Calciphylaxis and the Concept of "Vital Mordanting"

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CALCIPHYLAXIS and THE CONCEPT OF "VITAL MORDANTING" HANS SELYE* In 1927, soon after the discovery ofvitamin D, it became evident that overdosage with irradiated ergosterol produces widespread soft-tissue calcifications and bone absorption in the rat (1-3). The next year I happened to see a patient in whom similar multiple organ calcifications occurred in combination with a parathyroid adenoma, nephritis, and colitis. The possibility was considered that, here, parathyroid stimulation might have represented an adaptive hormonal reaction; an attempt, as it were, to rectify the derangement caused by damage to the organs concerned with the absorption and excretion ofcalcium (4). A few years later we noted that in the newborn rat parathyroid hormone can produce cutaneous calcinosis with sclerosis resembling the calcifying type ofscleroderma (5). This finding raised the suspicion that an increased parathyroid activity—such as occurs, for instance, as an adaptive response to derangements in calcium metabolism—may participate in the pathogenesis of connective-tissue diseases (6). However, it was not until twenty-five years later that we succeeded in reproducing similar lesions in rats with dihydrotachysterol (DHT), a vitamin-D derivative that closely imitates the actions of parathyroid hormone (7). Unfortunately, these cutaneous lesions—whether produced by parathyroid hormone or by DHT—could not serve as practical models ofdisease because they were invariably accompanied by high mortality and developed only inconstantly in newborn rats, and on the scalp and neck, not wherever the experimenter wanted to induce them. * Institut de Médecine et de ChirurgieExpérimentales, Université deMontréal, Montreal, Canada. The experimental work described here was supported by U.S. Public Health Service Grants Nos. A-l64i(C3), B-2037(C2), and H-6182, as well as by the Gustavus and Louise Pfeiffer Research Foundation and the Office of the Surgeon General, U.S. Army Medical and Research Command, Contract No. DA-49-193-MD-2039. 233 However, more recently we learned that cutaneous calcinosis with sclerosis can be regularly produced at will in predetermined skin regions, even in adult rats, ifthe selected area is lightly traumatized (e.g., by epilation or pinching) at a "critical time" ofDHT-treatment (9). Very dilute solutions ofvarious substances (egg white, egg yolk, salts ofiron, chromium , aluminum, etc.) also proved to be effective topical challenging agents conducive to a local calcifying response in rats sensitized by DHT or parathyroid hormone (10, 11). It was thought that these compounds may act as "vital mordants," attracting calcium as histologic mordants attract dyes. The response produced by a challenger, or "vital mordant," in an organism appropriately sensitized by a systemic calcifying agent, has been designated as "calciphylaxis" (8). The scope ofthese studies was greatly broadened oflate by the finding that intravenous injection ofvarious "vital mordants" can produce a wide variety of essentially distinct calciphylactic syndromes in the DHT-sensitized rat. The nature and distribution of the lesions elicited in this manner depends largely upon the physicochemical characteristics ofthe mordants and their specific affinities for certain organs. Calcium deposition and subsequent hyalinization with sclerosis appear to play a cardinal role in all calciphylactic syndromes, but the amount of calcium deposited is often small, and the precipitate may vanish so rapidly that its detection is often impossible with histochemical methods now available. Hence, the absence of demonstrable tissue calcification in a morbid lesion does not exclude the possibility that calciphylaxis occurred. Specific examples illustrating certain variants ofcalciphylaxis have been described elsewhere (8, 11-15). However, in view ofrecent developments in this field, a synoptic outline of the basic concept may be appropriate at this time as a guide to further research. I. BriefCharacterization ofCalciphylaxis A. DEFINITION Calciphylaxis is a condition of induced systemic hypersensitivity in which tissues respond to appropriate challenging agents with a precipitous, though sometimes evanescent, local calcification. The term was coined in analogy with such designations as "anaphylaxis," "tachyphylaxis," or "skeptophylaxis," which likewise refer to induced systemic alterations in the body's responsiveness to certain challenging agents (8). 234 Hans Selye · Calciphylaxis and "Vital Mordanting" Perspectives in Biology and Medicine · Winter 1962 We distinguish (a) topical calciphylaxis, induced by the direct application ofthe challenger to the responsive tissue from (b) systemic calciphylaxis, in which the challenger is distributed throughout the organism...

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