Porphyrias are a group of genetic disorders caused by disruptions in heme production, a stepwise process that involves multiple enzymes. Heme is an essential molecule made up of iron and protoporphyrin IX that helps transport oxygen throughout the body.
When this stepwise process becomes impaired, intermediate molecules used to make heme, known as porphyrins and their precursors, accumulate to toxic levels and limit the amount of oxygen carried in the blood.
Each type of porphyria stems from the loss or dysfunction of a specific enzyme in the heme production pathway. These types are roughly subdivided into two groups: cutaneous porphyrias that largely affect the skin, and acute porphyrias that mainly affect the nervous system.
Acute porphyrias are characterized by sudden and potentially severe attacks, whose symptoms develop over hours to days and may last for days to weeks. Time to treating symptoms often affects the quickness of recovery, making it important to get help as soon as possible.
There are four types of acute porphyria.
ALAD porphyria arises from mutations in the ALAD gene, leading to acute bouts of intense symptoms, or “attacks,” that often involve abdominal pain, nausea, and constipation. Attacks of ALAD porphyria can be more severe than those of other types and occur during childhood. ALAD porphyria is distinguished from other types in having, so far, only been reported in men.
Acute intermittent porphyria
Acute intermittent porphyria (AIP) is the most common form of acute porphyrias, with European studies putting its prevalence at 1 in every 20,000 people. It often presents with a range of symptoms involving multiple organs. Although it can be found throughout the world, AIP tends to be found more often in northern European countries. Because of this, it is sometimes called Swedish porphyria.
Hereditary coproporphyria (HCP) usually manifests in a person’s second or third decade of life, but can also occur around the time of puberty. Its onset before puberty is extremely rare. HCP tends to affect women more than men, and is considered a “low penetrance” disorder, meaning that many people who carry disease-causing mutations never actually show any symptoms of HCP. This may be because active disease, which can be severe, generally requires outside factors such as the use of certain drugs, hormonal changes (including use of oral contraceptives or those of the menstrual cycle), or dietary changes.
Variegate porphyria (VP) is caused by mutations in the protoporphyrinogen oxidase enzyme gene, PPOX. People with VP may have symptoms affecting their skin, as well as neurological symptoms. Attacks typically begin with severe abdominal pain, although they can sometimes start with pain in the chest, back, or thighs. Nausea, vomiting, and constipation often accompany these attacks. VP occurs more frequently in South Africa and among people of Dutch ancestry.
Cutaneous porphyrias encompass five forms of the disease that mainly affect the skin. In these five conditions, porphyrins are transported to the skin, most often from the liver.
Once near the skin surface, they absorb light, which pushes them into an “excited” or high-energy state. This state enables them to cause damage to the surrounding tissues, resulting in light sensitivity — usually to sunlight, but sometimes to artificial light, too — as well as fragile skin that blisters easily, grows red and swells, and changes color.
Porphyria cutanea tarda
Porphyria cutanea tarda (PCT), the most common form of porphyria, is characterized by sunlight sensitivity that leads to the formation of painful skin lesions and blistering in sun-exposed areas. The underactive uroporphyrinogen decarboxylase (UROD) enzyme resulting in PCT is more often due to environmental factors than genetics, making PCT a frequently “acquired,” rather than inherited, disorder.
Liver involvement in PCT is common, and this form can lead to cirrhosis and liver cancer, which are estimated to affect, respectively, around 35% and 7–24% of patients.
Hepatoerythropoietic porphyria (HEP) occurs when UROD enzyme activity levels fall under 10% of its normal values. This causes porphyrins to accumulate throughout the body, but especially within the bone marrow, red blood cells, liver, and skin. Because of this, HEP is very similar to PCT, but occurs more often in childhood, is normally more severe, and inherited in an autosomal recessive way, meaning that both copies of the UROD gene must contain disease-causing mutations for HEP to manifest.
Congenital erythropoietic porphyria
Congenital erythropoietic porphyria (CEP), also known as Günther disease, is the rarest type of porphyria. Most often seen in infancy, it is characterized by severe light sensitivity and subsequent infections that can lead to the loss of fingers and facial features. CEP results from mutations in either the UROS or GATA1 genes.
Erythropoietic protoporphyria and X-linked protoporphyria
Together, erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are the third most common form of porphyria, triggered by mutations in the FECH and ALAS2 genes, respectively. Both cause protoporphyrin levels to rise in the body, which raises the risk of gallstones, as these contain protoporphyrin.
Both conditions are marked by skin hypersensitivity to sunlight and to some types of artificial light, like fluorescent lights. They affect males and females in roughly equal proportions, but males tend to develop a more severe form of XLP. Skin symptoms typically occur in infancy, but in some cases only manifest in adolescence or adulthood.
Last updated: April 5, 2021
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