The specific tissue changes which follow the deprivation of fat-soluble vitamin A in albino white rats and in the human concerns epithelial tissues. This effect is the substitution of stratified keratinizing epithelium for normal epithelium in various parts of the respiratory tract, alimentary tract, eyes, and paraocular glands and the genitourinary tract. We have described the morphological sequences which clearly show that the replacement of epithelium arises from focal proliferation of cells arising from the original epithelium and not by differentiation or change of preexisting cells. Young rats respond to the deficiency more promptly than adults. Growth activity of epithelium is not diminished. On the contrary, there is convincing evidence that it is greatly augmented. In a few of our animals the behavior of the replacing epithelium in respect to numbers of mitotic figures and response on the part of connective tissue and blood vessels suggests the acquisition of neoplastic properties. While the epitheliums which are the seats of these changes are largely of covering types, glandular epithelium is involved, specifically in the paraocular glands and salivary glands. It is highly probable also that the epithelium of gland ducts, respiratory mucosa, and genitourinary tract have secretory functions so that we conclude that the deficiency results in loss of specific (chemical) functions of the epitheliums concerned, while the power of growth becomes augmented. Explanation for the substitution of a chemically inactive (nonsecretory) epithelium, common in type for all locations, remains a matter of speculation. We can only speculate also in regard to the absence of change in the epithelium of such organ as the liver, parenchyma of the kidney, stomach, and intestines. The significance of the order or sequence in which different organs exhibit this change has not been determined. In general the respiratory mucosa in nares, trachea, and bronchi respond first, then the salivary glands, eye, genitourinary tract, then paraocular glands and pancreas, although as has been noted there are exceptions to this order. Our studies show that the mitochondrial apparatus is not primarily affected. Study of individual cells indicates that the first morphological evidence of avitaminosis will be found in the nucleus. We have not devoted sufficient study to be certain, but an increase of chromatin and in some instances in size of nucleoli are early morphological manifestations. Other important effects of fat-soluble A deficiency are atrophy of glandular organs, emaciation, localized edema of testes, submaxillary gland, and connective tissue structures of the lungs and focal myocardial lesions. From our own limited experience with rats fed on a water-soluble B deficient diet and from work by Cramer, Drew, and Mottram, the loss of fat in water-soluble B deficiency is as great, if not greater than in vitamin A deuciency, so that tor tne present we assume that this is not a specific manifestation of any one avitaminosis. The same applies to glandular atrophy. Both of these effects probably concern the nutrition as a whole and may be ascribed to inanition. The occurrence of transient edema in testes and salivary gland coinciding with a period of maximum atrophic change, suggests the hypothesis that this edema is the result of failure of epithelium to utilize transported material, which leads further to the hypothesis that the capillaries of these organs are differentiated in regard to permeability to the respective materials utilized by the cells. It would seem that in the case of the testis we have a unique instance of complete atrophy producible at will without impairment of circulation and supporting tissues. This phenomenon may possibly be followed with advantage in the study of the mechanism of edema. Vascularization of the cornea, as we have shown it to be independent of infection, must be a physiological response to the increased demands of the rapidly growing epithelium which has replaced the corneal epithelium. We have assumed throughout this work that the diet on which we kept our animals was deficient in respect to a single substance or group of substances having similar physiological properties, designated by the term fat-soluble vitamin A. Whether or not more than one so called vitamin or accessory substance was missing in the diet we employed does not affect the theoretical importance of the morphological results. Work by Evans and Bishop would indicate that other factors affecting fertility in addition to the so called antixerophthalmic or vitamin A factor may have been missing. Our own experience leads us to believe the specific effects we have described upon epithelial tissues were in all probability due to withdrawal of a single factor. We have shown how these effects, that is the replacement of uterine epithelium by keratinizing epithelium can account for sterility in the female. Whether or not the atrophy of the testis is due to the same factor remains to be proved, but presumptive evidence is strong that this is the case. The study of the reverse changes that follow in the rapid amelioration when the rats are restored to an adequate diet has been begun and will be reported later. We have shown that the substitution of keratinizing epithelium in all locations is not secondary to infections, and presumably is a primary effect of the withdrawal of factors essential for the chemical activities or maintenance of differentiation of the epitheliums concerned. It is, of course, possible that the phenomenon is produced in a roundabout way in that it may be secondary to the effects of the avitaminosis upon the metabolism of tissue-sustaining substances. This possibility is supported by the cessation of growth of the skeleton and teeth, although we know that other avitaminoses produce retardation of growth.
