Page 120 - JSOM Spring 2021

and fortified foods such as breakfast cereals, milk, cheese, and both sides of the conflict, with more than 8,000 cases recorded
yogurt. 7,8 among Union soldiers. The actual numbers were likely much
greater because of underreporting among black soldiers. When
There is little risk that excessive consumption from provita- cases among black soldiers were included (after 1863), blacks
min A compounds (from plant foods) could be toxic because were found to have more than 2.5-fold higher rates of night
of their lower absorption from the gastrointestinal tract and blindness compared with white soldiers. Lack of appreciation
effective down-regulation when vitamin A status is adequate. that this condition was due to vitamin A deficiency caused
On the other hand, preformed vitamin A substances are very many physicians to ascribe this condition to malingering. 27,28
efficiently absorbed (70% to 90%), tend to bioaccumulate in
the liver with little metabolic regulation, and have a long half- Besides night blindness, vitamin A deficiency can reduce im-
life. Toxicity can result from high dosages over short periods mune function through several mechanisms. Deficiency im-
or lower dosages over long periods, resulting in hypervita- pairs the regeneration of mucus that forms a barrier over
minosis A. 8–10 Case reports of hypervitaminosis A invariably epithelial cells and functions to trap pathogenic bacteria and
involve high dosages obtained from dietary supplements, 11–17 move them to the respiratory or gastrointestinal tract for dis-
liver oils, 18,19 or both 2,20,21 (i.e., preformed vitamin A sources). posal. Vitamin A deficiency reduces the activity of neuropils
Patients consuming large amounts of vitamin A in these case and macrophages that encapsulate and ingest pathogenic bac-
reports have reduced bone mineral density, skeletal defor- teria (phagocytosis). Deficiency reduces the number and activ-
16
mities, 2,11–13,15,18,19 hypercalcemia (presumably due to loss from ity of natural killer cells that break down tumor and viral cell
bone), 13–15,17,21 and increased bone resorption. 16 membranes (lysis). Vitamin A deficiency also affects some as-
pects of acquired immunity in response to specific pathogens. 29
Recommended Amounts of Vitamin A
Vitamin A deficiency also has effects on gene expression and
The Food and Nutrition Board (FNB) at the Institute of Medi- development. Deficiency can alter stem cell differentiation and
cine of the National Academies in Washington, DC, establishes embryonic development and cause abnormalities in the devel-
the recommended dietary allowances (RDAs) and tolerable opment of epithelial cells, bones, and teeth. 3
upper limit (UL) for vitamin A (and other nutrients) based on
the best available evidence at the time of determination. RDAs Excessive Vitamin A Effects on Bones in
are the average daily level of intake sufficient to meet the nu- Animal Models and Isolated Tissue
trient requirements of nearly all (97% to 98%) healthy indi-
viduals. The UL is the maximum daily intake unlikely to cause It has long been known that excessive intake of vitamin A (as
adverse health effects. Since the metabolically active form of retinyl acetate or rentinyl palmitate) induced fragile bones
vitamin A is retinol, the FNB established the RDA for vitamin and bone fractures in rats. 30,31 Osteoclasts are cells that resorb
A at 900µg and 700µg retinol activity equivalents (RAE) per (remove) bone tissue, while osteoblasts are cells that form
day for adult men and women, respectively, and the UL at new bone tissue. 32,33 Several studies indicated that short-term
3,000µg RAE per day. Data from the National Health and (≤9 days) treatment of rodents with retinol caused enhanced
1
Nutrition Examination Survey (NHANES) indicate that many osteoclast formation, hypercalcemia, and decreased bone
Americans exceeded the RDA, with an average usual intake of mass. 34–36 In young, pair-fed rats that acquired similar body
1,010µg RAE per day; 5% exceeded the UL. 22 weight, a group given excess vitamin A for 7 days had thinner
cortical bones, a reduced mineralization surface, reduced bone
The gold standard for determining the body reserves of vita- formation rate, and reduced mineral apposition rate. Addition
min A is the liver level. Values of <0.01µmol/g are considered of retinoic acid to the cell medium of cultured human and/
deficient, 0.1 to 0.7µmol/g adequate, 0.7 to 1.0µmol/g high, or murine osteoblasts reduced calcium deposition 37–39 and the
>1µmol/g hypervitaminotic, and ~10µmol/g toxic. However, transcription of key proteins (Runx2 and Osterix), necessary
23
obtaining liver samples to determine vitamin A deficiency is in- for osteoblast differentiation. 37
vasive, requires skill, and can have complications. Although
24
commonly used in epidemiological studies, serum retinol may Bone strength is dependent on bone geometry, size, architecture,
not reflect vitamin A stores in the liver because blood levels and composition and bone will remodel and become stronger
appear to be regulated and liver levels do not decline until in response to appropriate physical activity by recruiting osteo-
liver reserves are low. Serum retinyl esters >10% of total vi- blasts to lay down bone matrix. 40–43 Rats fed a clinically relevant
25
tamin A (retinol plus retinyl esters) have been suggested as a vitamin A dose (13 times more RAE than control rats, 4.5 vs
marker for excess retinol storage and chronic hypervitamino- 60µg RAE/g chow) for 6 weeks, had a lower mechanically load-
sis A. These measures can be obtained from analysis of blood induced gain in bone mass due to decreased bone formation. 44
samples. In NHANES III (1988–1994), 37% of the population
met or exceeded this level. 26 Receptors for vitamin A (retinoic acid) have been found in
osteoblasts and osteoclasts and have been shown to upregulate
proteins involved in bone resorption. 45,46 This indicates that
Vitamin A Deficiency
bone is a target organ for vitamin A. There are interactions
An early indication of vitamin A deficiency is night blindness. between vitamin A, vitamin D, and calcium that might affect
In night blindness, the small amount of light at night does bone. Vitamin A can alter the activity of calcium-regulating
not activate the rods of the eyes due to the lack of adequate hormones and reduce the ability of vitamin D to increase se-
rhodopsin, the light-sensitive pigment in the rods. Vitamin A rum calcium. 45,47–49
forms a compound (11-cis-rentinal) that combines with op-
sin in the eye to form rhodopsin. During the American Civil In summary, these studies (mostly from nonhuman animal
3
War (1861–1865), night blindness was a common problem on models) suggest that excessive vitamin A intake (primarily from

116 | JSOM Volume 21, Edition 1 / Spring 2021