".<ref>{{cite journal |vauthors=Macalpine I, Hunter R, Rimington C | title = Porphyria in the royal houses of Stuart, Hanover, and Prussia. A follow-up study of George 3d's illness | journal = Br Med J | volume = 1 | issue = 5583 | pages = 7–18 | date = January 1968 | pmid = 4866084 | pmc = 1984936 | doi = 10.1136/bmj.1.5583.7 }}</ref> The papers, by a mother/son [[psychiatrist]] team, were written as though the case for porphyria had been proven, but the response demonstrated that many experts, including those more intimately familiar with the manifestations of porphyria, were unconvinced. Many psychiatrists disagreed with the diagnosis, suggesting bipolar disorder as far more probable. The theory is treated in ''Purple Secret,''<ref>{{Cite book|author1=Warren, Martin |author2=Rh̲l, John C. G. |author3=Hunt, David C. |title=Purple Secret: Genes, "Madness" and the Royal Houses of Europe |publisher=[[Bantam Books]] |location=London |year=1998 |isbn=978-0-593-04148-2}}</ref> which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to have had it.<ref>The authors demonstrated a single point mutation in the [[PPOX gene]] but not one that has been associated with disease.</ref> In 2005, it was suggested that [[arsenic]] (which is known to be porphyrogenic) given to George III with [[antimony]] may have caused his porphyria.<ref>{{cite journal |vauthors=Cox TM, Jack N, Lofthouse S, Watling J, Haines J, Warren MJ | s2cid = 13109527 | title = King George III and porphyria: an elemental hypothesis and investigation | journal = [[The Lancet]] | volume = 366 | issue = 9482 | pages = 332–335 | year = 2005 | pmid = 16039338 | doi = 10.1016/S0140-6736(05)66991-7 }}</ref> 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.<ref>{{cite journal |vauthors=Peters TJ, Wilkinson D | s2cid = 22391207 | title = King George III and porphyria: a clinical re-examination of the historical evidence | journal = History of Psychiatry | volume = 21 | issue = 81 Pt 1 | pages = 3–19 | year = 2010 | pmid = 21877427 | doi = 10.1177/0957154X09102616 }}</ref>   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 King's symptoms suggest that he had porphyria, and note that the disease is "periodic, unpredictable, and hereditary". The traditional argument that George III did not have porphyria, but rather bipolar disorder, is thoroughly defended by [[Andrew Roberts, Baron Roberts of Belgravia|Andrew Roberts]] in his new biography ''The Last King of America''.<ref>{{Cite web|url=https://www.amazon.com/Last-King-America-Misunderstood-George-ebook/dp/B08XNB1RYY|title=The Last King of America: The Misunderstood Reign of George III|first=Andrew|last=Roberts|date=9 November 2021|publisher=Viking|via=Amazon}}</ref>
* Descendants of George III. Among other descendants of George III theorized by the authors of ''Purple Secret'' to have had porphyria (based on analysis of their extensive and detailed medical correspondence) were his great-great-granddaughter [[Princess Charlotte of Prussia]] ([[William II, German Emperor|Emperor William II]]'s eldest sister) and her daughter [[Princess Feodora of Saxe-Meiningen]]. They uncovered better evidence that George III's great-great-great-grandson [[Prince William of Gloucester]] was reliably diagnosed with variegate porphyria.<ref>{{Cite book |url=https://books.google.com/books?id=OckqbM7hcGAC&pg=PA21 |title=Tetrapyrroles: Birth, Life and Death |isbn=9780387785189 |last1=Smith |first1=Martin |last2=Smith |first2=Alison |date=2009-12-21 |publisher=Springer |url-status=live |access-date=9 April 2014 |archive-url=https://web.archive.org/web/20140704171216/http://books.google.com/books?id=OckqbM7hcGAC&pg=PA21 |archive-date=4 July 2014 |df=dmy-all }}</ref>
* [[Mary, Queen of Scots]]. It is believed that Mary, Queen of Scots, [[George III|King George III]]'s ancestor, also had acute intermittent porphyria,<ref>{{cite web |last=Röhl |first=John |date=25 June 1999 |title=The Royal Family's Toxic Time-Bomb |url=http://www.sussex.ac.uk/internal/bulletin/archive/25jun99/article1.html |work=Bulletin: The University of Sussex Newsletter |url-status=dead |archive-url=https://web.archive.org/web/20130915114324/http://www.sussex.ac.uk/internal/bulletin/archive/25jun99/article1.html |archive-date=15 September 2013 |df=dmy-all |access-date=18 August 2013}}</ref> 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.{{cn|date=December 2024}}
* [[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 (physician)|Francis Willis]], the physician who treated George III, was even summoned by the Portuguese court but returned to England after the court limited the treatments he could oversee. Contemporary sources, such as Secretary of State for Foreign Affairs [[Luís Pinto de Sousa Coutinho, 1st Viscount of Balsemão|Luís Pinto de Sousa Coutinho]], noted that the queen had ever-worsening stomach pains and abdominal spasms: hallmarks of porphyria.<ref>{{cite book |last=Roberts |first=Jenifer |date=2009 |title=The Madness of Queen Maria |trans-title=The Remarkable Life of Maria I of Portugal |publisher=Templeton Press |isbn=978-0954558918 }}</ref>
* [[Vincent van Gogh]]. Other commentators have suggested that Vincent van Gogh may have had acute intermittent porphyria.<ref>{{cite journal |vauthors=Loftus LS, Arnold WN | title = Vincent van Gogh's illness: acute intermittent porphyria? | journal = BMJ | volume = 303 | issue = 6817 | pages = 1589–1591 | year = 1991 | pmid = 1773180 | pmc = 1676250 | doi = 10.1136/bmj.303.6817.1589 }}</ref>
* [[Nebuchadnezzar II|King Nebuchadnezzar of Babylon]]. The description of this king in [[Daniel 4]] suggests to some that he had porphyria.{{cn|date=December 2024}}
* Physician [[Archie Cochrane]]. He was born with porphyria, which caused health problems throughout his life.<ref name="outline">{{cite book |last1=Ranpura |first1=Dhruv |title=One Man's Medicine: An Autobiography of Professor Archie Cochrane |last2=Dhyey |first2=Khavdu |publisher=[[HarperCollins]] |year=2009 |isbn=978-0-9540884-3-9 |location=India |language=English |orig-year=1989}}</ref>
* [[Paula Frías Allende]]. The daughter of the Chilean novelist [[Isabel Allende]]. She fell into a porphyria-induced coma in 1991,<ref>{{Cite book |last=Allende |first=Isabel |year=1995 |title=Paula |title-link=Paula (novel) |location=New York |publisher=HarperCollins |isbn=978-0-06-017253-4}}</ref> which inspired Isabel to write the memoir ''[[Paula (novel)|Paula]]'', dedicated to her.

<gallery widths="200px" heights="200px">
File:Allan Ramsay - King George III in coronation robes - Google Art Project.jpg|[[George III of the United Kingdom|George III]] in his coronation robes. [[Coronation Portrait of George III|Portrait]] by [[Allan Ramsay (artist)|Allan Ramsay]], 1762
File:Mary, Queen of Scots after Nicholas Hilliard.jpg|[[Mary, Queen of Scots]] {{circa|1578}}
File:Maria I, Queen of Portugal - Giuseppe Troni, atribuído (Turim, 1739-Lisboa, 1810) - Google Cultural Institute.jpg|[[Maria I of Portugal]] in a {{Circa|1790s}} portrait attributed to [[Giuseppe Troni]] or [[Thomas Hickey (painter)|Thomas Hickey]]
</gallery>

===Uses in literature===
Stated or implied references to porphyria are included in some literature, particularly gothic literature. These include the following:
* The condition is the name of the title character in the gothic poem "[[Porphyria's Lover]]," by [[Robert Browning]].{{cn|date=December 2024}}
* The condition is heavily implied to be the cause of the symptoms suffered by the narrator in the gothic short story "[[Stone Mattress|Lusus Naturae]]," by [[Margaret Atwood]]. Some of the narrator's symptoms resemble those of porphyria, and one passage of the story states that the name of the narrator's disease "had some Ps and Rs in it." {{citation needed|date=January 2022}}

==References==
{{Reflist}}

==External links==
{{Wiktionary}}
* [http://www.drugs-porphyria.org/ The Drug Database for Acute Porphyria - comprehensive database on drug porphyrinogenicity]
* [http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=738.0 Orphanet's disease page on Porphyria]

{{Heme metabolism disorders}}
{{Medical resources
|DiseasesDB     =
|ICD10          = {{ICD10|E|80|0|e|70}}-{{ICD10|E|80|2|e|70}}
|ICD9           = {{ICD9|277.1}}
|ICDO           =
|OMIM           =
|MedlinePlus    = 001208
|eMedicineSubj  =
|eMedicineTopic =
|MeshName       = Porphyrias
|MeshNumber     = C17.800.849.617
|Orphanet       = 738
|}}
{{Authority control}}

[[Category:Porphyrias| ]]
[[Category:Diseases of liver]]
[[Category:Red blood cell disorders]]
[[Category:Skin conditions resulting from errors in metabolism]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Wikipedia neurology articles ready to translate]]