porphyria porphyria porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system. the types that affect the nervous system are also known as acute porphyria, as symptoms are rapid in onset and short in duration. symptoms of an attack include abdominal pain, chest pain, vomiting, confusion, constipation, fever, high blood pressure, and high heart rate. the attacks usually last for days to weeks. complications may include paralysis, low blood sodium levels, and seizures. attacks may be triggered by alcohol, smoking, hormonal changes, fasting, stress, or certain medications. if the skin is affected, blisters or itching may occur with sunlight exposure. porphyrialeft 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/pɔːrˈfɪriə/ or /pɔːrˈfaɪriə/ specialtyhematology, dermatology, neurologysymptomsdepending on subtype—abdominal pain, chest pain, vomiting, confusion, constipation, fever, seizures, blisters with sunlightusual onsetrecurrent attacks that last days to weekscausesusually geneticdiagnostic methodblood, urine, and stool tests, genetic testingdifferential diagnosislead poisoning, alcoholic liver diseasetreatmentdepends on type and symptomsfrequency1 to 100 in 50,000 people 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 genes that make heme. they may be inherited in an autosomal dominant, autosomal recessive, or x-linked dominant manner. one type, porphyria cutanea tarda, may also be due to hemochromatosis (increased iron in the liver), hepatitis c, alcohol, or hiv/aids. the underlying mechanism results in a decrease in the amount of heme produced and a build-up of substances involved in making heme. porphyrias may also be classified by whether the liver or bone marrow is affected. diagnosis is typically made by blood, urine, and stool tests. genetic testing may be done to determine the specific mutation. treatment depends on the type of porphyria and the person's symptoms. 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. rarely, a liver transplant may be carried out. the precise prevalence of porphyria is unclear, but it is estimated to affect between 1 and 100 per 50,000 people. rates are different around the world. porphyria cutanea tarda is believed to be the most common type. the disease was described as early as 370 bc by hippocrates. the underlying mechanism was first described by german physiologist and chemist felix hoppe-seyler in 1871. the name porphyria is from the greek πορφύρα, porphyra, meaning "purple", a reference to the color of the urine that may be present during an attack. signs and symptoms 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). 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 quadriplegia (paralysis of all four limbs) and central nervous system symptoms such as seizures and coma. 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 for guillain–barré syndrome, and porphyria testing is commonly recommended in those situations. elevation of aminolevulinic acid from lead-induced disruption of heme synthesis results in lead poisoning having symptoms similar to acute porphyria. 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 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 of 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 blistering (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. cause the porphyrias are generally considered genetic in nature. genetics subtypes of porphyrias depend on which enzyme is deficient. porphyria type deficient enzyme type of porphyria inheritance symptoms prevalence aminolevulinate dehydratase deficiency porphyria (aladp) 5-aminolevulinate dehydratase (alad) hepatic autosomal recessive abdominal pain, neuropathy extremely rare; fewer than 10 cases ever reported. acute intermittent porphyria (aip) hydroxymethylbilane synthase (hmbs) formerly porphobilinogen deaminase (pbgd) hepatic autosomal dominant periodic abdominal pain, peripheral neuropathy, psychiatric disorders, tachycardia 1 in 10,000–20,000 congenital erythropoietic porphyria (cep) uroporphyrinogen synthase (uros) erythropoietic autosomal recessive severe photosensitivity with erythema, swelling and blistering. hemolytic anemia, splenomegaly 1 in 1,000,000 or less. porphyria cutanea tarda (pct) uroporphyrinogen decarboxylase (urod) hepatic approximately 80% sporadic, 20% autosomal dominant photosensitivity with vesicles and bullae 1 in 10,000 hereditary coproporphyria (hcp) coproporphyrinogen oxidase (cpox) hepatic autosomal dominant photosensitivity, neurologic symptoms, colic 1 in 500,000 harderoporphyria coproporphyrinogen oxidase (cpox) erythropoietic autosomal recessive 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 photosensitivity, neurologic symptoms, developmental delay 1 in 300 in south africa1 in 75,000 in finland erythropoietic protoporphyria (epp) ferrochelatase (fech) erythropoietic autosomal recessive photosensitivity with skin lesions. gallstones, mild liver dysfunction 1 in 75,000–200,000 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 the autosomal recessive types, if a person inherits a single gene they may become a carrier. generally they do not have symptoms, but may pass the gene onto offspring. 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: sulfonamides, including sulfadiazine, sulfasalazine and trimethoprim/sulfamethoxazole. sulfonylureas 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 (e.g. indinavir, nevirapine, ritonavir, saquinavir, etc.) progestogens some anticonvulsants including: carbamazepine, ethosuximide, phenytoin, topiramate, valproate. some 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 heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow) in humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, and p450 liver cytochromes. 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 enzymes 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. deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. heme function plays a central role in cellular metabolism. this is not the main problem in the porphyrias; most heme synthesis enzymes—even dysfunctional enzymes—have enough residual activity to assist in heme biosynthesis. the principal problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. the chemical properties of these intermediates determine the location of accumulation, whether they induce photosensitivity, and whether the intermediate is excreted (in the urine or feces). there are eight enzymes in the heme biosynthetic pathway, four of which—the first one and the last three—are in the mitochondria, while the other four are in the cytosol. defects in any of these can lead to some form of porphyria. the hepatic porphyrias are characterized by acute neurological attacks (seizures, psychosis, extreme back and abdominal pain, and an acute polyneuropathy), while the erythropoietic forms present with skin problems, usually a light-sensitive blistering rash and increased hair growth.variegate porphyria (also porphyria variegata or mixed porphyria), which results from a partial deficiency in proto oxidase, manifests itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. 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. diagnosis porphyrin studies porphyria is diagnosed through biochemical analysis of blood, urine, and stool. in general, urine estimation of porphobilinogen (pbg) is the first step if acute porphyria is suspected. as a result of feedback, the decreased production of heme leads to increased production of precursors, pbg being one of the first substances in the porphyrin synthesis pathway. in nearly all cases of acute porphyria syndromes, urinary pbg is markedly elevated except for the very rare ala dehydratase deficiency or in patients with symptoms due to hereditary tyrosinemia type i. in cases of mercury- or arsenic poisoning-induced porphyria, other changes in porphyrin profiles appear, most notably elevations of uroporphyrins i & iii, coproporphyrins i & iii, and pre-coproporphyrin. repeat testing during an attack and subsequent attacks may be necessary in order to detect a porphyria, as levels may be normal or near-normal between attacks. the urine screening test has been known to fail in the initial stages of a severe, life-threatening attack of acute intermittent porphyria. up to 90% of the genetic carriers of the more common, dominantly inherited acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) have been noted in dna tests to be latent for classic symptoms and may require dna or enzyme testing. the exception to this may be latent post-puberty genetic carriers of hereditary coproporphyria. as most porphyrias are rare conditions, general hospital labs typically do