The Malnourished Child, edited by Robert
M. Suskind and Leslie Lewinter-Suskind.
Nestle Nutrition Workshop Series, Vol. 19.
Nestec Ltd., Vevey/Raven Press, Ltd.,
New York © 1990.
Malnutrition and Fat/Water-Soluble
Vitamin Metabolism
Christopher J. Bates
Medical Research Council, Dunn Nutrition Unit, Cambridge CB4 1XJ, England
The unraveling of functional mechanisms for single nutrients has been a necessary stage in the research strategy of human nutrition. Nevertheless, it has become
fashionable to say that in human populations, single nutrient deficiencies seldom if
ever arise. Thus, complex interactions are part of the natural order and must be analyzed. The aim of this chapter is to examine some of the functional aspects of nutritional deficiencies, which possess a link with both vitamins and protein-energy
malnutrition (PEM) and to attempt to highlight some important areas of ignorance,
where further research is needed.
From the point of view of the malnourished child, the provision of a balanced
diet, adequate in all known micronutrient requirements, may provide adequate therapy. Constrained by limited financial resources and presented with a wide variety of
possible intervention options, it is essential from the public health point of view to
understand the complexities of these processes in order to predict the outcome of a
•particular intervention at the population level and to weigh potential advantages
against cost and against possible adverse effects.
THE STAGES OF NUTRIENT UTILIZATION AT WHICH PEM MAY
INTERACT WITH VITAMINS
Table 1 gives a brief summary of the known functions of the individual vitamins,
highlighting those aspects that may be of particular relevance to PEM. Table 2 summarizes currently available information concerning the metabolism and turnover of
vitamins and their cofactor derivatives, and indicates the many gaps in our knowledge. Investigations of these processes in humans will soon be facilitated by the development of stable isotope-labeled vitamins. This should provide new information
about the estimation of daily requirements and about specific nutrient interactions.
Since, of all vitamin deficiencies, that of vitamin A causes the most serious damage to quality of life and life expectancy, especially of children in Asia today, and
since vitamin A deficiency interacts with PEM in a characteristic manner, a major
topic to be reviewed will be the interaction of these two insults.
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TABLE 1. Functions of individual vitamins
Vitamin
Fat-soluble
A
D
E
K
Water-soluble
Thiamine (B,)
Riboflavin (B2)
Vitamin B6
Niacin
Functions with a clear
relevance to PEM
Cell differentiation; protection against infection
Catabolism of carbohydrates; keto acid metabolism
Electron transport; fatty acid oxidation
Well-established
Retinal pigment cycles
Calcium homeostasis; bone
mineralization
Membrane lipid protection
Hemostasis
Glycoprotein synthesis
Membrane fluidity; arachidonate metabolism
Bone mineralization
CNS function
Glutathione reduction; B6 activation; iron mobilization; other
redox processes
Group transfers, especially in amino acid
metabolism; protection against infection
Energy release via pyridine nucleotide coenzymes
DNA synthesis; methionine synthesis
Folacin activation/enablement
Fatty acid biosynthesis (carboxylation)
Folacin
Vitamin B,2
Biotin
Pantothenate
> Fatty acid utilization
Carnitine*
Vitamin C
Collagen biosynthesis
Other functions
Equivocal or poorly understood
CNS function
Catecholamine and carnitine synthesis; tyrosine catabolism; iron
absorption
Cytochrome-P450-dependent hydroxylations;
other oxygen-dependent reactions; histamine
removal; tissue protection
'Not regularly included in the current lists of vitamins in human nutrition, but included here because of its PEM-related functions. Other "borderline" vitamins
include the bioflavonoids and biopterin, which can become limiting in special circumstances, but these and substances that do not feature as vitamins in human
nutrition (e.g., choline, inositol, etc.) have been excluded. Certain carotenoids may have the characteristics of vitamins, independently of their conversion to
vitamin A, but this needs further investigation.
TABLE 2. Metabolic pathways of interconversion and turnover of vitamins in the body
Vitamin
Fat-soluble
A
Known metabolic pathways
Biosynthesis from carotenoids
? Catabolism of retinol, probably via retinoic acid, to inactive
products
Biosynthesis of cholecalciferol in the skin
Activation by conversion to 25-hydroxy and 1,25-dihydroxy forms
in liver and kidney, respectively
Catabolism/inactivation: poorly characterized
Redox function involves interconversion of reduced and oxidized
forms; this may involve vitamin C for regeneration
Redox cycle with epoxidation
Water-soluble
B,
B2
B6
Niacin
Folacin
B«
Biotin
Carnitine
Vitamin C
Activation requires conversion to thiamine pyrophosphate
Comments
Carotene dioxygenase (intestinal mucosa) is depressed by protein
deficiency in rats
Little known about metabolic control of turnover
Requires sunlight or equivalent light exposure
Conversion to 25-hydroxy form depends mainly on availability of
the parent vitamin D, but the 1-hydroxylation is strictly limited
and controlled by functional requirement
Recent evidence for increased vitamin D turnover when dietary
calcium is limiting
Little known about ultimate control of turnover
Little known about turnover
Little known about control of activation or turnover. "Thiaminase" enzymes in some biological material cause irreversible inactivation
Activation requires conversion to flavin mononucleotide (FMN),
Little known about turnover; some inactive urinary products deflavin adenine dinucleotide (FAD), or covalent binding to enzyme
scribed
protein. Thyroid hormone involvement
Activation requires oxidation (B2-dependent) and phosphorylation Impaired by B2 deficiency. Inactivation involves oxidation, mainly to
pyridoxic acid. Little known about control
Synthesis from tryptophan (B6-dependent); preformed niacin is
Turnover yields urinary N'-methyl nicotinamide and N'-methyl
poorly available in some foods
2-pyridone 5-carboxamide, in relatively large amounts. Increased in burned patients
Complex cycles of interconversions of different forms, including re- Little known about turnover, but recent evidence suggests an indox changes, ^-substitutions, and polyglutamate side-chain
creased rate during pregnancy (rats)
alterations, some of which are B12-dependent
Several interconvertible forms
Turnover extremely slow and poorly understood
Generally synthesized by intestinal microflora in sufficient amounts Turnover little studied
Usually, but not always, sufficiently supplied in diet; de novo synthesis requires lysine and vitamins C and B6
Redox function involves interversion of reduced form with two par- Rate of turnover in humans fairly constant at —3% body pool/day.
tially oxidized forms (semi-dehydroascorbate and dehydroascorControl not understood
bate). Some sulfation. Degradation via oxalic acid
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MALNUTRITION I FAT I WATER-SOLUBLE VITAMINS
It is necessary first to consider the relationship of vitamin deficiencies to growth
of the organism and the different stages of development and maturation during
which deficiencies usually become evident. Second, one must examine the successive stages of utilization during which vitamin deficiencies may affect, or be affected by, PEM.
VITAMIN REQUIREMENTS IN RELATION TO GROWTH
Several micronutrients, if withheld from the diet of a weanling, rapidly growing
rat, will cause a drastic reduction in, or even a cessation of, growth. Only at a much
later stage, after prolonged and severe deprivation, do pathologic signs of deficiency
appear. Clearly, such a reduction in growth rate is a protective, homeostatic mechanism, designed to relieve the demand on limited micronutrient resources needed for
tissue accretion and growth. A similar response occurs during protein or zinc deprivation.
Although this homeostatic response is a common phenomenon in the major part
of the animal (and plant) kingdoms, it occurs to only a very limited extent in humans
and in higher primates. With a few possible exceptions [e.g., (1)], stunting and
wasting are not characteristic results of specific vitamin deficiencies in children,
whereas pathologic deficiency signs are. Rapidly growing children become especially vulnerable to nutritional insults, whether they be PEM, vitamin deficiencies,
or a mixture. By the same token, male children are likely to be more vulnerable to
nutrient deficiencies than females, because of their relatively higher growth rates.
VITAMIN REQUIREMENTS IN RELATION TO STAGE OF MATURITY
For several reasons (which include the variable size of body vitamin stores at
birth; the variable contribution from mothers' milk and other sources; and the variability in rates of demand, accretion, and turnover during development and aging),
each vitamin differs with respect to the peak age for association with deficiency
signs and symptoms. A brief summary of this is provided in Table 3.
A few examples may be selected: Vitamin K is perhaps the prime example of a
nutrient for which the peak vulnerability to deficiency occurs at birth (2). The problem then disappears almost entirely after the first few weeks of life. Requirements
for vitamin E may also peak very early in postnatal life, particularly for preterm infants when exposed to high oxygen tensions when lung function is inadequate (3).
For vitamin A, peak vulnerability to deficiency occurs in the preschool child,
probably due to the very low content of vitamin A and its precursors in Third World
weaning foods (4). The coincidence of the vitamin A deficiency and PEM peaks, together with peak susceptibility to childhood infections such as measles in Africa and
gastrointestinal and respiratory diseases elsewhere, results in a potentially lethal
combination of insults.
Vitamin D deficiency appears as rickets in children, and in adults as osteomala-
MALNUTRITION I FAT I WATER-SOLUBLE VITAMINS
123
TABLE 3. Prevalence of overt nutrient deficiency syndromes related to age and development
Nutrient
Population groups exhibiting
highest prevalence
of overt deficiency
Protein-energy
Preschool children
Marasmus, kwashiorkor, marasmickwashiorkor
Preschool children
(Pregnant women)*
Schoolchildren
Elderly
(Preterm infants)
Keratomalacia and other morbidity
(Nightblindness)
Rickets
Osteomalacia
(E-responsive anemia, intracranial bleeding, retinopathy, lung disease)
Hemorrhagic disease of the newborn
Fat-soluble vitamins
A
D
E
K
Water-soluble vitamins
B,
B2
B6
Niacin
Folacin
B12C
Biotin
Pantothenate
Carnitine
Vitamin C
Newborn infants
Infant; preschool children
Adults
Pregnant women
(Formula-fed infants)
Adults and schoolchildren
Young infants
Pregnant women
(Young infants)
All ages
(Infants)
Rarely encountered
(Infants)
Infants
Adults and elderly
Name/description of
deficiency states or
responsive syndromes
"Wet" beriberi*
"Dry" beriberi*, Wernicke's (alcoholic)
encephalopathy
Mucocutaneous lesions
(B6-responsive seizures)
Pellagra*
Growth retardation
Megaloblastic bone marrow/anemia
(Failure to thrive)
Pernicious anemia
(Seborrheic dermatitis and other biotinresponsive inborn errors)
(Carnitine-responsive inborn errors)
Infantile scurvy
Scurvy
•The items in parentheses either are relatively uncommon, are controversial, or are insufficiently investigated to rank as well-established deficiency diseases.
'Current controversies about the attribution of beriberi and pellagra to thiamine and niacin deficiencies (7-9) should be noted.
T h e most common occurrence of vitamin B12 deficiency is that of pernicious anemia, due to lack of
intrinsic factor secreted by the stomach, leading to impaired intestinal absorption. Therefore, it ranks as
a metabolic error (comparable to other instances of inborn errors of vitamin metabolism), not as a dietary deficiency.
cia. Lack of exposure to sunlight is a major factor, exacerbated by calcium deficiency (5). Under ideal conditions of light exposure, vitamin D would not be needed
as a component of the diet at all. Like carnitine, it is required in the diet only when
the alternative (biosynthetic) pathway is overstretched.
Folate deficiency is particularly common during pregnancy, and a major increment in its intake is needed to avoid bone marrow megaloblastosis (6). During pregnancy, most micro- and macronutrient requirements are increased, and severe
maternal deficiencies often result in fetal resorption, but during moderate deficiency, the fetus takes precedence over maternal tissues, and the consequent nutri-
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MALNUTRITION I FAT I WATER-SOLUBLE VITAMINS
ent drain into the fetus can result in overt maternal deficiency. Recent evidence
suggests that folate turnover may be enhanced during pregnancy (7).
There are major geographic variations in the prevalence of certain vitamin deficiency signs or associations; thus, Bitot's spots are frequently observed in some
vitamin-A-deficient populations but not in others. A close association between vitamin A deficiency and measles is encountered in certain parts of Africa, but not to
the same degree elsewhere (3). These observations highlight the fact that the clinical
manifestation of diseases that are primarily nutritional in origin has a strongly regional aspect, either through interactions with the particular environment and with
other exacerbating disease processes or perhaps through genetic variations in response or susceptibility. Clearly, these variations need further study.
Clinical signs may be very age-dependent; thus, although scurvy has been observed in all age groups, from young infants to elderly people, the characteristic
signs of scurvy in a young infant are quite different from those of an adult, and likewise the signs and symptoms of vitamin D deficiency differ radically between a
growing child and an elderly person. The nature of the links between metabolic
function and clinical deficiency signs are not well understood, especially for the
water-soluble vitamins. Many B-vitamin deficiencies affect epithelial surfaces in
ways that are not easily explicable in terms of their known biochemical functions.
Although ingenious suggestions have been made about possibly convergent pathways (8), it would be premature to claim that we have a clear picture of the links between the biochemistry and the pathology of deficiency, either for PEM or for
deficiencies of other micronutrients. Pellagra and beriberi are examples of human
diseases that are frequently portrayed as representing simple, well-understood deficiencies of certain specific vitamins, but the evidence remains conflicting and controversial (9-11). They may present with different clinical signs in different age
groups, and their appearance in, or disappearance from, specific populations cannot
be satisfactorily explained by known changes in dietary patterns. Likewise, there remain many uncertainties about the ways in which functional variables such as physical work capacity (12,13) or brain function (14) can be affected by PEM or by
micronutrient status.
POTENTIAL SITES OF INTERACTION BETWEEN
PEM AND VITAMINS
Intestinal Absorption
It is well known that there are many nutritional insults that affect the integrity and
competence of the intestinal mucosa. Because of the rapid turnover of nutrients at
this site, they are highly vulnerable, responding very rapidly to a wide variety of insults. An example of this phenomenon is the induction of localized malabsorption of
folacin and vitamin B12 in tropical sprue, a situation that is temporarily ameliorated
by vitamin supplements even when the causative infective agent is still present
MALNUTRITION I FAT I WATER-SOLUBLE VITAMINS
125
(15,16). Likewise, fat-soluble vitamin malabsorption can arise through steatorrhea
or diarrhea, and PEM can interfere with vitamin A or carotenoid absorption in a
variety of ways (17). In extreme cases of intestinal damage, for example, after extensive surgical removal or in the case of patients with inborn abnormalities of intestinal function or with developmental immaturity such as that of preterm infants,
parenteral nutrition may become necessary in order to break the cycle of poor nutrient absorption, which leads to further gut deterioration and hence to extensive loss
of absorptive capacity. Further work clearly is needed to determine the balance of
advantages of enteral versus parenteral nutrition in subjects who are generally malnourished and who therefore cannot absorb nutrients efficiently. An objective index
of intestinal function would facilitate the choice of rehabilitation schedules.
Transport Between Organs and Tissues
At this level, general malnutrition or PEM may also affect specific vitamin transport or utilization. An obvious example is the failure of hepatic synthesis of retinolbinding protein in conditions of protein deficiency, with reduced transport of retinol
from the liver and hence peripheral tissue deficiency, even when the central store is
adequate (17-19). There are numerous instances in the literature of children with
kwashiorkor having low circulating levels of retinol with consequent ocular effects,
despite adequate vitamin stores in the liver.
Another example of an adverse effect of PEM on vitamin status is that of starvation and hence muscle wasting on riboflavin status. Even short periods of fasting or
starvation result in the liberation of riboflavin into the circulation and an overflow
into the urine (20), thus resulting in a "false" picture of riboflavin sufficiency by
conventional status tests, whereas in reality, the body is losing part of its normal
complement of riboflavin cofactors. Naturally, when the tissue is later replaced during refeeding, these losses must be replaced. While it appears obvious that the rebuilding of wasted tissue requires all the essential micronutrient components, as
well as macronutrient building blocks, this fact has often been forgotten during the
checkered history of rehabilitation and parenteral feeding. It is certainly inefficient,
and probably dangerous, to provide an imbalanced supplement during the rehabilitation of malnourished subjects.
Chemical Activation and Cofactor Synthesis
All the B-vitamins and some others require chemical transformation before they
become effective in their metabolic tasks. These activation processes may be vulnerable to general malnutrition. Activation of riboflavin provides an example. Its
conversion to the flavin mononucleotide (FMN) and flavin adenine nucleotide
(FAD) enzyme cofactors requires high-energy phosphate in the form of adenosine
triphosphate (ATP), which may be in short supply during PEM, in addition to which
the activation steps are also adversely affected by hypothyroidism, a condition that
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MALNUTRITION I FAT I WATER-SOLUBLE VITAMINS
may well arise as a secondary result of PEM (21). Here again, a vicious circle is encountered, which must be broken by appropriate supplementation. As long as the
tissue demand is minimized by the inhibitory effects of PEM on metabolic pathways, equilibrium between supply and demand may be maintained. However, during rehabilitation the increased demand may fail to be met, and latent vitamin
deficiencies may become overt.
A somewhat different relationship between protein and vitamins is illustrated by
the specific utilization of tryptophan for niacin synthesis. Niacin status is protected
by a generous dietary supply of tryptophan-containing proteins (22). On the other
hand, requirements for vitamin B 6 , which is a key cofactor in the transformation of
all amino acids into energy substrates, are increased by a high intake of protein (23).
ORGAN-SPECIFIC ROLES OF VITAMINS
As a prelude to the consideration of interactions between PEM and vitamins in individual organs and tissues in the body, it is necessary to consider the organ specificity of vitamin action, which is clearly a major and complex subject. It is well
known that some vitamins have sites of action that are clearly localized and confined
to one or a small number of target organs or tissues. This is true for the special actions of vitamin D in the intestine and in bone, controlling calcium transport, and for
those actions of vitamin K at the sites of blood clotting and bone formation. The actions of vitamin A are of particular significance in the eye and the gonads, but a major function of vitamin A, which crosses many organ boundaries, is the maintenance
of epithelia, wherever these occur. Vitamin E has an even more widespread sphere
of activity, being required at all sites where polyunsaturated fats come into contact
with oxygen and its free radical derivatives.
The B-vitamins are required in all metabolically active tissues. However, by focusing on each in turn, we find a considerable complexity of distribution patterns
and a gradation of susceptibility to the effects of dietary deficiency between different organs and tissues. Our own studies on riboflavin deficiency in rats (24) have
illustrated this: It was found, for instance, that the extent of depletion of the riboflavin-derived cofactor, FAD, from the enzyme glutathione reductase, during dietary riboflavin deficiency, differed very markedly between red blood cells, liver,
kidney, intestine, and skin. The same was also true for two other flavoproteins: succinate dehydrogenase and NADH dehydrogenase. Similar interorgan differences
have been reported for several other B-vitamin-dependent enzymes.
The reasons for these interorgan differences in avidity for limited vitamin supplies are not clear, nor are the mechanisms by which they are achieved. It may be
assumed that they represent a gradation of requirements at different sites and that
they are achieved by the differences in potency of specific transport or activation
processes between different tissues. It is clear that the different vitamin-dependent
enzymes within a tissue have different priority ratings for limited supplies of cofactors. For some enzymes and within some tissues, the cofactor-depleted apoenzyme
MALNUTRITION I FAT I WATER-SOLUBLE VITAMINS
127
may be stable for long periods in vivo and can be reactivated when supplies of the
vitamin are restored. An example of this is the riboflavin-dependent enzyme glutathione reductase in erythrocytes. For others, however (e.g., hepatic NADH dehydrogenase), the loss of the coenzyme is paralleled by loss of activatable apoenzyme,
and new apoenzyme must be synthesized when the vitamin supply is restored (24).
Clearly, this is of potential relevance during rehabilitation: Whereas the resaturation
of some enzyme functions is very rapid after refeeding, that of others is slower and
perhaps out of synchrony with the restoration of growth. Vitamin B 6 , in particular,
shows a high degree of mobility between tissue and enzyme compartments, and
there is a characteristic pattern under hormonal control, which is altered during
pregnancy and during oral contraceptive use (25). The altered ratio of free pyridoxal
to pyridoxal phosphate in the plasma of women during pregnancy (26), for instance,
may have important implications for the use of pyridoxal phosphate as an index of
B 6 status.
Vitamin C shows a unique and unexpected distribution pattern between tissues
and organs, with high concentrations occurring in adrenals, pituitary, leukocytes,
and ocular tissues, and relatively low concentrations in plasma, skin, and muscle
(27). These tissue gradients are maintained by tissue-specific active transport
systems. The requirement for adrenal hormone synthesis, and the characteristic
changes in adrenal ascorbate concentration that occur in response to stress, may well
give us clues as to the reasons for the particularly high concentrations of ascorbate
that occur in the adrenal glands.
RESPONSE TO STRESS
It seems reasonable to suggest that the body's response to stress, whether due to
infections, noxious or toxic chemicals, or trauma, is an important aspect of the
maintenance of homeostasis in the face of malnutrition. A better understanding of
the normal armament of defenses against stress will clearly enhance our understanding of the deterioration that results from malnutrition. Clues may be obtained from
the pattern of localization and relocation of vitamins at particular sites, particularly
in response to stressful situations [e.g., the homing of vitamin C into areas of tissue
damage (28)].
Protection Against Infection
The immune system is sensitive to nutrient deficiencies in a wide variety of ways
and is influenced differently by various nutrient deficiencies (29,30). Cell-mediated
immunity probably heads the list of nutrient-sensitive immune systems. Recent advances in recognizing the complexity of its component parts have shown that there
is a great deal still to be learned about the nature of responses of individual components to particular nutrient deficiencies. Delayed hypersensitivity, secretory immu-
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MALNUTRITION I FAT I WATER-SOLUBLE VITAMINS
noglobulins, and the complement system all respond in characteristic ways to
nutrient deprivation, whereas humoral immunity seems somewhat less sensitive. In
certain cases where the host and parasite are differently affected by nutrient deficiencies, paradoxic effects may arise; thus, malarial parasitemia may in some circumstances be reduced by marginal nutrient depletion of the host (31,33).
Clearly, immunocompetence is affected both by PEM and by specific nutrient deficiencies. Overall immune status reflects the sum of several different nutritional inputs. It also seems likely that the development and maturation of immune functions
may be especially sensitive to nutrient deprivation, with important consequences for
young children. However, this field is totally unexplored.
Protection Against Free-Radical Damage
Dietary components have an important influence on the tissue balance between
oxidative stress and antioxidative protective mechanisms (34). It has recently been
proposed that uncontrolled oxidative damage to tissue components by oxygenderived free radicals may be an important factor in the etiology of kwashiorkor and
that certain vitamins, particularly carotenoids and vitamins E and C, may play a protective role (35). The next few years will undoubtedly see a clarification of freeradical nutrient and tissue interactions, and may help to put the concept on a sounder
footing.
VITAMIN A
In considering the subject of vitamin deficiency and PEM, particularly when
these are placed in the context of Indonesia, it seems essential to put special emphasis on the important relation of PEM to vitamin A deficiency.
Mode of Action of Vitamin A
Despite a great deal of research, several of the functions of vitamin A at the molecular level are very poorly understood. It has a fairly well-characterized function
in the retina, involving the translation of light energy to nerve impulses in the optic
nerve, mediated by the cis—trans conversion of retinaldehyde, in rhodopsin. This
represents, however, only one of a diverse array of actions of vitamin A (36). It is
not responsible for the life-threatening morbidity associated with vitamin A deficiency. Cell differentiation is undoubtedly the principal area of current interest,
e.g., the significance of retinoic acid for morphogenesis (37). The visual pigments,
the germinal epithelia, spermatogenesis and testosterone synthesis, and placental
and fetal development all require a reduced form of vitamin A (retinol or retinaldehyde), whereas the oxidized form, retinoic acid, can support the other somatic functions, including oogenesis, fertilization, and implantation in the female (36). These
MALNUTRITION I FAT I WATER-SOLUBLE VITAMINS
129
observations clearly are germane to the question of the mode of action of vitamin A.
However, a unifying theory has yet to emerge.
Evidence for a Link Between Vitamin A Deficiency and PEM
An association between vitamin A deficiency and kwashiorkor has been recognized in many diverse populations (4,38,39), although the two do not invariably occur together (40). In Indonesia, the severity of corneal lesions due to vitamin A
deficiency was closely correlated with serum albumin and transferrin levels. Nevertheless, it is unlikely that protein malnutrition in the absence of vitamin A deficiency
can result in xerophthalmia (53). It is of interest that anorexia nervosa, a form of
PEM that is increasing in Western society, is frequently accompanied by deranged
vitamin A metabolism (41).
There are several probable sites of interaction between PEM and vitamin A biochemistry and physiology. These will be discussed briefly in the following sections.
Absorption of Retinol from Dietary Esters and Utilization of Carotenoids
In a classic study (42), South American children suffering from PEM (mainly
kwashiorkor) showed virtually no serum response to a 75,000-ji.g oral dose of retinyl ester until milk therapy had restored their protein-energy status: Impaired absorption was therefore inferred. Reduced or delayed absorption of vitamin A was
also observed in Indian children with PEM (4). Two possible reasons for the deleterious effects of PEM on vitamin A absorption are a decreased secretion of conjugated bile acids, which are required for the actions of retinyl ester hydrolase and
synthetase (43-45), and reduced synthesis of these enzymes.
The utilization of carotenoids for vitamin A synthesis is also vulnerable, partly
because the rate-limiting step in the conversion, intestinal carotene dioxygenase, is
depressed by protein deficiency (46-48). Vitamin A deficiency, on the other hand,
enhances the activity of this enzyme, at least in the rat (49). Dietary fat can assist
carotenoid utilization (50). Several types of parasitic infestations that predispose to
PEM also appear to increase the risk of vitamin A deficiency (51-53), and impaired
absorption presumably contributes to this (54-56).
Effect of PEM on Metabolism and Transport of Vitamin A
Plasma retinol binding protein and thyroxine binding prealbumin, both of which
are required for the transport of vitamin A from liver stores to peripheral tissues, are
sensitive to the effects of PEM, since they have high turnover rates and small pool
sizes (17-19,57,58).
Children with severe kwashiorkor nearly always have diminished plasma retinol
levels. However, a proportion have sufficient hepatic vitamin A stores to permit mo-
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MALNUTRITION I FAT I WATER-SOLUBLE VITAMINS
bilization of vitamin A with restoration of dietary protein alone (59). Studies have
been made of the time course and characteristics of repletion by combinations of
protein, energy, and vitamin A in children with PEM (60,61). The first few weeks
of treatment are accompanied by a considerable increase in plasma retinol and retinol-binding protein (RBP) levels. However, these are then followed by a paradoxic
fall, suggesting some delayed compensatory changes (60). The holo-RBP response
to massive-dose vitamin A therapy is directly related to the level of protein nutrition
(61).
Another possibly relevant effect of protein deficiency observed in weanling rats is
a reduction in hepatic retinyl palmitate hydrolase activity (62).
Zinc deficiency has similar effects to those of protein deficiency on plasma transport of vitamin A. Zinc supplementation may prove effective in mobilizing liver retinol stores in refractory cases (63).
Effects of Vitamin A Deficiency on Immunocompetence
Of all the micronutrient deficiencies reviewed by Scrimshaw (64), that of vitamin
A stood out as being associated most clearly with frequent and severe bouts of infection in children. In vitamin-A-deficient animals and children, the numbers of circulating T-lymphocytes and the bacteriocidal activity of the macrophages are reduced.
Conversely, episodes of infection depress circulating levels of retinol and retinolbinding protein by decreasing absorption of vitamin A (65,66) and by increasing the
rate of vitamin A turnover (67,68), thus depleting body stores. Measles and acute
hepatitis have major effects on vitamin A status. The coincidence of measles epidemics with signs of vitamin A deficiency makes it appear practically certain that
either insult lowers the body's defenses against the other (53,69,70). Studies of Indonesian children by Sommer's group (71) have demonstrated clear associations between mild xerophthalmia (vitamin A deficiency) and systemic infections,
especially those associated with diarrhea and respiratory disease. They showed that
it is possible to reduce childhood mortality very significantly by vitamin A supplementation alone in this population.
Various infective agents (viral, bacterial, and eukaryotic) have all been shown to
act more virulently in vitamin-A-deficient than in vitamin-A-replete animals. Atrophy of the thymus, bursa, spleen, and other lymphoid tissues occurs in vitamin-Adeficient rats (72). Gnotobiotic rats can be maintained for much longer periods than
conventional ones without vitamin A in their diet (73).
Thus, both animal and human studies exist to support the contention that vitamin
A deficiency has a profound influence on immunocompetence and resistance to infection, acting synergistically with PEM in increasing morbidity and mortality, especially in preschool children.
LITERATURE REVIEW
During the past 3 decades, several studies of specific vitamin deficiencies in
protein-energy-malnourished human subjects have been reported (Table 4). Not sur-
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131
TABLE 4. Changes in vitamin status reported in association with PEM
Vitamin
Thiamine
Riboflavin
Niacin
Vitamin B6
Folic acid
Vitamin B12
Vitamin C
Vitamin A
Vitamin D
Vitamin E
Vitamin K
Review articles
Country (ref.)
Thailand (89,91), Dominica (90), Ghana (92)
India (85), Guatemala (86)*, Sicily (87), Kenya (88), Thailand (89,91),
Dominica (90)
S. Africa (93,94)
S. Africa (95), Egypt (96)
India (74,121), Colombia (75), Egypt (76,77,123), Sudan (78), S. Africa
(79,122), Nigeria (80), France (81), Thailand (89)
Guatemala (82), Israel (83), Zaire (84), Egypt (123), India (121)
Guatemala (97)
Jordan (37,38,112), Guatemala (41,58), India (16,18,39,85,100,102,
104,119,120), Thailand (67,91,101,107), Sumatra (60), Senegal (68),
Sri Lanka (103), Egypt (56,98,99)
Nigeria (105), Egypt (106), Thailand (107), Israel (83), Brazil (108)
Jamaica (34), Lebanon (116), Uganda (109,117), Jordan (110,112,115),
Zaire (118), Thailand (113), India (114), Egypt (111)
S. Africa (124)
(3,63,125,126)
•Paradoxic increase reported.
prisingly, the countries of origin have mainly been developing countries, and nearly
all the known vitamins have, at some time, been reported as either clinically or biochemically deficient, or both, in various protein-energy-deficient groups. Clearly,
such associations are strongly influenced by the particular characteristics of the diet
of different regions and of human groups, and in PEM, it is possible to observe single or multiple associated micronutrient deficiencies or occasionally none. The essential challenge for future studies will now be to determine how the different
nutrient deficiencies interact metabolically with one another and what practical lessons can thereby be learned about prevention and cure of those diseases that have
important nutritional components.
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DISCUSSION
Dr. Karyadi: What is the role of riboflavin in improving iron status in starved and/or malnourished children?
Dr. Bates: If starvation is sufficiently prolonged to result in muscle wasting, riboflavin will
be released and riboflavin status of other tissues improves (1). The same could theoretically
be true for iron. The body's response to starvation may complicate the picture, but it will not
alter the fact that adequate riboflavin is essential for the efficient utilization of iron, either
from stores or from the diet.
Dr. Karyadi: Does iron supplementation improve vitamin A status of malnourished
children?
Dr. Bates: Whereas the correction of vitamin A deficiency may improve iron status (2), I
am not aware of any mechanism by which iron supplementation or the correction of iron deficiency can improve vitamin A status, although any interventions that correct defects in the
immune system might have an indirect beneficial effect on vitamin A status (3). The adult
Gambian subjects we studied generally had acceptable vitamin A status, despite their very
low intakes of vitamin A and its precursors. We are currently looking at the vitamin A status
of young children there. The development of new and more sensitive techniques for the detection and confirmation of marginal vitamin A deficiency should facilitate the study of such
interactions.
Dr. Suskind: While vitamin A status has been well studied in malnourished children, it is
my impression that the metabolism of vitamin D and the water-soluble vitamins are areas that
need further investigation.
Dr. Bates: I agree that the relationship of vitamin deficiencies to general malnutrition is, at
present, poorly understood. In the case of vitamin D, we have observed deficiencies even in
areas of abundant sunlight. Calcium is clearly an important factor, since there is now evidence that calcium deficiency may increase the turnover of vitamin D (4). There may also be
the lack of exposure, even in countries where sunlight is plentiful. There is little information
at the moment about the possibility that the metabolism of vitamin D to its active metabolites
may be affected by other types of malnutrition.
Although we are at a very early stage in defining which nutrient deficiencies can occur in
association with general malnutrition, I believe that a research priority should be to understand the pathophysiology involved at the tissue level. Second, we must try to understand the
mechanisms and adaptive processes that permit some individuals and populations to withstand very low levels of certain micronutrients, while other populations are functionally suboptimal, even at higher intakes.
Dr. Suskind: In studying the vitamin B complex deficiency states, we look at various red
cell enzymes. Would these be good markers in the child who is protein-energy-deficient, or
are these enzymes affected by the protein-calorie status of the child as well as by the status of
the vitamin B complex? If we were going to document the prevalence of deficiency states,
which is the most effective method of assessment? What treatment would you recommend?
MALNUTRITION I FAT I WATER-SOLUBLE VITAMINS
137
In Thailand, we developed a supplement, given to each child, which provided at least twice
the RDA for each of the water- and fat-soluble vitamins.
Dr. Bates: One criterion for selecting status indicators, in animal models, is that they
should be specific for the particular vitamin and not affected by inanition alone. This is not
always easy to achieve. A good example is the problem of recognizing zinc deficiency, because suppression of growth dominates and overshadows the more specific responses.
With respect to supplementation programs, it is probably advisable to give a generous micronutrient supplement in the early stages of repletion, in order to prevent secondary deficiencies from developing as the requirement for the micronutrient increases. It is also
important to avoid imbalanced supplements and to remember that some nutrients, such as
iron, may be contraindicated if body stores are already high.
Dr. Soriano: Benton and Roberts (5), studying children with subclinical deficiencies,
found that children supplemented with vitamins and minerals for 8 months showed a significant increase in nonverbal intelligence over controls. What might the implications be for
Third World countries?
Dr. Bates: I believe it was essentially mineral, rather that vitamin, intake that was cited.
I also believe more evidence is needed to substantiate the effects of supplementation on
nonverbal intelligence. Vitamin B 6 is required for several reactions involved in the metabolism of neurotransmitters, but there is little evidence at present that a deficiency can affect intelligence in humans. Although some studies from India suggest that vitamin B6 deficiency
can accompany general malnutrition, the close link between B 6 requirements and protein intake usually prevents B 6 from becoming severely limiting in general malnutrition (6).
There are now reports of toxic effects of B 6 after prolonged daily doses of several hundred
mg (7). One has to take account of the risk/benefit ratio, when vitamins above the normal dietary range are consumed.
Dr. Durie: Could you provide the evidence for malabsorption of fat and fat-soluble vitamins in malnutrition?
Dr. Bates: Except for vitamin A (8), uncomplicated protein-energy malnutrition (PEM)
may well have little effect on fat-soluble vitamin absorption. Substances like carotenoids
seem to be better absorbed and utilized if they are eaten with fatty foods. Diarrheal disease
and other intestinal malfunction reduce absorption of fat-soluble vitamins, so that one may
encounter a vicious circle in malnourished subjects with intestinal malfunction, especially in
relation to vitamin A deficiency (2,9). There is need for further studies of these interactions.
Dr. Guesry: The Japanese report breast-fed babies' experiencing vitamin K deficiency and
bleeding, even when the mother is well-nourished. Do you know anything about the relationship between the nutritional status of the mother, especially vitamin status, and the quantity of vitamin K in human milk?
Dr. Bates: It is paradoxical, but even in well-nourished communities, there is a proportion
of newboms who have too little vitamin K for normal hemostasis, leading to intracranial
bleeding and other problems during the first weeks of life (10). I know of no evidence that
suggests much difference between well-nourished and malnourished populations.
The small amount of vitamin K normally found in human milk can be increased considerably by high-dose supplementation. The practice of supplementing all newborn babies, although only a small percentage need it, has greatly reduced the problem (11). However,
having to intervene in an entire population is not an entirely satisfactory solution.
Dr. Warrier: Regarding infection as the possible starting point for most malnutrition,
could you comment on the role of vitamin A and mucosal immunity in PEM?
138
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FAT I WATER-SOLUBLE VITAMINS
Dr. Bates: Obviously, vitamin A has a very important role for epithelial surfaces in general, but there are effects on cell-mediated immunity as well.
Dr. Tanner: We have found that in malnourished rats with mucosal hypoplasia, the gut
functioned normally with respect to absorption and recovered from an acute chemical insult
exactly the same as the normally fed rats (12). Also, in the United Kingdom, we see vitamin
D deficiency, not in the schoolchild, but in the toddler and in the adolescent. Except for preterm babies, the child with vitamin E deficiency, whether due to abetalipoproteinemia or prolonged cholestasis, presents with neurologic problems in later childhood.
Regarding vitamin A and collagen, it is known that in gross excess, vitamin A causes hepatic fibrosis. Vitamin A is, of course, stored in the Ito cell, which in situations of vitamin A
excess, can secrete collagen and indeed become a fibroblast. Is it possible that in a situation
of malnutrition in which the synthesis of retinol-binding protein is impaired, a more modest
vitamin A excess might cause hepatic fibrosis?
Dr. Bates: One of the responses that a cell may make to damage or to metabolic insult is
to become fibrotic, and this could theoretically happen in situations of periodic vitamin A
dosing, although I do not know of any specific evidence for it. I doubt whether the impairment of retinol-binding-protein synthesis alone would produce such an effect, because in that
case, vitamin A would presumably remain in the esterified form in the liver cells instead of
being liberated into the circulation. I believe that the danger of toxicity arises mainly when
vitamin A, and especially vitamin A as free retinol, is present in the lipid fraction of the blood
instead of being transported as the complex with retinol-binding protein (RBP) (13). RBP is
not, as far as I know, of particular importance in protecting liver cells against vitamin A overload, although there is one report of hepatotoxicity associated with liver accumulation of vitamin A in a protein-deficient subject (14). There are, however, gaps in our knowledge about
the effects of malnutrition on the transport of vitamin A between different hepatic cells.
I agree that my description for the age distribution of fat-soluble vitamin deficiency states
was somewhat simplified, and there are exceptions.
Dr. M. Mehta: I should like to question the supplementation of vitamin K for all newborns,
and add that administering vitamin K to pregnant women has no effect on the potential of
hemorrhagic disease in the baby.
Dr. Bates: In the United Kingdom, nearly all newborn babies receive vitamin K supplement prophylactically, although only a small proportion would otherwise suffer from hemorrhagic disease. The potential is greater, of course, for premature infants, because transfer of
vitamin K to the fetus occurs most rapidly at the end of gestation (15). Supplementation of
the mother during pregnancy does not seem to be at all effective.
Dr. Truswell: Several studies show that vitamin A absorption in untreated PEM is impaired, although massive doses may produce some effect. Second, in attempting to determine
vitamin E status, the plasma vitamin E level is measured. Since vitamin E is carried on lowdensity lipoproteins, and these lipoproteins are half-normal, it appears vitamin E is also deficient, although tissue levels may not be as low. I agree that we need a systematic reevaluation
of these laboratory assessments. As another example, I understand that the amino transferase
test for vitamin I$6 is not specific, and a better test would be to use plasma pyridoxal 5' phosphate or free pyridoxal. Another test that needs replacing is the one for niacin, where either
measuring metabolites in the urine, which depends on the methylation process, or looking at
tryptophan levels in the plasma is very difficult to interpret (16). To determine niacin activity
accurately, a good test, like that used to determine thiamine status, the red blood cell (RBC)
transketolase, and thiamine pyrophosphate (TPP) effect, is needed.
MALNUTRITION I FAT I WATER-SOLUBLE VITAMINS
139
Dr. Suroto: We have studied 4,000 mothers from gestation through the first month after
delivery. We found a positive correlation between arm circumference and low birth weight.
We found no hemorrhagic disease in the newborns, even though there was no intervention.
The nonexistence of hemorrhagic disease could be because 95% of our babies were breastfed.
Dr. Haschke: Kries et al. (17) indicated that pharmacologic doses of vitamin K, between
0.5 and 3 mg of oral vitamin K|, produced substantial rises in breast milk vitamin K, with
peak levels between 12 and 24 hr. Preliminary data from our study showed that daily vitamin
Ki supplements in the range of the recommended dietary intakes (RDI) of vitamin K did not
influence vitamin Ki concentrations in breast milk at 1 and 3 months of lactation (18).
Dr. Suskind: Our studies in Thailand found that vitamin E was not an important factor in
the development of the anemia of PEM. In addition, we found that the production of vitaminK-dependent coagulation factors was also dependent on protein intake. There are also several
questions regarding vitamin D metabolism in PEM. If one were to postulate that PEM has a
significant effect on liver and renal function, one might anticipate that there might be an effect of PEM on the hydroxylation of vitamin D, both in the liver and in the kidney. This is an
area open for development, especially in reference to the population that consumes vitamins
and minerals in amounts far above and below the RDA.
Dr. Bates: There are several potentially sensitive steps in the hydroxylation of vitamin D,
such as the cytochrome P-450-dependent hydroxylation pathway (19). Dr. Truswell, could
you comment on this?
Dr. Truswell: 25-Hydroxylation of vitamin D is little impaired in adults with alcoholic
fatty liver, but I have not been able to track down a systematic study of vitamin D metabolism
in PEM (20).
Dr. Soriano: In the Brazilian study (21), they determined 25-hydroxy-vitamin D3 levels in
malnourished children and found no abnormalities when there was exposure to sunlight.
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