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The porphyrias are a group of inherited disorders resulting from enzyme defects in the heme biosynthetic pathway. Depending on the specific enzyme involved, various porphyrins and their precursors accumulate in different specimen types. The patterns of porphyrin accumulation in erythrocytes and plasma, and excretion of the heme precursors in urine and feces allow for the detection and differentiation of the porphyrias.
The porphyrias are typically classified as erythropoietic or hepatic based upon the primary site of the enzyme defect. In addition, hepatic porphyrias can be further classified as chronic or acute, based on their clinical presentation.
The primary acute hepatic porphyrias: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP), are associated with neurovisceral symptoms, which typically onset during puberty or later. Common symptoms include severe abdominal pain, peripheral neuropathy, and psychiatric symptoms. Crises may be precipitated by a broad range of medications (including barbiturates and sulfa drugs), alcohol, infection, starvation, heavy metals, and hormonal changes. Photosensitivity is not associated with AIP, but may be present in HCP and VP.
Cutaneous photosensitivity is associated with the chronic hepatic porphyrias: porphyria cutanea tarda (PCT) and the erythropoietic porphyrias; erythropoietic protoporphyria (EPP), X-linked dominant protoporphyria (XLDPP), and congenital erythropoietic porphyria (CEP). Although genetic in nature, environmental factors may exacerbate symptoms, significantly impacting the severity and course of disease.
CEP is an erythropoietic porphyria caused by uroporphyrinogen III synthase deficiency. 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. A few milder adult-onset cases have been documented as well as cases that are secondary to myeloid malignancies.
PCT is the most common form of porphyria and is most commonly sporadic (acquired), but in about 25% of cases it is inherited in an autosomal dominant manner. The most prominent clinical characteristics are cutaneous photosensitivity and scarring on sun-exposed surfaces. Patients experience chronic blistering lesions resulting from mild trauma to sun-exposed areas. These fluid-filled vesicles rupture easily, become crusted, and heal slowly. Secondary infections can cause areas of hypo- or hyperpigmentation or sclerodermatous changes and may result in the development of alopecia at sites of repeated skin damage. Liver disease is common in patients with PCT as evidenced by abnormal liver function tests and 30% to 40% of patients developing cirrhosis. In addition, there is an increased risk of hepatocellular carcinoma.
Hepatoerythropoietic porphyria (HEP) occurs when an individual inherits PCT from both parents. Patients exhibit a similar clinical presentation to what is seen in CEP.
Clinical presentation of EPP and XLDPP is identical with onset of symptoms typically occurring in childhood. Cutaneous photosensitivity in sun-exposed areas of the skin generally worsens 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.
Increased fecal porphyrin excretions are observed most commonly in symptomatic patients with CEP, PCT, HCP, and VP. In quiescent phases, as well as prior to puberty, fecal porphyrin excretion may be within normal limits. Patients with AIP may have elevated fecal porphyrin levels during severe attacks. EPP and XLDPP patients may have elevated protoporphyrin levels, however, these disorders cannot be diagnosed by fecal analysis alone.
The workup of patients with a suspected porphyria is most effective when following a stepwise approach. See Porphyria (Acute) Testing Algorithm and Porphyria (Cutaneous) Testing Algorithm in Special Instructions or contact Mayo Medical Laboratories to discuss testing strategies.
Evaluation of patients who present with signs or symptoms suggestive of porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria, congenital erythropoietic porphyria, erythropoietic protoporphyria, or X-linked dominant protoporphyria
Abnormal results are reported with a detailed interpretation that may include an overview of the results and their significance, a correlation to available clinical information provided with the specimen, differential diagnosis, recommendations for additional testing when indicated and available, and a phone number to reach one of the laboratory directors in case the referring physician has additional questions.
Heme from red meat can contribute to fecal protoporphyrin concentrations and cause a misleading indication of erythropoietic protoporphyria, X-linked dominant protoporphyria, or variegate porphyria.
Aspirin ingestion may cause minimal gastrointestinal bleeding, leading to false elevations of protoporphyrin.
Specimen submitted should contain at least 100 g of feces. Specimens smaller than 100 g may not provide interpretable results. Specimens weighing less than 10 grams will be rejected.
<120 mcg/24 hours
<50 mcg/24 hours
HEPTACARBOXYL PORPHYRIN I
<40 mcg/24 hours
HEPTACARBOXYL PORPHYRIN III
<40 mcg/24 hours
<30 mcg/24 hours
HEXACARBOXYL PORPHYRIN I
<10 mcg/24 hours
HEXACARBOXYL PORPHYRIN III
<10 mcg/24 hours
<10 mcg/24 hours
PENTACARBOXYL PORPHYRIN I
<20 mcg/24 hours
PENTACARBOXYL PORPHYRIN III
<20 mcg/24 hours
<80 mcg/24 hours
<500 mcg/24 hours
<400 mcg/24 hours
<200 mcg/24 hours
<1,500 mcg/24 hours
COPROPORPHYRIN III/COPROPORPHYRIN I RATIO
See The Heme Biosynthetic Pathway in Special Instructions.
1. Tortorelli S, Kloke KM, Raymond KM: Chapter 15: Disorders of porphyrin metabolism. In Biochemical and Molecular Basis of Pediatric Disease. Fourth edition. Edited by DJ Dietzen, MJ Bennett, ECC Wong. AACC Press, 2010, pp 307-324
2. Nuttall KL, Klee GG: Analytes of hemoglobin metabolism - porphyrins, iron, and bilirubin. In Tietz Textbook of Clinical Chemistry. Fifth edition. Edited by CA Burtis, ER Ashwood. Philadelphia, WB Saunders Company, 2001, pp 584-607
3. Anderson KE, Sassa S, Bishop DF, et al: 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 Book Company, 2001, pp 2991-3062