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Porphyrias result from genetic 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 synthesized mostly in the bone marrow (by erythroblasts and reticulocytes) and is incorporated into hemoglobin. Heme is also synthesized in the liver and incorporated into certain enzymes (eg, cytochromes). 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), which are toxic if they accumulate.

Etiology

Most porphyrias are autosomal dominant. Homozygous or double heterozygous states may be incompatible with life, generally causing fetal death; the exceptions are δ-aminolevulinic acid (ALA) dehydratase (ALAD)-deficiency porphyria and uroporphyrinogen III cosynthase deficiency, in which only homozygous or double heterozygous conditions (ie, 2 separate heterozygous mutations in the same gene in the same patient) 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.

Table 1
Substrates and Enzymes of the Heme Biosynthetic Pathway and the Diseases Associated With Their Deficiency This table is presented as a PDF and requires the free Adobe PDF reader. Get Adobe Reader

Pathophysiology

Porphyrias result from a deficiency of any of the last 7 enzymes of the heme biosynthetic pathway (deficiency of the first enzyme in the pathway, ALA synthase, causes sideroblastic anemia). Single genes encode each enzyme; any of numerous possible mutations can incapacitate 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 produce toxicities. 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
• Cutaneous

Acute porphyrias manifest as intermittent attacks of abdominal, mental, and neurologic symptoms. They are typically triggered by drugs and other exogenous factors. Cutaneous porphyrias tend to produce continuous or undulating symptoms involving cutaneous photosensitivity. Some acute porphyrias 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 oxidized porphyrins, 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 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.

Table 2
Major Features of the Two Most Common Porphyrias Porphyria Presenting Symptoms Exacerbating Factors Most Important Screening Tests* Treatment Acute intermittent porphyria Neurovisceral (intermittent, acute) Drugs (mostly cytochrome P-450 inducers) Fasting Alcohol ingestion Organic solvents Infections Stress Urinary PBG Glucose Heme Porphyria cutanea tarda Blistering skin lesions (chronic) Iron Alcohol ingestion Estrogens Some Trade Names PREMARIN Click for Drug Monograph Hepatitis C virus Halogenated hydrocarbons Urinary or plasma porphyrins Phlebotomy Low-dose chloroquine Some Trade Names ARALEN Click for Drug Monograph *In symptomatic phase. PBG = porphobilinogen.

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.

Table 3
Screening for Porphyrias Testing In Patients With Acute Neurovisceral Symptoms In Patients With Photosensitivity Screening Urinary PBG (semiquantitative, random urine sample) Plasma porphyrins* Confirmation(when screening test results are significantly abnormal) Urinary ALA and PBG† (quantitative‡) Fecal porphyrins† RBC PBG deaminase Plasma porphyrins* RBC porphyrins Urinary ALA, PBG, and porphyrins (quantitative) Fecal porphyrins† Plasma porphyrins* *The preferred method is by direct fluorescent spectrophotometry. †Urinary and fecal porphyrins are fractionated only if the total is increased. ‡Results are corrected according to urine creatinine level. ALA = δ-aminolevulinic acid; PBG = porphobilinogen.

Last full review/revision August 2008 by Stig Thunell, MD, PhD

Content last modified August 2008