Vitamin A Deficiency

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Excerpt from “The Pathologic Changes Resulting from Vitamin Deficiency,” The Journal of the American Medical Association, January 2, 1937. NOTE: A Glossary of Terms appears at the end of this article

The primary effect of vitamin A deficiency is on epithelial structures. The sequences are atrophy of the epithelium concerned and the substitution for it of a stratified keratinizing epithelium, identical in appearance in all locations, and arising from focal proliferation of basal cells. These sequences have been carefully worked out in rats and guinea-pigs. Since replacement by keratinizing epithelium in many organs has also been found in human infants, in the monkey (Macacus rhesus) and in the albino mouse, and since gross changes indicate the same histologic changes in swine, in dogs, in rabbits, in cattle, and in the domestic fowl, the conclusion seems unavoidable that vitamin A is essential in most vertebrate species and that its withdrawal is followed by a common effect on epithelial structures.

For convenience this change will be called keratinizing metaplasia, regardless of exact connotations of the term. The detailed studies by Howe and myself have led us to the conclusion that the absence of vitamin A creates a starvation specific for many epitheliums. The consequence is atrophy, which progresses to a state wherein the cells, although having the appearances of viability, become inert in physiologic activities and in their role of covering membranes. An invariable sequence in pathology is that a break in the continuity of a tissue is followed by reparative proliferation. In vitamin A deficiency the basal cells normally concerned in maintaining the integrity of epithelium respond by active mitotic division.

As the basal cells have a focal distribution in all nonstratified epitheliums, the next effect of the deficiency after atrophy is the appearance of scattered areas of proliferative activity beneath the original epithelium. The new (reparative) cells by their continued growth undermine and replace the original epithelium and, regardless of previous function and morphology of the region, develop into a stratified keratinizing epithelium.

An important feature in explanation of much of the gross pathologic change is the fact that this replacement epithelium is identical in all locations and comparable in all its layers with epidermis. It has a continuous layer of basal cells—a stratum germinativum—in continuous proliferative activity while superficially it is continuously casting off keratinized cells.

The striking gross pathologic condition of vitamin A deficiency in animals and in human infants is the outcome of the accumulation of keratinized epithelial cells in many glands and their ducts and in other organs. In glandular organs, cysts of considerable size are formed, filled with yellowish cheesy masses of keratinized cells. In the lungs of human beings as well as of experimental animals this process leads to cyst formation, bronchial occlusion, and consequences such as bronchiectasis and atelectasis.

Early students of vitamin A deficiency, chemists and physiologists, neglected to study these cysts and believed them to be abscesses. Hence, for many years vitamin A was believed to protect against infection. As a matter of fact, the plugs of desquamated epithelial cells in ducts, bronchi and trachea, opening as they do on regions normally infected with bacteria, provide a culture medium for their growth. In spite of the fact that in both human beings and laboratory animals such bacterial growths were frequently found by us, very rarely was there invasion of the tissues, presumably because of the protection afforded by the stratified epithelium.

Distribution of the Keratinizing Metaplasia

In the rat, the order of response to vitamin A deficiency by metaplasia is:

1. Salivary glands, including submaxillary, parotid and all accessory glands of the tongue, buccal cavity and pharynx.

2. Respiratory tract, including nares, maxillary sinuses, Jacobson’s organ, trachea and bronchi.

3. Genito-urinary tract, including the renal pelves, ureters, bladder, epididymis, prostate, seminal vesicles, coagulating glands, uterus, oviducts and accessory sex glands of the vulva.

4. Eye and parocular glands, including the corneal and palpebral conjunctiva and the harderian, intra-orbital and extra-orbital lacrimal glands and the meibomian glands.

In the guinea-pig, lesion of the conjunctiva and parocular glands did not develop in our experiments even though advanced lesions (keratinizing metaplasia and its consequences) were found in all other locations as recorded for the rat. A marked difference in behavior as compared with the rat was early and extraordinary degrees of metaplasia in the uterus and bladder.

In human infants, keratinizing metaplasia has been found in the conjunctiva, mucosa of the nares, accessory sinuses, trachea, bronchi, pancreas, renal pelves, ureters, salivary glands, uterus, and periurethral glands. The commonest and earliest appearance of the metaplasia is in the trachea and bronchi. Next in frequency and sequence is the pelvis of the kidney. The early effect of the deficiency on the respiratory mucosa is a satisfactory explanation of the frequency, severity and persistence of the pneumonias that have been in most instances responsible for death in vitamin A deficient infants.

In the human being, as in the rat, involvement of the eye occurs late. The first change is metaplasia of the epithelium of the cornea and of the conjunctival sac. Atrophy and metaplasia of ducts of the parocular glands contribute to the consequences of the accumulation of keratinizing cells in the conjunctival sac. The cornea becomes vascularized, edematous and infiltrated with leukocytes. Infection of the cornea, favored by excessive accumulation of keratinizing cells, may lead to ulceration of the cornea and hypopyon.

The Teeth in Vitamin A Deficiency

The continuously growing incisor teeth of rodents—rats and guinea-pigs—are profoundly affected owing first to atrophy and metaplasia of the enamel-forming organ and subsequently to atrophy and cessation of or irregular functioning of odontoblasts. Enamel formation is suppressed, and striking deformities of the dentin result. May Mellanby has summarized her work on teeth in an excellent review and presents convincing proof that absent or defective enamel and dentin formation are consequences of vitamin A deficiency.

Boyle has described in the tooth germ of a human infant with vitamin A deficiency enamel organ changes comparable to those we have studied in rodent incisor teeth. In all probability, vitamin A deficiency, during the formative period of teeth, outranks all other vitamins deficiencies in importance.

Secondary Effects of Vitamin A Deficiency

While the keratinizing metaplasia produces impressive gross lesions which are often the immediate cause of death, as in the lungs of infants and in experimental animals leading to complete suppression of urine by occlusion of ureters and renal pelves, it must be remembered that is a late effect of the deficiency; in fact, the consequences of attempted repair following atrophy of essential epitheliums. The effects on the organisms as a whole which follow reduced activities of many epitheliums in earlier periods of atrophy preceding metaplasia replacement must be considered.

The secondary effects, common both to infants and to laboratory animals, are (1) loss of weight due largely to loss of fat in all storage depots, but also to atrophy of musculature and many organs which do not undergo keratinizing metaplasia, (2) anemia, (3) cessation of growth of bones, (4) degenerative lesions of skeletal muscle, and (5) lymphoid hypoplasia of the spleen.

The loss of fat in experimental animals in the absence of vitamin A takes place in spite of abundant fat in the diet, but this is also the case with other vitamin deficiencies accompanied by emaciation, notably the B2 complex. The anemia in infants and experimental animals is accompanied by hemosiderosis in the spleen and liver and, finally, by atrophy of the spleen and bone marrow.

In animals, restoration of vitamin A to this diet is followed by regeneration of the bone marrow, disappearance of hemosiderin from the spleen and liver, and in the rat also in the spleen by an active hyperplasia of lymphoid tissue and an outburst of erythroblastic activity. Again, the anemia and hemosiderosis are not peculiar to vitamin A deficiency. Both occur in striking degree in animals in vitamin B2 complex deficiency and in long continued partial vitamin C deficiency.

The cessation of growth of bone is due to cessation of proliferative activity of the epiphyseal cartilages. A narrow band of atrophic cartilage results, which becomes bounded by a thin plate of bone on the diaphyseal side. In recovery from vitamin A deficiency the cartilage regenerates, and blood vessels from the diaphyseal marrow penetrate the limiting bony plate, and normal endochondral bone formation is resumed. The effect on bone is that common to any athrepsia, of vitamin deficiency origin or otherwise.

The degeneration of skeletal muscle in vitamin A deficiency, while often very striking and even terminating in calcification, is also common to deficiencies of diverse causation.

Lesions of the nervous system, evidenced by degeneration of the myelin sheath, have been described by several workers, notably in swine, fowls and cows by Hughes and his associates, in rats by Zimmerman and Aberle.

Recently, Edward Mellanby, on the basis of studies of the trigeminal and a few other nerves by the capricious Marchi technic, suggests that the epithelial responses to vitamin A deficiency are secondary to lesions of afferent nerves.

Degeneration of the myelin sheath is common to so many disorders of man and animals as a result of several vitamin deficiencies and divers causes that very careful work will be required to establish a specific relationship of its presence to vitamin A deficiency. For the present, it seems logical to regard the lesions of the nervous system as among the late secondary consequences of vitamin A deficiency.

Repair in Recovery from Vitamin A Deficiency

The lesions of vitamin A deficiency, uncomplicated by destruction of tissue by infectious process, disappear rapidly after restoration of the diet. In rats, gain in weight, resumption of growth in bones and teeth, and regeneration of the bone marrow and spleen become apparent in from six to eight days. Reparative changes in the metaplastic epithelium begin as early as the fifth day. The initial changes are separation of superficial keratinized cells and vacuolization of cells of intermediate layers. The epithelium becomes divided into two zones by further vacuolar degeneration and leukocytic infiltrations. The superficial zone of cells degenerate, the deep zone, consisting of the lowermost layers of cells corresponding to the stratum germinativum of the epidermis, survives and the cells proceed to differentiate into the type of epithelium originally present. On the whole, the change back to the normal epithelium is an abrupt one and affords further evidence that the primary consequence of vitamin A deficiency is epithelial and not of nervous origin. This reparative sequence of the epithelium has its normal counterpart in changes in the vagina of rodents during that part of the estrous cycle in which the cornified vaginal mucosa returns to the mucous type.

GLOSSARY OF TERMS

(In Order of Appearance in the Article)

Epithelium: Membranous tissue, usually in a single layer, composed of closely arranged cells separated by very little intercellular substance and forming the covering of most internal surfaces and organs and the other surface of an animal body (the outer layer of the skin).

Keratinizing: Hardening; characterized by the production of keratin, a tough fibrous protein produced by the epidermis in vertebrates, and forming the main component of hair, nails, claws, horns, feathers and the dead outer layers of skin cells.

Basal Cells: Small, round cells found in the lower part, or base, of the epidermis, the outer layer of the skin.

Atrophy: Emaciation or wasting away of tissues and organs.

Mitotic: Characterized by mitosis, a method of indirect division of a cell, the process by which the body grows and replaces cells.

Epidermis: The outer protective layer of the skin.

Bronchiectasis: Persistent and progressive dilation of bronchi or bronchioles as a consequence of inflammatory disease (lung infections), obstruction (tumour) or congenital abnormality (for example cystic fibrosis). Symptoms include fetid breath and paroxysmal coughing, with the expectoration of matter.

Atelectasis: A term used to describe partial or complete collapse of the lung, usually due to an obstruction of a bronchus (with mucus plug, infection or cancer).

Metaplasia: The change in the type of adult cells in a tissue to a form which is not normal for that tissue.

Lesion: An area of pathological alteration of tissue.

Parocular glands: Salivary glands, including the parotid gland, the largest of the salivary glands in man.

Hypopyon: The presence of leukocytes (white blood cells) in the anterior chamber of the eye.

Odontoblasts: Cells that give rise to the dentine matrix that underlies the enamel of a tooth.

Hypoplasia: Incomplete or arrested development of an organ or part.

Hemosiderosis: Conditions in which there is a generalized increase in the iron stores of body tissues.

Epiphyseal: Pertaining to the epiphyses, the part of a long bone where bone growth occurs.

Diaphyseal: Relating to the diaphysis, the shaft of a long bone.

Endochondral: Growing or developing within cartilage; applied especially to developing bone.

Athrepsia: A wasting of flesh without fever or apparent disease; a kind of consumption.

Vacuolization: Formation of any spaces or cavities within a cell.

Afferent: Moving or carrying inward or toward a central part. Refers to vessels, nerves, etc. For example: blood vessels carrying blood toward the heart, or nerves conducting signals to the brain.

This article appeared in Wise Traditions in Food, Farming and the Healing Arts, the quarterly magazine of the Weston A. Price Foundation, Winter 2005/Spring 2006.

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