Test ID: PEE    
Porphyrins Evaluation, Whole Blood

Diagnosis of erythropoietic protoporphyria and congenital erythropoietic porphyria

Evaluation of chronic intoxication from exposure to a variety of agents including heavy metals and chemicals

Differentiating iron-deficiency anemia from other causes of elevated porphyrin levels

There are 2 test options: PEE/88886 Porphyrins Evaluation, Whole Blood and PEWE/31893 Porphyrins Evaluation, Washed Erythrocytes. The whole blood option is easiest for clients but requires that the specimen arrive at Mayo Medical Laboratories within 48 hours of draw. When this cannot be ensured, washed RBCs should be submitted.

The porphyrias are a group of inherited disorders resulting from an enzyme deficiency in the heme biosynthetic pathway. Depending on which enzyme is deficient, various porphyrins and their precursors accumulate in plasma, erythrocytes, and tissues, and are excreted in the urine, feces, or both.

The porphyrias can be classified as either erythropoietic or hepatic. Both the erythropoietic porphyrias and the chronic hepatic porphyrias are associated with cutaneous photosensitivity, but not with the neurological symptoms that accompany the acute hepatic porphyrias. Diagnosis of the erythropoietic porphyrias (ie, erythropoietic protoporphyria [EPP] and congenital erythropoietic porphyria [CEP]) can be determined by analysis of porphyrins in the erythrocytes.

Erythrocyte (RBC) porphyrins consist almost entirely of protoporphyrin. Increased RBC protoporphyrin is characteristic of EPP and of the intoxication porphyrias that may be caused by heavy metals, halogenated solvents, some pesticides, and medications. However, iron deficiency anemia is the most common cause of increased RBC protoporphyrin. Therefore, when total RBC porphyrins are elevated, fractionation and quantitation of zinc-complexed and noncomplexed (free) protoporphyrin are necessary to differentiate the inherited porphyrias from other causes of elevated porphyrin levels.

Zinc-complexed protoporphyrin may be increased in RBCs in association with:

-Iron-deficiency anemia (the most common cause of elevated zinc protoporphyrin)

-Chronic intoxication by heavy metals (primarily lead) or various organic chemicals

-CEP

-Hepatoerythropoietic porphyria, a rare form of porphyria caused by homozygous or compound heterozygous mutations in the uroporphyrinogen decarboxylase gene (UROD)

-X-linked dominant protoporphyria, a form of protoporphyria caused by a gain of function mutation in the C-terminal end of ALAS2 gene

Free protoporphyrin is increased in RBCs in association with EPP, an erythropoietic porphyria that is inherited in an autosomal dominant fashion. EPP is considered to be the third most common form of porphyria. It is caused by diminished ferrochelatase activity, which results in increased free protoporphyrin levels in RBCs, plasma, and feces. Onset of symptoms typically occurs in childhood with cutaneous photosensitivity in sun-exposed areas of the skin, generally becoming worse in the spring and summer months. Common symptoms may include itching, edema, erythema, stinging or burning sensations, and occasionally scarring of the skin in sun-exposed areas.

CEP is an erythropoietic porphyria that is inherited in an autosomal recessive fashion. CEP is caused by uroporphyrinogen III synthase deficiency, which results in the accumulation and excretion of uroporphyrin I and coproporphyrin I in urine and feces. Circulating RBCs contain measurable amounts of uroporphyrin and coproporphyrin. RBC zinc protoporphyrin may also be elevated due to increased erythropoiesis. Symptoms typically present in early infancy with red-brown staining of diapers, severe cutaneous photosensitivity with fluid-filled bullae and vesicles. Other common symptoms may include thickening of the skin, hypo- and hyperpigmentation, hypertrichosis, cutaneous scarring, and deformities of the fingers, eyelids, lips, nose, and ears.

PORPHYRINS, TOTAL, RBC

<80 mcg/dL packed cells

FREE PROTOPORPHYRIN

<20 mcg/dL packed cells

ZINC-COMPLEXED PROTOPORPHYRIN

<60 mcg/dL packed cells

UROPORPHYRIN

< or =2 mcg/dL packed cells

HEPTACARBOXYLPORPHYRIN

< or =1 mcg/dL packed cells

HEXACARBOXYLPORPHYRIN

< or =1 mcg/dL packed cells

PENTACARBOXYLPORPHYRIN

< or =1 mcg/dL packed cells

COPROPORPHYRIN

< or =2 mcg/dL packed cells

PROTOPORPHYRIN

<80 mcg/dL packed cells

An elevation of total RBC porphyrins can be an expression of a primary or secondary defect in the biosynthesis of heme. However, the specific type of porphyria cannot be determined by total porphyrin analysis alone.

Total RBC porphyrin values >80 mcg/dL suggest the existence of an intoxication problem or a metabolic problem that involves accelerated erythropoiesis. If the total RBC porphyrin concentration is elevated, additional testing (fractionation assays) is required to identify and quantify the specific affected porphyrin. Increased total RBC porphyrin concentrations may be due to:

-Free protoporphyrin, the predominant form that is elevated in patients with erythropoietic protoporphyria

-Zinc protoporphyrin, elevated in patients with heavy metal intoxication or iron deficiency anemia

-Uroporphyrin and coproporphyrin, preferentially elevated in patients with congenital erythropoietic porphyria

A written interpretation is included with all reports. When abnormal results are detected, a detailed interpretation is given, including:

-An overview of the results and their significance

-Elements of a differential diagnosis

-Recommendations for additional biochemical testing

A normal RBC porphyrin evaluation does not rule out other forms of porphyria including porphyria cutanea tarda (PCT), acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP).

See The Heme Biosynthetic Pathway in Special Instructions.

Abstinence from alcohol for at least 24 hours prior to specimen collection is essential as ethanol induces some enzyme activity and suppresses other enzymes along the heme biosynthetic pathway.

It is essential to proceed expeditiously with obtaining, processing, and dispatching the specimen, paying special heed to maintaining low temperatures (see Specimen Required). Failure to adhere to these directions may result in analyte degradation, yielding false-negative values.

1. Nuttall KL, Klee GG: Analytes of hemoglobin metabolism-porphyrins, iron and bilirubin. In Tietz Fundamentals of Clinical Chemistry. Fifth edition. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 2001, pp 584-607

2. Ellefson RD: Porphyrinogens, porphyrins and the porphyrias. Mayo Clin Proc 1982;57:454-458

3. Anderson KE, Sassa S, Bishop DF, Desnick RJ: Disorders of heme biosynthesis: X-linked sideroblastic anemia and the porphyrias. In The Metabolic Basis of Inherited Disease. Eighth edition. Edited by CR Scriver, AL Beaudet, WS Sly, et al. New York, McGraw-Hill Medical Published Division, 2001, pp 2991-3062

4. Sassa S: Modern diagnosis and management of the porphyrias. Br J Haematol 2006;135:281-292

5. Whatley SD, Ducamp S, Gouya B, et al: C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. Am J Hum Genet 2008 Sep;83(3):408-414

• The Heme Biosynthetic Pathway
• Informed Consent for Genetic Testing
• Porphyria (Acute) Testing Algorithm
• Porphyria (Cutaneous) Testing Algorithm