Interpretive Handbook

The porphyrias are a group of inborn errors of metabolism resulting from defects in the heme biosynthetic pathway. Enzymatic deficiencies result in the accumulation and excretion of intermediary metabolites in different specimen types. The pattern of excretion of the heme precursors in urine and feces and the accumulation within erythrocytes allow for the detection and differentiation of the hereditary porphyrias. These accumulations cause characteristic clinical manifestations, which may include neurologic and psychological symptoms and cutaneous photosensitivity depending upon the specific disorder. Although genetic in nature, environmental factors may exacerbate symptoms, significantly impacting the severity and course of disease. Early diagnosis coupled with education and counseling of the patient regarding the disease and treatment including avoidance of precipitating factors are important for successful management.

Urinary porphyrin determination is helpful in the diagnosis of most porphyrias including congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). In addition, measurement of porphobilinogen (PBG) in urine is important in establishing the diagnosis of the acute neurologic porphyrias (AIP, HCP, and VP). Neither urine porphyrins nor PBG are helpful in evaluating patients suspected of having erythropoietic protoporphyria (EPP).

Historically, the porphyrias have been divided into 2 groups, erythropoietic and hepatic based on the major site of substrate accumulation and/or overproduction. Another classification is based on clinical presentation and divides the porphyrias into acute or nonacute (cutaneous) categories. The acute porphyrias include AIP, HCP, and VP. The nonacute porphyrias include CEP, PCT, and EPP.

PCT is the most common form of porphyria. It presents clinically with increased skin fragility and the formation of vesicles and bullae on sun-exposed areas of the skin. PCT can be either sporadic (acquired) or inherited in an autosomal dominant manner. A biochemical diagnosis of PCT is characterized by increased urinary excretion of uroporphyrin and heptacarboxylporphyrin. Lesser amounts of hexacarboxylporphyrin, pentacarboxylporphyrin, and coproporphyrin may also be excreted. Hepatoerythropoietic porphyria (HEP) is observed when an individual inherits PCT from both parents. Patients exhibit a similar porphyrin excretion pattern as PCT, although the clinical presentation is similar to what is seen in CEP.

The clinical features of the acute porphyrias include abdominal pain, sensory neuropathy, and psychosis. Photosensitivity is not associated with AIP, but may be present in HCP and VP. The biochemical diagnosis of AIP is based upon an increased urinary excretion of PBG and aminolevulinic acid (ALA). In addition, uroporphyrin is also usually increased. A urine specimen obtained during an acute episode is most informative, as these analytes may be normal or only slightly increased between acute episodes of AIP. With respect to HCP and VP, the excretion pattern observed in urine is indistinguishable from one another with elevations of both coproporphyrin and PBG excretion being observed in urine. Fecal porphyrins analysis is recommended to differentiate VP from HCP.

CEP is a rare disorder typically presenting in childhood with prominent photosensitivity and voiding of dark, wine-colored urine. A few milder adult-onset cases have been documented as well as cases that are secondary to myeloid malignancies. A biochemical diagnosis of CEP is characterized by increased urinary excretion of uroporphyrin and coproporphyrin with the excretion of uroporphyrin usually exceeding that of coproporphyrin and the series I isomers predominating. Lesser amounts of the heptacarboxyl-, hexacarboxyl-, and pentacarboxyl porphyrins may be excreted. The urinary excretion of ALA and PBG is usually within normal limits.    

In addition to being a sign of an inheritable problem, porphyrinuria may result from exposure to certain drugs and toxins or other medical conditions (ie, renal disease, hereditary tyrosinemia type I). Heavy metals, halogenated solvents, various drugs, insecticides, and herbicides can interfere with heme production and cause "intoxication porphyria." Chemically, the intoxication porphyrias are characterized by increased excretion of ALA, PBG, uroporphyrin and/or coproporphyrin in urine.

Typically, the work up 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. Refer to The Challenges of Testing For and Diagnosing Porphyrias, Mayo Medical Laboratories Communique 2002 Nov;27(11) for more information.

Preferred screening test during symptomatic periods for acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria (additional confirmatory testing is required to establish a diagnosis)

Preferred screening test to begin assessment for congenital erythropoietic porphyria and porphyria cutanea tarda (additional confirmatory testing is required to establish a diagnosis)

Abnormal results are reported with a detailed interpretation including an overview of the results and their significance, a correlation to available clinical information provided with the specimen, differential diagnosis, and 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.

Porphobilinogen (PBG) and porphyrins are susceptible to degradation at high temperature, at pH <7.0, and on exposure to light. Twenty-four hour urine collections should be preserved by adding 5.0 g of sodium carbonate to a light-resistant collection container prior to beginning collection.

Ethanol and a variety of medications are known to interfere with heme synthesis leading to elevations in urine porphyrins, particularly coproporphyrin. Coproporphyrin elevation without concomitant PBG elevation should not be used as the basis for the diagnosis of porphyria, but may warrant follow-up testing with fecal porphyrin analysis.

UROPORPHYRINS (octacarboxyl)

< or =30 nmol/24 hours

HEPTACARBOXYLPORPHYRINS

< or =9 nmol/24 hours

HEXACARBOXYLPORPHYRINS

< or =8 nmol/24 hours

PENTACARBOXYLPORPHYRINS

< or =10 nmol/24 hours

COPROPORPHYRINS (tetracarboxyl)

Males: < or =230 nmol/24 hours

Females: < or =168 nmol/24 hours

PORPHOBILINOGEN

< or =2.2 mcmol/24 hours

1. Tortorelli S, Kloke K, Raymond K: 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, 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 BookCompany, 2001, pp 2991-3062