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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 1: Porphyrias: 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.
Etiology
Most porphyrias are autosomal dominant. Homozygous or compound heterozygous states (ie, 2 separate heterozygous mutations in the same gene in the same patient) may be incompatible with life, typically causing fetal death; the exceptions are δ-aminolevulinic acid (ALA) dehydratase (ALAD)–deficiency porphyria, congenital erythropoietic porphyria, and erythropoietic protoporphyria, in which only homozygous or compound heterozygous conditions cause disease. Disease penetrance in heterozygotes varies. In terms of genetic prevalence, the 2 most common porphyrias are acute intermittent porphyria (AIP) and porphyria cutanea tarda (PCT). The prevalence of each is about 1/10,000, but prevalence varies widely among regions and ethnic groups.
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Table 1
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| Substrates and Enzymes of the Heme Biosynthetic Pathway and the Diseases Associated With Their Deficiency |
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Substrate/Enzyme*
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Porphyria
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Neurovisceral Symptoms
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Cutaneous Symptoms
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Inheritance
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Glycine + succinyl CoA
Erythroid specific δ-aminolevulinic acid synthase-2 (ALAS 2)
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None (deficiency causes sideroblastic anemia)
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No (not a porphyria)
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No (not a porphyria)
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X-linked recessive
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δ-Aminolevulinic acid
δ-Aminolevulinic acid dehydratase (ALAD)
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ALAD-deficient porphyria
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Yes
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No
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Autosomal recessive
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Porphobilinogen
Porphobilinogen deaminase
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Acute intermittent porphyria
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Yes
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No
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Autosomal dominant
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Hydroxymethylbilane
Uroporphyrinogen III cosynthase
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Congenital erythropoietic porphyria
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No
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Severe, mutilating skin disease
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Autosomal recessive
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Uroporphyrinogen III
Uroporphyrinogen decarboxylase
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Porphyria cutanea tarda
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No
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Fragile skin, blisters
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Two variants: one autosomal dominant and one without known genetic correlate
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Hepatoerythropoietic porphyria
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No
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Severe blistering
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Autosomal recessive
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Coproporphyrinogen III
Coproporphyrinogen oxidase
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Hereditary coproporphyria
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Yes
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Fragile skin, blisters
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Autosomal dominant
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Protoporphyrinogen IX
Protoporphyrinogen oxidase
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Variegate porphyria
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Yes
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Fragile skin, blisters
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Autosomal dominant
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Protoporphyrin IX†
Ferrochelatase
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Erythropoietic protoporphyria
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No, except in patients with severe hepatobiliary pathology
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Skin pain, lichenification and other minor skin changes
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Autosomal recessive
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Heme (final product incorporated in various heme proteins)
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None
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—
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—
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—
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*Listed are successive intermediates in the heme biosynthetic pathway, beginning with glycine and succinyl CoA and ending with heme. Deficiency of an enzyme causes buildup of precursor compounds.
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† Increasedactivity of erythroid-specific ALAS 2, an X-linked disorder, can cause accumulation of protoporphyrin and thus a form of protoporphyria (X-linked protoporphyria).
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Pathophysiology
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 2: Porphyrias: 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) in the latent phase.
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Table 2
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| Major Features of the Two Most Common Porphyrias |
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Porphyria
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Presenting Symptoms
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Exacerbating Factors
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Most Important Screening Tests*
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Treatment
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Acute intermittent porphyria
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Neurovisceral (intermittent, acute)
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Drugs (mostly cytochrome P-450 inducers)
Fasting
Alcohol ingestion
Organic solvents
Infections
Stress
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Urinary PBG
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Glucose
Heme
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Porphyria cutanea tarda
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Blistering skin lesions (chronic)
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Iron
Alcohol ingestion
Estrogens
Hepatitis C virus
Halogenated hydrocarbons
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Urinary or plasma porphyrins
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Phlebotomy
Low-dose chloroquine or hydroxychloroquine
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*In symptomatic phase.
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PBG = porphobilinogen.
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Diagnosis
Patients with symptoms suggesting porphyria are screened by blood or urine tests for porphyrins or the porphyrin precursors PBG and ALA (see Table 3: Porphyrias: 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.
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Table 3
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| Screening for Porphyrias |
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Testing
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In Patients With Acute Neurovisceral Symptoms
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In Patients With Photosensitivity
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Screening
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Urinary PBG (semiquantitative, random urine sample)
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Plasma porphyrins*
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Confirmation (when screening test results are significantly abnormal)
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Urinary ALA and PBG†
(quantitative‡
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Fecal and urinary porphyrins†
RBC PBG deaminase
Plasma porphyrins*
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RBC porphyrins
Urinary ALA, PBG, and porphyrins (quantitative)
Fecal porphyrins†
Plasma porphyrins*
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*The preferred method is by direct fluorescent spectrophotometry.
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†
Urinary and fecal porphyrins are fractionated only if the total is increased.
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‡
Results are corrected according to urine creatinine level.
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ALA =
δ-aminolevulinic acid; PBG = porphobilinogen.
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Secondary porphyrinuria
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, benzene, lead) can cause elevated urinary coproporphyrin excretion. 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. 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. 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.
Last full review/revision March 2013 by Herbert L. Bonkovsky; Vinaya Maddukuri, MD
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