Porphyria

Porphyria is a group of disorders in which substances called porphyrins build up in the body, adversely 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.
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, 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. Hepatic porphyrias are those in which the enzyme deficiency occurs in the liver. Hepatic porphyrias include acute intermittent porphyria, variegate porphyria, aminolevulinic acid dehydratase deficiency porphyria, hereditary coproporphyria, and porphyria cutanea tarda.
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

Acute porphyrias

, variegate porphyria, aminolevulinic acid dehydratase deficiency porphyria and hereditary coproporphyria. 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, and tachycardia.
The most severe episodes may involve neurological complications: typically motor neuropathy, which leads to muscle weakness and potentially to quadriplegia 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, congenital erythropoietic porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria. 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 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 and open sores 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 ; 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	5-aminolevulinate dehydratase	Hepatic	Autosomal recessive	Abdominal pain, neuropathy	Extremely rare; fewer than 10 cases ever reported.
Acute intermittent porphyria	Hydroxymethylbilane synthase formerly porphobilinogen deaminase	Hepatic	Autosomal dominant	Periodic abdominal pain, peripheral neuropathy, psychiatric disorders, tachycardia	1 in 10,000–20,000
Congenital erythropoietic porphyria	uroporphyrinogen synthase	Erythropoietic	Autosomal recessive	Severe photosensitivity with erythema, swelling and blistering. Hemolytic anemia, splenomegaly	1 in 1,000,000 or less.
Porphyria cutanea tarda	uroporphyrinogen decarboxylase	Hepatic	Approximately 80% sporadic, 20% Autosomal dominant	Photosensitivity with vesicles and bullae	1 in 10,000
Hereditary coproporphyria	coproporphyrinogen oxidase	Hepatic	Autosomal dominant	Photosensitivity, neurologic symptoms, colic	1 in 500,000
Harderoporphyria	coproporphyrinogen oxidase	Erythropoietic	Autosomal recessive	Jaundice, anemia, enlarged liver and spleen, often neonatal. Photosensitivity later.	Extremely rare; fewer than 10 cases ever reported.
Variegate porphyria	protoporphyrinogen oxidase	Hepatic	Autosomal dominant	Photosensitivity, neurologic symptoms, developmental delay	1 in 300 in South Africa 1 in 75,000 in Finland
Erythropoietic protoporphyria	ferrochelatase	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, anyone who inherit a single gene may become a carrier. Generally they do not have symptoms but may pass the gene on to 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 that 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.
Certain antibiotics like rifapentine, rifampicin, rifabutine, isoniazid, nitrofurantoin and, possibly, metronidazole.
Ergot derivatives including dihydroergotamine, ergometrine, ergotamine, methysergide, etc.
Certain antiretroviral medications
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.