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Editorial |
Cecil Watson Laboratory, University of Minnesota, and, Abbott Northwestern Hospital, Minneapolis, MN 55407-3799
Address correspondence to: Abbott Northwestern Hospital, 800 East 28th St., Minneapolis, MN 55407-3799. Fax 612-863-4144; e-mail Claus.A.Pierach-2{at}tc.umn.edu
Jan Waldenström spoke of porphyria as the "little imitator" (when syphilis was the great imitator). This caveat is still true today: The clinical presentation may vary widely and may encompass cutaneous and neurological signs and symptoms. Appropriate therapy requires as precise a diagnosis as possible. Although the clinical presentation might be telling, as, for example, in porphyria cutanea tarda, in which the skin changes are fairly typical, other porphyrias can overlap in their cutaneous and neurologic findings, at times urgently requiring a detailed and focused workup with the help of the laboratory. Simple screening tests can lead the way, but they must always be followed by more sophisticated analyses. Thus, the Watson-Schwartz test (1) for excessive amounts of urinary porphobilinogen, recently called "hoary" by this Journal's Editor (2), although still widely used in emergencies and favored for its easy execution with just a few test tubes and some reagents, must always lead to further detailed studies. A newer test, although slightly more complicated, is more sensitive (3).
Although the clinical presentation might be confusing in itself, so is
the array of available laboratory studies for porphyria. It should be
noted that no single test covering all porphyric
possibilities exists and that caution is due: If porphyria is
suspected, testing for porphyrins might not even yield an answer
because in the inducible porphyrias (acute intermittent porphyria,
variegate porphyria, and hereditary coproporphyria), assays for
porphyrin precursors (
-amino levulinic acid and porphobilinogen) are
by far more helpful. In fact, porphyrin studies may be
unrevealing, and thus misleading.
Because the porphyrias are most often inborn errors of metabolism and
produced by enzymatic deficiencies, the ideal test would assay the
specific heme biosynthetic enzyme. This, however, is for technical
reasons routinely available for only one porphyria, the acute
intermittent type. For the other six or seven types of porphyria, tests
of porphyrins and their precursors are called for. These can be
performed with ease in blood and excreta, but require an understanding
of porphyrin chemistry. If one suspects porphyria as an explanation for
neurologic symptoms, tests for -amino levulinic acid and
porphobilinogen are called for. Because cutaneous manifestations of the
porphyrias are the result of excessive amounts of porphyrins, these
should be tested for. For that purpose, urinary and blood tests are
widely available. However, if a patient is anuric (e.g., on
dialysis), tests of feces or plasma must be performed. For the
latter, a new version is reported by Hindmarsh et al. (4) in
this issue of the Journal. The methodology seems sound, but the
required equipment, although not unique, reserves the procedure for
highly specialized laboratories and makes it unlikely that community
hospitals would introduce this method, helpful as it might be.
Hindmarsh et al. (4) see a unique indication for their method in analyzing plasma from patients with renal failure for whom the question of porphyria arises, although a rather small number of patients have this combination of problems. No major advantage is proposed for the other porphyric problems, and the method is not geared to measure protoporphyrin or porphyrin precursors. It is surprising that in five patients with hereditary coproporphyria (one with skin manifestations), normal or very near normal plasma concentrations for all porphyrins were found. One wonders what the patients' urinary or fecal porphyrin concentrations were at that time. It should also be kept in mind that coproporphyrinuria is not uncommon, for example, after alcohol ingestion (5), and at times leads to the erroneous diagnosis of coproporphyria.
Although the authors claim that follow-up of patients under treatment for porphyria cutanea tarda can be guided by assaying plasma for uroporphyrin, one could argue that this is not necessary because clinical guidance is usually sufficient: If the skin looks good, the porphyrin values are of very little importance.
With their method, Hindmarsh et al. (4) confirm previous
observations of an increase of plasma coproporphyrin in patients with
porphyria cutanea tarda. Here, the enzymatic impasse in the
biosynthetic pathway to heme is ahead of coproporphyrin formation, and
excessive amounts of the latter are not to be expected. The authors
explain their finding with the assumption of an overreaction of the
feedback loop in which -amino levulinic acid synthase formation is
excessively stimulated through a deficiency of the regulatory end
product, heme. This assumption by Hindmarsh et al. (4) and
others (6) has a logical flaw because if sufficient amounts
of coproporphyrin were produced, there would be no reason for a heme
deficiency. It seems best to abandon the term "counterregulatory
compensatory enhancement" (6) in this context and to
acknowledge that the increase of coproporphyrin concentrations in
porphyria cutanea tarda remains unexplained.
It would have been of interest and of potential clinical importance to attempt an adaptation of this method to detect heme in plasma, in particular in the clinical setting of treatment of a porphyric attack with hematin or heme arginate (7). This therapy uses bedside assessment of the patient, supplemented by measurements of porphyrin precursors, but measurement of the plasma concentrations of the therapeutically administered heme might be of great help, for example, if peak and trough concentrations were readily available to adjust the dose.
Another clinical problem in which this method could be of help is in transfused neonates with transient porphyrinemia (8), but the methodology might need to be adjusted because the withdrawal of ~5 mL of blood, as required for this method, might be quite large for a newborn.
Thus, the new method to assay plasma for porphyrins is appealing, but, as Hindmarsh et al. (4) acknowledge, its use seems limited to a few very specific questions to be answered with the help of highly specialized laboratories.
References
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