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Overview of Porphyrias
Porphyrias result from genetic or acquired deficiencies of enzymes of the heme biosynthetic pathway. These deficiencies allow heme precursors to accumulate, causing toxicity. Porphyrias are defined by the specific enzyme deficiency. Two major clinical manifestations occur: neurovisceral abnormalities (the acute porphyrias) and cutaneous photosensitivity (the cutaneous porphyrias).
Heme, an iron-containing pigment, is an essential cofactor of numerous hemoproteins. Virtually all cells of the human body require and synthesize heme. However, most heme is synthesized in the bone marrow (by erythroblasts and reticulocytes) and is incorporated into hemoglobin. The liver is the second most active site of heme synthesis, most of which is incorporated into cytochrome P-450 enzymes. Heme synthesis requires 8 enzymes (see Table: Substrates and Enzymes of the Heme Biosynthetic Pathway and the Diseases Associated With Their Deficiency). These enzymes produce and transform molecular species called porphyrins (and their precursors); accumulation of these substances causes the clinical manifestations of the porphyrias.
With the exception of the sporadic type of porphyria cutanea tarda (PCT), the porphyrias are inherited diseases. Autosomal dominant (AD) inheritance is most common. In the AD porphyrias, homozygous or compound heterozygous states (ie, 2 separate heterozygous mutations, one in each allele of the same gene in the same patient) may be incompatible with life, typically causing fetal death. Disease penetrance in heterozygotes varies; thus, clinically expressed disease is less common than genetic prevalence. The 2 most common porphyrias, PCT and acute intermittent porphyria (AIP), are AD (20% of PCT is AD). The prevalence of PCT is about 1/10,000. The prevalence of the causative genetic mutation for AIP is about 1/1500, but because penetrance is low, the prevalence of clinical disease is also about 1/10,000. Prevalence of both PCT and AIP varies widely among regions and ethnic groups. In the autosomal recessive porphyrias, only homozygous or compound heterozygous states cause disease. Erythropoietic protoporphyria, the 3rd most common porphyria, is autosomal recessive. X-linked inheritance occurs in one of the porphyrias, X-linked protoporphyria.
Substrates and Enzymes of the Heme Biosynthetic Pathway and the Diseases Associated With Their Deficiency
Porphyrias result from a deficiency of any of the last 7 enzymes of the heme biosynthetic pathway or from increased activity of the first enzyme in the pathway, ALA synthase-2 (ALAS 2). (Deficiency of ALAS 2 causes sideroblastic anemia rather than porphyria.) Single genes encode each enzyme; any of numerous possible mutations can alter the levels and/or the activity of the enzyme encoded by that gene. When an enzyme of heme synthesis is deficient or defective, its substrate and any other heme precursors normally modified by that enzyme may accumulate in bone marrow, liver, skin, or other tissues and have toxic effects. These precursors may appear in excess in the blood and be excreted in urine, bile, or stool.
Although porphyrias are most precisely defined according to the deficient enzyme, classification by major clinical features (phenotype) is often useful. Thus, porphyrias are usually divided into 2 classes:
Acute porphyrias manifest as intermittent attacks of abdominal, mental, and neurologic symptoms. They are typically triggered by drugs, cyclic hormonal activity in young women, and other exogenous factors. Cutaneous porphyrias tend to cause continuous or intermittent symptoms involving cutaneous photosensitivity. Some acute porphyrias (hereditary coproporphyria, variegate porphyria) may also have cutaneous manifestations. Because of variable penetrance in heterozygous porphyrias, clinically expressed disease is less common than genetic prevalence (see Table: Major Features of the Two Most Common Porphyrias).
Urine discoloration (red or reddish brown) may occur in the symptomatic phase of all porphyrias except erythropoietic protoporphyria (EPP) and ALAD-deficiency porphyria. Discoloration results from oxidation of the porphyrinogens, the porphyrin precursor porphobilinogen (PBG), or both. Sometimes the color develops after the urine has stood in light for about 30 min, allowing time for non-enzymatic oxidation. In the acute porphyrias, except in ALAD-deficiency porphyria, about 1 in 3 heterozygotes (more frequently in females than males) also have increased urinary excretion of PBG (and urine discoloration) during the latent phase.
Major Features of the Two Most Common Porphyrias
Patients with symptoms suggesting porphyria are screened by blood or urine tests for porphyrins or the porphyrin precursors PBG and ALA (see Table: Screening for Porphyrias). Abnormal results on screening are confirmed by further testing.
Asymptomatic patients, including suspected carriers and people who are between attacks, are evaluated similarly. However, the tests are less sensitive in these circumstances; measurement of RBC or WBC enzyme activity is considerably more sensitive. Genetic analysis is highly accurate and preferentially used within families when the mutation is known. Prenatal testing (involving amniocentesis or chorionic villus sampling) is possible but rarely indicated.
Screening for Porphyrias
Several diseases unrelated to porphyrias may involve increased urinary excretion of porphyrins; this phenomenon is described as secondary porphyrinuria.
Hematologic disorders, hepatobiliary diseases, and toxins (eg, alcohol, benzene, lead) can cause elevated urinary coproporphyrin excretion. Elevated coproporphyrin excretion in the urine can occur in any hepatobiliary disorder because bile is one the routes of porphyrin excretion. Uroporphyrin may also be elevated in patients with hepatobiliary disorders. Protoporphyrin is not excreted in urine because it is water insoluble.
Some patients present with abdominal pain and neurologic symptoms mimicking acute porphyrias. Urinary ALA and PBG are typically not elevated in these diseases, and normal levels help distinguish secondary porphyrinuria from acute porphyrias. However, some patients with lead poisoning can have elevated urinary ALA levels. Blood lead levels should be measured in such patients. If urinary ALA and PBG are normal or only slightly increased, measurement of urinary total porphyrins and high-performance liquid chromatography profiles of these porphyrins are helpful for differential diagnosis of acute porphyric syndromes.
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