Variegate Porphyria Workup

Updated: Dec 20, 2019
  • Author: Carol E Cheng, MD; Chief Editor: Dirk M Elston, MD  more...
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Workup

Laboratory Studies

Urinary aminolevulinic acid and porphobilinogen levels are greatly elevated during attacks but often normalize during quiescent phases. [40] Older urinary porphobilinogen screening assays (eg, Watson-Schwartz and Hoesch methods) [41] had been supplanted for the last several years by a rapid semiquantitative test kit that is no longer commercially available. An alternative quantitative kit (PBG by Column Test #187-6001, BioRad; Hercules, Calif) remains available. Rapid determination of elevated urinary porphobilinogen allows early confirmation of an attack episode in variegate porphyria, acute intermittent porphyria, or hereditary coproporphyria porphyria.

Because medical management of an attack is the same for all three of these acute porphyrias, screening or rapid test kit evidence of elevated porphobilinogen is sufficient to justify initiating therapies in crisis situations, before other quantitative laboratory data for porphyrins and porphyrin precursors that establish a precise diagnosis can be obtained. Progressive motor weakness due to porphyric neuropathy, typically accompanied by high urinary porphobilinogen but normal cerebrospinal fluid protein levels, can be differentiated from acute ascending polyneuropathy (Landry-Guillain-Barré syndrome) by the normal urinary porphobilinogen but increased cerebrospinal fluid protein levels typical of the latter disorder. [33]

During symptomatic phases of variegate porphyria, urinary porphyrin levels are abnormally high, with coproporphyrin greater than uroporphyrin. Total fecal porphyrin excretion is also high; both protoporphyrin and coproporphyrin fractions are elevated, [42] with protoporphyrin greater than or equal to coproporphyrin. The isomer ratio of coproporphyrin III to coproporphyrin I is several-fold higher than normal. [43]

Erythrocyte porphyrin levels are typically normal in patients with one normal allele for the protoporphyrin oxidase gene and one with a deleterious mutation, but when 2 mutant alleles are present, zinc-protoporphyrin is elevated. [4, 23, 27]

Plasma porphyrin levels are increased in symptomatic patients. A fluorescence emission peak maximal at 625-627 nm detected by spectrofluorometry is unique to variegate porphyria, enabling rapid diagnostic confirmation. [44] Spectrofluorometry detects such plasma porphyrin peaks in many, but not all, asymptomatic adult carriers of protoporphyrin oxidase gene mutations, but only in some prepubertal carriers. [42]

Porphyrin abnormalities in urine, stool, and plasma may normalize during quiescent phases, or remain increased at variable levels. Increased biliary porphyrin levels may be the most sensitive biochemical indicator during quiescence. [45]

Assays for protoporphyrinogen oxidase enzyme activity are technically difficult, but are available in specialized porphyria laboratories in several countries.

Mutation analysis of the protoporphyrinogen oxidase (PPOX) gene is performed in several centers with particular interest in porphyrias and is commercially available in the United States. Genetic testing is often used to distinguish variegate porphyria from other acute hepatic porphyrias, in which clinical features may overlap significantly, and provides confirmation of the diagnosis. [46, 47] Because variegate porphyria in most individuals carrying a mutated gene remains clinically silent and may also be biochemically silent, family studies aimed at identifying all adults and children at risk for developing variegate porphyria require mutation analysis for absolute certainty of identifying all carriers. In order to accurately characterize the results of their mutational analysis, a genetic database of verified benign and pathological variants is necessary. To meet this need, the International Porphyria Molecular Diagnostic Collaborative was initiated in 2017 with the goal of establishing such a database. [48] Identifying asymptomatic patients with a pathologic mutation in their PPOX gene is important, as they should be counseled on avoiding triggers that may precipitate acute porphyric episodes. [47]

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Imaging Studies

Ultrasonography screening for hepatocellular carcinoma is indicated at least annually for individuals with variegate porphyria aged 50 years or older, especially those who have had long-term elevations of porphyrins and porphobilinogen. Gallstones may also be detected by ultrasonography.

Bone mineral density scanning can be performed to detect significant bone loss in individuals who have avoided sunlight over long periods because of unremitting porphyric photosensitivity.

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Other Tests

Serum vitamin D levels are recommended to assess insufficient or deficient levels resulting from long-term avoidance of sunlight exposure.

Periodic serum α-fetoprotein assessment is useful in surveillance for the development of hepatocellular carcinoma.

Periodic assessment of renal function is indicated in individuals with chronic arterial hypertension.

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Histologic Findings

Histologic findings resembling those of porphyria cutanea tarda are well described. [49, 50] Bullae are subepidermal and cell poor; a mild perivascular lymphocytic inflammatory infiltrate may be present. Thickened, hyalinized superficial dermal blood vessel walls contain periodic acid-Schiff stain–positive, diastase-resistant glycoprotein deposits. Ultrastructural examination of the dermal vasculature and the dermoepidermal junction reveals replicated basement membranes believed to be elaborated by multiple episodes of damage and repair and fine fibrillar material in the surrounding dermis. Immunoglobulin and complement deposits that are present perivascularly and at the dermoepidermal junction are believed to be due to leakage of these proteins from damaged blood vessels rather than to immunologically mediated events.

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