Porphyria Overview
The Porphyrias
The Porphyrias are disorders of heme biosynthesis, each caused by a deficiency of one of the enzymes necessary for the production of heme for hemoglobin, myoglobin, cytochromes, and other heme-containing proteins. These enzymes are found in all organs in the body and are arranged sequentially in a pathway, which is most active in the bone marrow and liver. Each enzyme deficiency results in the accumulation of certain pathway intermediates, which are either porphyrins or porphyrin precursors. Excess porphyrins cause skin photosensitivity, and excess porphyrin precursors are associated with neurological manifestations.
Classification of the porphyrias
Porphyrias are classified as acute or cutaneous depending on whether the symptoms are neurological or cutaneous. They are also classified as hepatic or erythropoietic depending on whether the primary site of overproduction and accumulation of pathway intermediates is the liver or bone marrow. Acute porphyrias cause attacks of pain (usually in the abdomen, extremities, and back), nausea, vomiting, constipation, heart palpitations due to rapid heart beat, high blood pressure, muscle weakness due to nerve impairment, urinary retention, confusion, hallucinations, and seizures. Most cutaneous porphyrias cause blistering, scarring and increased hair growth; one type causes a more immediate nonblistering reaction to sunlight.
The sequence of intermediates and enzymes, as well as the specific types of porphyria associated with deficiencies of these enzymes, are shown in the diagram.
( Click on image to see larger version )
The Acute Porphyrias:
The acute porphyrias include Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), Variegate Porphyria (VP), and d-Aminolevulinic Acid Dehydratase Porphyria (ADP). AIP is the most common of the acute porphyrias in all countries except South Africa, where VP is especially common (among people of Dutch ancestry). ADP is the least common, with less than 10 known cases worldwide. The acute attacks of neurological symptoms in the acute porphyrias may develop within hours and last for days or weeks. Pain in the abdomen and elsewhere is usually severe and accompanied by nausea, vomiting, constipation, and urinary retention. Increases in heart rate and blood pressure are common. A peripheral neuropathy may develop and lead to severe muscle paralysis. Central nervous system manifestations can include agitation, confusion, and seizures. Low sodium levels in the blood may result from inappropriately increased production of antidiuretic hormone (ADH) by the hypothalamus. The attacks are very rare in children before puberty. In adults, attacks are often provoked by certain drugs, dietary restrictions, alcohol, hormones, infections, and perhaps stress. HCP and especially VP may cause blistering skin photosensitivity as well as neurological symptoms, and, therefore, these porphyrias are classified as both acute and cutaneous. Long-term complications in some patients have included chronic pain, depression, kidney damage, and liver cancer. The acute porphyrias are classified as hepatic, because the excess intermediates accumulate initially in the liver. These porphyrias are always associated with gene mutations that reduce the function of a specific heme pathway enzyme (see diagram). The porphyrin precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG), are substantially increased in the three most common acute porphyrias (AIP, HCP, and VP), with only ALA being increased in ADP. The porphyria precursors are presumed to cause the neurological manifestations of these diseases.
Learn More:
The Cutaneous Porphyrias
All but one of the cutaneous porphyrias cause skin blistering and fragility on sun-exposed areas of the body, most commonly the backs of the hands, forearms, face, ears and neck. These occur in porphyria cutanea tarda (PCT), sometimes in HCP, and quite often in VP. Porphyrin levels are extremely high in most cases of congenital erythropoietic porphyria (CEP), and the more severe blistering skin lesions often lead to infection and mutilation with loss of facial features and fingers. Anemia due to hemolysis is also common in CEP. Erythropoietic protoporphyria (EPP) and a variant form of EPP, X-Linked protoporphyria (XLP) cause a distinctive, immediate, painful but nonblistering reaction to sunlight.
PCT is due to inhibition in the liver of the fifth enzyme in the heme pathway (see diagram). Excess iron, some environmental factors (alcohol, smoking, estrogens), and certain infections (hepatitis C, HIV) predispose certain individuals to developing PCT. About 20% of patients have inherited a mutation of the affected enzyme from one parent, and therefore have familial PCT (fPCT), but some of these other factors must also be present and the liver enzyme further inhibited before the disease becomes manifest. Patients with fPCT may have earlier onset of disease, but often there is no family history of the disease. Hepatoerythropoietic porphyria (HEP) is the autosomal recessive form of fPCT, with symptoms similar to CEP. PCT is readily treated by repeated phlebotomies to reduce iron or with a low-dose regimen of hydroxychloroquine. There is a long term risk of cirrhosis and liver cancer.
Most cases of EPP are due to an inherited deficiency of the last enzyme in the heme pathway. A variant X-linked form results from the inheritance of a mutation of the first enzyme in the pathway. Although EPP causes severe skin pain and greatly impairs quality of life, the diagnosis is often delayed more than any other type of porphyria because visible skin changes are not prominent and urine porphyrins are normal. Gallstones containing protoporphyrin may develop. A minority of patients develop severe liver disease due to protoporphyrin deposition, which can be life threatening and require liver transplantation.
Learn More:
Inheritance of the Porphyrias
Each type of porphyria is caused by a mutation, or change, in the gene coding for a specific heme biosynthetic enzyme. However, only about 20% of patients with PCT inherit such a mutation, and inhibition of the affected enzyme in the liver occurs due to additional inherited and acquired factors that affect iron metabolism and oxidative stress.
Table 1. Types of porphyria, their patterns of inheritance, and the enzyme that is deficient in each.
| Type | Inheritance |
Deficient Enzyme |
Gene | Gene Locus |
|---|---|---|---|---|
ALA-Dehydratase Porphyria (ADP) |
Autosomal recessive |
ALA-Dehydratase |
ALAD | 9q34 |
Acute Intermittent Porphyria (AIP) |
Autosomal dominant |
Hydroxymethylbilane synthase (Porphobilinogen deaminase) |
HMBS | 11q23 |
Congenital Erythropoietic Porphyria (CEP) |
Autosomal recessive |
Uroporphyrinogen III synthase |
UROS | 10q25-26 |
Porphyria Cutanea Tarda (PCT), familial form |
Autosomal dominant |
Uroporphyrinogen decarboxylase |
UROD | 1p34 |
Hepatoerythropoietic Porphyria (HEP) |
Autosomal recessive |
Uroporphyrinogen decarboxylase |
UROD | 1p34 |
Hereditary Coproporphyria (HCP) |
Autosomal dominant |
Coproporphyrinogen oxidase |
CPOX | 3q12 |
Variegate Porphyria (VP) |
Autosomal dominant |
Protoporphyrinogen oxidase |
PPOX | 1q22 |
Erythropoietic Protoporphyria (EPP) X-linked Protoporphyria (XLP) |
Autosomal recessive X-linked |
Ferrochelatase δ-Aminolevulinate synthase 2 |
PECH ALAS2 |
18q21 Xp11.21 |
For more information about inheritance, please visit Genetics 101.
The inherited porphyrias are either autosomal dominant (inherited from one parent), autosomal recessive (inherited from both parents), or X-linked (the gene is located on the X-chromosome; in males, inherited from the mother, and in females, inherited from either parent). "Autosomal" genes always occur in pairs, with one coming from each parent. Individuals with an autosomal dominant form of porphyria have one mutated gene paired with a normal gene, and there is a 50% chance with each pregnancy that the mutated gene will be passed to a child. Some of those who inherit the mutated gene may develop symptoms.
Individuals with an autosomal recessive type of porphyria have a pair of mutated genes, one passed to them from each of their parents. Each of their children will inherit one mutated gene for that porphyria, which will be paired with a normal gene from the other parent, and the child will be a “carrier” but will not have symptoms. If two carriers of mutated genes for the same enzyme have children, there is a 25% chance with each pregnancy that the child will inherit two mutated genes (one from each carrier parent), and these children will develop symptoms of the disease. It is very rare that a family or individual will have two types of porphyria.
In X-linked disorders, the gene is located on one of the sex chromosomes, called the X-chromosome. Females have two X-chromosomes, and males have one X-chromosome (and one Y-chromosome). Both males and females will likely have symptoms from a mutated gene on the X-chromosome, but females, with a normal gene on the other X-chromosome, usually are much less severely affected than males. The risk for children depends on the gender of the affected parent. A female with an X-linked gene mutation will have a 50% risk of passing that mutation to any of her children with each pregnancy. However, a male with such a mutation will pass the mutation to all of his daughters but none of his sons.
Treatment of the Porphyrias
Treatment approaches for the various types of porphyria are very different. For attacks of the acute porphyrias, harmful drugs and dietary indiscretions are stopped, and patients are usually hospitalized for treatment of severe pain, nausea and vomiting, correction of electrolyte imbalances, and observation for muscle and respiratory weakness, and are given intravenous glucose or hemin. PCT is effectively treated by phlebotomy or low-dose hydroxychloroquine. However, these therapies are not useful in other porphyrias with blistering skin lesions. Avoidance of sunlight and use of sun-protective clothing is most important in CEP and EPP. CEP is most effectively treated by marrow stem cell transplantation as early as possible in childhood. EPP patients may benefit from treatment with β-carotene, cysteine, or a variety of methods to darken the skin. Liver complications of EPP that do not respond to medical therapy may necessitate liver transplantation.
Diagnosis of the Porphyrias
Symptoms and signs of porphyria are not specific, so the diagnosis must be established by biochemical and DNA testing. Biochemical testing measures amounts of porphyrin precursors (ALA and PBG) and porphyrins in urine, blood plasma, red blood cells, and stool. Enzymes can also be measured, usually in red blood cells. Some biochemical tests are especially suitable for screening, and others for further testing to better establish the type of porphyria. DNA analysis identifies the specific mutation, or change, in a person’s gene for a specific enzyme. When acute porphyria is suspected as a cause of severe acute symptoms, urinary porphobilinogen (PBG), which can be determined quickly, should be assessed as part of first-line screening, with delta-aminolevulinic acid (ALA) and total urinary porphyrins measured later. When blistering skin lesions are present, first-line screening consists of measuring total plasma porphyrins or urine porphyrins. If EPP is suspected in a patient with nonblistering photosensitivity, total erythrocyte protoporphyrin should be measured, although plasma porphyrins are usually elevated also. If one of these initial screening tests is positive, additional testing will be needed to confirm the diagnosis and establish the specific type of porphyria. DNA analysis should then be done to identify the mutation in the specific porphyria gene. This will not only establish the diagnosis more definitively, but enable other family members to be tested and accurately identified as carriers of the same gene mutation, often before symptoms develop. These family members can be counseled about how to avoid symptoms and whether there may be risks of the disease to their offspring.
