British Medical Bulletin (1981) Vol. 37, No. 1, pp.
19-24
BIOCHEMISTRY AND PHYSIOLOGY OF KWASHIORKOR AND MARASMUS
THE BIOCHEMISTRY AND
PHYSIOLOGY OF KWASHIORKOR
AND MARASMUS
W A COWARD PhD
P G LUNN PhD
University of Cambridge
and
Medical Research Council
Dunn Nutritional Laboratory, Cambridge
Concepts and definitions: protein-energy malnutrition,
kwashiorkor and marasmus
Adaptation to a deficiency of energy: the pathogenesis of
marasmus
Failure of adaptation to protein deficiency: the pathogenesis
of kwashiorkor
Pathogenesis of intermediate forms of protein-energy
malnutrition
Regulation of body fluid volumes in protein-energy
malnutrition
a The distribution of extracellular fluid volume
b Sodium and water balance
c Membrane defects and the sodium pump
Plasma proteins in kwashiorkor and marasmus
References
It is just four years since Alleyne et al. (1977) published their
comprehensive treatise on protein-energy malnutrition. In this
paper we will focus on a few developments in biochemistry and
physiology that we believe are important for our understanding
of how the clinical features of the disease emerge in children
subjected to a hostile environment and inadequate diet.
1 Concepts and Definitions: Protein-Energy Malnutrition,
Kwashiorkor and Marasmus
In recent years it has been customary to use the term
"protein-energy malnutrition" to describe a group or spectrum
of diseases that often affect children living in poor communities
in most developing countries. The expression suggests impor-
tant concepts. These are that inadequate intakes of energy or
protein, or both, are causative factors and that there is a
continuous connection in terms of biochemistry and physiology
between the extreme forms of protein-energy malnutrition,
which are kwashiorkor and marasmus.
For comprehensive clinical descriptions of the two syndromes
the reader may refer to Alleyne et al. (1977), but for the present
it will be sufficient to use a series of internationally accepted
definitions suggested by a Wellcome Trust Working Party
(Lancet, 1970). The crucial diagnostic features are the degree
of body wasting and the presence of oedema. Thus, when
Harvard weight standards (Stuart & Stevenson, 1959) are used,
children of 60-80% expected weight-for-age are called cases of
kwashiorkor if oedema is present. Below 60% the diagnosis is
marasmic kwashiorkor if they have oedema or marasmus if
oedema is absent. These definitions have the merit of simplicity
19
Vol. 37 No. 1
WA Coward&PGLunn
but they do not, in any way, distinguish causes in the same
manner that the term protein-energy malnutrition quite
specifically suggests a dietary cause.
We can therefore make clinical distinctions between kwashi-
orkor and marasmus, but the object of many experimental
studies, and of dietary surveys in different parts of the world,
has been to find differences in their dietary aetiology. It is well
known that it is necessary to feed experimental animals
unrestricted amounts of diets low in protein to produce a
syndrome resembling kwashiorkor; restricting the intake of any
diet will result in severe wasting. Survey work in Uganda
(Whitehead et al. 1977) also showed that, when diets with a
wide range of protein: energy ratios are available within a
community, it is the children who habitually consume diets from
the low end of the range (protein: energy, 0.04-0.06) who are at
risk of developing kwashiorkor. These observations contrast
with others typified by those of Gopalan (1968). He showed
that, in Indian children eating cereal-based diets with a relatively
constant protein: energy ratio (0.08), either kwashiorkor or
marasmus could emerge if energy intakes were low. Taking
extreme views would therefore suggest that kwashiorkor and
marasmus represent different aspects of the same disease (as the
term protein-energy malnutrition suggests) or that they are
different diseases with distinguishable aetiologies.
Protagonists of each idea have ample support for their
arguments but it is unrewarding to initiate a discussion of the
aetiology of kwashiorkor and marasmus by emphasizing one
theory to the exclusion of the other. A more realistic approach
is to accept that each idea makes a worthwhile contribution in a
worldwide context but that causes can differ in individual,
regional circumstances.
2 Adaptation to a Deficiency of Energy: the Pathogenesis
of Marasmus
It is now widely accepted that the severe wasting seen in
marasmic children represents the end-product of metabolic
adaptation to an inadequate energy intake, mediated by changes
in hormonal pattern. Although a child is not clinically identified
as a case of marasmus until weight-for-age falls below 60%, the
relevant metabolic changes can be detected, within a community
where marasmus occurs, well before this stage is reached.
Whitehead et al. (1977) and Lunn et al. (1979a) showed that
fasting plasma cortisol and growth hormone (GH) levels were
high but insulin concentrations were low in Gambian children
with faltering growth rates, and insulin: cortisol ratios were
strongly correlated with growth velocities (Lunn et al. 1979a).
The changes seen when children are admitted to hospital
(reviewed by Alleyne et al. 1977) are only more exaggerated
examples of the same pattern.
A reduction in plasma insulin concentration is a normal
response to a reduced food intake and extremely low values are
seen in marasmic children admitted to hospital. Cahill (1970)
suggested that a decreased level of this hormone is the main
regulator for the release of energy metabolites from endogenous
sources. Raised plasma cortisol concentrations will augment
the effect on the mobilization of skeletal muscle protein,
releasing amino acids for gluconeogenesis and perhaps for the
hepatic synthesis of plasma proteins. Adipose tissue
mobilization will be enhanced by changes in GH concentra-
tions, and free fatty acids will become available as alternative
sources of energy (Parra et al. 1973).
BIOCHEMISTRY AND PHYSIOLOGY OF KWASHIORKOR AND MARASMUS
Reductions in the plasma concentration of thyroid hormones
have also been reported for marasmic children admitted to
hospital (Alleyne et al. 1977). This change can be regarded as
an effective adaptation, since lowering the basal metabolic rate
will conserve the meagre supplies of energy available.
3 Failure of Adaptation to Protein Deficiency: the
Patbogenesls of Kwashlorkor
The study of Lunn et al. (1973) in Uganda remains the most
complete source of information on the hormonal profiles of
pre-school children living in an area where kwashiorkor is
endemic. Fasting plasma insulin concentrations in these
children were higher than in children who had recovered from
malnutrition, and much higher than those found in Gambian
pre-school children of the same age (Whitehead et al. 1977).
Plasma cortisol and GH levels were not elevated, but no
information on thyroid hormone concentrations was obtained.
When the low protein content of a diet limits growth there
must be a relative excess of energy, even when energy intakes
are lower than recommended requirements. There need,
therefore, be no hypoglycaemic stress and consequently no
elevation of plasma cortisol or GH to cause wasting. The
problem of adaptation is how to deal with the energy excess.
There can be only two options: energy can be stored as fat or it
can be removed by oxidation. The course taken may ultimately
determine the kind of protein-energy malnutrition that even-
tually develops (see MacLean & Graham, 1979).
The endocrine pattern in non-hospitalized Ugandan pre-
school children indicates that the first of these possible pathways
is the one adopted. If the excess energy is not removed, blood
glucose concentrations will tend to rise and result in hyper-
insulinaemia and fat deposition. By promoting muscle protein
synthesis, high insulin concentrations will deplete the plasma of
essential amino acids, already in short supply, and by inhibiting
gluconeogenesis will cause an accumulation of alanine and other
non-essential amino acids typical of the developmental phases of
kwashiorkor (Grimble & Whitehead, 1970). Locking away
essential amino acids in muscle when protein intake is low is
likely to produce a fall in hepatic synthesis of export proteins,
including albumin and apo-proteins for (J-lipoprotein synthesis.
Hypoalbuminaemia could lead to defects in body fluid homo-
eostasis and oedema, and deficiencies in (J-lipoprotein synthesis
to a fatty liver.
Rats do not respond to low-protein diets in this way and
instead have a much reduced plasma insulin concentration
(Coward et al. 1977) and a markedly elevated tri-iodothyronine
level (Edozien et al. 1978; Tulp et al. 1979). This latter
response enables the animals to "burn-off' any energy excess
and will prevent the development of changes we have described
in children. Thus the rat is a poor model for kwashiorkor and
only by feeding diets virtually free of protein (Edozien, 1968;
Enwonwu & Sreebny, 1971; Philbrick & Hill, 1974; Anthony &
Edozien, 1975; Fiorotto & Coward, 1979) can this adaptation
be overcome.
The mechanisms we have discussed are clearly similar to
those involved in the development of obesity and, if the
considerable degree of individual variation to over-eating
(James & Trayhurn, 1981) also exists in the response of children
to low-protein diets, then the situation described by Gopalan
(1968) in India, where children can develop either kwashiorkor
or marasmus on identical diets, becomes easier to understand.
Waterlow (1974) has previously pointed out the likely signifi-
20
W A Coward & P G Lunn
cance of a high variability in the unrelated individual require-
ments for protein and energy.
A child admitted to hospital with kwashiorkor is usually
described as apathetic and anorexic and the hormone profile is
very different from that which existed earlier in his illness but
much more like that found in marasmus. The considerable
variation that exists between reports is not surprising, as values
will be influenced by the duration and severity of the clinical
phase of the illness. In general, plasma insulin concentrations
are reduced but can be normal; cortisol values are often elevated
and correlate with the degree of wasting and the severity of
intercurrent infections (Abbassy et al. 1967; Lunn el al. 1973).
GH concentration is elevated and thyroid hormone concentra-
tions are either normal or reduced (Alleyne et al. 1977). The
changes described are in most cases the expected responses to
anorexia and hypoglycaemia, but there are some features not
fully understood.
Children with all forms of protein-energy malnutrition have a
poor insulin response to a glucose load (Alleyne et al. 1977). It
could be argued that this might be expected in a child whose
metabolism is geared to survival, and certainly it has been
shown that short-term fasting in healthy subjects results in
impaired glucose tolerance (Vance et al. 1968). However,
Mann et al. (1975) have shown that, in South African children,
potassium supplementation of rehabilitation diets results in a
faster return to a normal insulin respose. Data from Jordan
(Hopkins et al. 1968) and Turkey (Giirson & Saner, 1971)
indicate that adding chromium to the diet produces a similar
effect, but this was not found to be the case in Egyptian children
(Carter et al. 1968).
Although plasma cortisol concentrations are elevated in
children with kwashiorkor, they are usually lower than those
found in marasmic children with the same degree of anorexia
and infection, and stimulation of the adrenal cortex with
Synacthen (synthetic P'~24 adrenocorticotrophic hormone)
results in a poor response (Jaya Rao et al. 1968). These
results suggest that a defect in the adrenals' ability to produce
cortisol may be a feature of kwashiorkor. Jaya Rao (1974)
proposed that some children develop kwashiorkor rather than
marasmus because they fail, from an early stage, to produce
amounts of cortisol adequate for adaptation to protein-energy
malnutrition. This view is substantially different from the
dietary ideas we have already outlined. If true, it would explain
the appearance of kwashiorkor in children who, because of in-
adequate food intakes, might otherwise be expected to become
marasmic. We believe, however, that there are other more
likely explanations (see section 4).
Plasma GH concentrations are high in children with
kwashiorkor and are not reduced by glucose loads (Pimstone et
al. 1967). However, it has been demonstrated that they fall after
a few days of feeding meals containing protein (Pimstone el al.
1968). Robinson et al. (1973) showed that this response occurs
even after a single meal. There is also an inverse relationship
between GH levels and the severity of protein deficiency as
assessed by plasma albumin concentrations (Pimstone el al.
1968; Lunn et al. 1973; Kajubi & Okel, 1974). The
mechanisms regulating plasma GH concentrations in kwashi-
orkor have not been identified, but a number of possibilities are
discussed by Pimstone et al. (1973). Although plasma
somatomedin concentrations are low in children with kwashi-
orkor, there is no evidence to support the suggestion (Grant el al.
1973) that impaired somatomedin production might cause a
feedback stimulus for GH release (Mohan & Jaya Rao, 1979).
Br. hied. Bull. 1981
 BIOCHEMISTRY AND PHYSIOLOGY OF KWASHIORKOR AND MARASMUS
Since plasma GH concentrations rise only in the terminal stages
of the development of kwashiorkor (Lunn et al. 1973), it is
unlikely that GH-mediated changes are directly involved in the
early pathogenesis of this disease.
4 Pathogenesis of Intermediate Forms of Protein-Energy
Malnutrition
We have suggested that the endocrine response to a diet can
determine how available nutrients are used, and it is theoretically
possible that, as a result of the alternating dominance of energy
or protein deficiencies, marasmic kwashiorkor might emerge
(Whitehead & Alleyne, 1972). However, in practice, it is more
likely that non-nutritional factors modulate the effects of the
diet.
A conventional view was outlined by Whitehead & Lunn
(1979). It was proposed that the incidence of infections that
elevate plasma glucocorticoid concentrations will alter the
effects of diet and accelerate wasting in children developing
marasmus. Alternatively, severe wasting could be induced in
children who are otherwise likely to present as cases of
kwashiorkor.
We have also recently suggested (Lunn et al. 1979b) that
there may be another important way in which marasmic
kwashiorkor can develop. We believe that many children
admitted to hospital with oedema have the underlying
metabolic features of marasmus. Superimposed on these,
oedema and hypoproteinaemia have appeared precipitously as a
result of an increased gastrointestinal loss of plasma proteins, not
compensated for by increased rates of protein synthesis. Likely
causes of such losses are a measles infection or the presence of
intestinal helminths.
5 Regulation of Body Fluid Volumes In Protein-Energy
Malnutrition
The appearance of oedema in malnourished children is an
example of a failure of homoeostasis that specifically dis-
tinguishes kwashiorkor from other forms of malnutrition, but
until recently little progress had been made in identifying its
cause. However, two distinctly different views can now be
identified.
a The Distribution of Extracellular Fluid Volume
Coward & Fiorotto (1979) and Fiorotto & Coward (1979)
believe that the most important factors are those that determine
the distribution of extracellular fluid between the vascular and
interstitial spaces. They observed that, when plasma protein
concentrations fall in protein-deficient rats, a normal balance of
transcapillary colloid osmotic pressures, preventing excessive
water filtration, was maintained by a reduction in the colloid
content of interstitial fluid that matched the changes in plasma.
This represented a proportionally larger change in interstitial
fluid protein concentration, because in normal animals the
plasma: interstitial fluid concentration ratio is about 2. While
this adaptation to hypoproteinaemia is effective over a large
range of plasma protein concentrations, the homoeostatic mech-
anism does not possess infinite gain because, when plasma
protein concentration is reduced by half, interstitial fluid protein
concentrations reach values close to zero. At this stage any
further reduction in plasma protein content will produce an
imbalance of the transcapillary forces and the organism's
control over the distribution of extracellular fluid volume will be
21
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WA Coward & P G Lunn
lost. Active renal salt and water retention might then occur to
prevent plasma volume contraction but, in the face of the
circulation's reduced ability to hold retained fluid, further
interstitial volume expansion will occur. This idea indicates that
blood and plasma volumes will be reduced in kwashiorkor and
the most recent observations with labelled erythrocytes (Viart,
1977) show that this is the case, contradicting much of the
earlier work. The differences could be attributed to different
methodologies; Viart suggested that in malnutrition plasma
volumes measured with protein-bound tracers could be mis-
leadingly large.
The development of these ideas was stimulated by an
insistence that changes in plasma albumin concentration are
functionally important in the development of kwashiorkor and
by the recognition that the contribution of albumin to the total
colloid osmotic pressure of plasma (>50%) is greater than that
of any other plasma protein, but other abnormalities occur and
their importance has to be considered.
b Sodium and Water Balance
The alternative, or perhaps complementary, idea begins with
the concept that children with kwashiorkor are over-hydrated
and suggests that, when a malnourished child develops sodium
and water retention, plasma albumin concentrations will fall
with the development of oedema, because albumin synthesis
rates are unalterably low (Patrick, 1979). In these cir-
cumstances the task is to identify the reasons for phases of
sodium retention in malnourished children.
In a review of the effects of protein-energy malnutrition on
renal function, Klahr & Alleyne (1973) identified factors that
could impair the ability of malnourished children to excrete
sodium loads. With only one exception (Srikantia, 1968),
published data show that renal plasma flow (RPF) and
glomerular filtration rate (GFR) are decreased but, while these
changes will undoubtedly limit the potential for salt and water
excretion, they are not specifically associated with the presence
of oedema in children (Alleyne, 1967). In addition, experi-
ments with sheep (Rabinowitz et al. 1973) and baboons (M
Fiorotto and W A Coward, in preparation) have shown that
reductions in RPF and GFR are early effects of feeding
low-protein diets and are not associated with evidence of
excessive salt and water retention.
At the tubular level, sodium retention could result from
elevated plasma aldosterone levels and increased plasma renin
activity but, again, evidence for a specific association with the
presence of oedema is ambiguous. For example, Migeon et al.
(1973) found either normal or increased aldosterone secretion
rates in malnourished children but plasma concentrations were
normal in children with marasmus and elevated in only half of
those with kwashiorkor. Furthermore, although Van der
Westhuysen et al. (1975a) found increased plasma renin
activity in oedematous malnourished rats but not in non-
oedematous animals, the same group of workers (Van der
Westhuysen et al. 1975b) showed that children suffering from
protein-energy malnutrition have elevated plasma renin ac-
tivities, irrespective of the presence of oedema. Worthington et
al. (1977) measured plasma aldosterone concentrations in
monkeys fed low-protein diets and found elevated levels when
oedema was present, but our own serial studies with baboons
(M Fiorotto & W A Coward, in preparation) showed that
changes in aldosterone concentration and plasma renin activity
can precede the appearance of oedema by many months.
Finally, Srikantia (1968) postulated a role for antidiuretic
 BIOCHEMISTRY AND PHYSIOLOGY OF KWASHIORKOR AND MARASMUS
hormone in oedema formation, but this idea has not been
universally accepted, essentially because urine osmolality is
never elevated in malnourished children.
The connection between these observations and those
showing that fractional sodium reabsorption can be decreased in
malnourished oedematous children (Alleyne, 1965; Nichols et
al. 1973) is not clear. It could be argued (Fiorotto, 1980) that
hypoproteinaemia and low plasma oncotic pressure in the
peritubular capillaries would limit sodium reabsorption in the
proximal tubules, and in protein deficiency reduced rates of urea
synthesis would lead to the dissipation of the hypertonic
environment in the renal medulla needed for salt and water
reabsorption in later segments. Thus excessive sodium and
water losses could be prevented only by reductions in RPF and
GFR; Wright & Briggs (1979) have recently reviewed the
evidence for the existence of a mechanism by which GFR in a
single nephron is regulated by the composition or rate of flow of
distal tubule fluid. In these circumstances the manner in which
the kidney regulates salt and water balance in relationship to
intake may not have the precision of response available in
normal children.
c Membrane Defects and the Sodium Pump
In following up lines of thought developed by Metcoff (1975),
Patrick (1979) commented on the significance of changes in
membrane permeability and the activity of the sodium pump in
malnutrition. There is no information on this aspect of renal
tubule cell physiology in malnutrition, but it is suggested that
findings for leucocytes (Patrick, 1979) and erythrocytes
(Kaplay, 1978; Fondu et al. 1979) may be relevant. For
leucocytes it was shown that there were dramatically increased
transport rates of sodium in kwashiorkor, which could be
achieved only by an increase in membrane permeability to
sodium and subsequent stimulation of the sodium pump. The
results obtained for erythrocytes, where it was found that
ouabain-sensitive Na-K adenosinetriphosphatase activity is
increased (compared with normal and recovery values) in
kwashiorkor but not in marasmus, are compatible with these
observations and, if mirrored at the level of the renal tubule,
could cause increased fractional sodium resorption. There
remains, however, the problem of the relationship of these
changes to dietary and environmental causes of kwashiorkor.
Trace element deficiencies1 could provide the link (Patrick,
1980) or, if an energy intake in excess of requirements is a
significant dietary component, a thermogenic response involving
increased sodium pumping might be relevant
It will be clear that we are some way from integrating all these
observations into a concise framework. Our general view is that
there is a need to separate the influence of those factors
responsible for the distribution of body water between plasma,
the interstitium and cells, and those controlling the general
degree of hydration. Observations made by Patrick et al.
(1978) illustrate the problem. Children with kwashiorkor can
lose their oedema and decrease their total body water from 77%
to 63% of body weight when they are fed diets not known to
produce substantial changes in rates of plasma protein synthesis.
However, marasmic children fed high-energy diets increase their
total body water from 64% to over 70% of body weight in 14
days but oedema does not appear; other workers report even
higher values in oedema-free marasmic children (Hansen et al.
1 1
See Golden & Golden, pp. 31-36 of this Bulletin.ED.
22
W A Coward & P G Lunn
1965). It is unlikely that changes in only one aspect of
regulative physiology will be able to explain these findings.
6 Plasma Proteins in Kwashiorkor and Marasmus
There are a multitude of reports on the usefulness of the
measurement of plasma protein concentrations for the assess-
ment of nutritional status, but before discussing them it is
necessary to develop a concept that describes an ideal marker
for malnutrition. In the first instance it should be responsive to
changes in nutrient intake and, secondly, changes in its plasma
concentration should be meaningful in terms of the ultimate
pathology of protein-energy malnutrition. Thus, if we accept
that a low plasma albumin concentration specifically contri-
butes to oedema formation, it is clear that its measurement is
useful in communities where kwashiorkor is the predominant
form of malnutrition. We have therefore often found it
convenient to classify children according to their albumin
concentration and to relate other biochemical changes to these
values (Whitehead et al. 1973). In this way it is possible to build
up a comprehensive picture of the development and resolution of
kwashiorkor.
In contrast to this situation, where the functional significance
of changes in the concentration of a plasma protein is
recognized, we can describe the "sensitivity" of a particular
protein in malnutrition without simultaneously considering
nutrient intake or the final form of malnutrition that emerges.
This strategy is inevitably empirical, since the plasma con-
centration of any protein is dependent not only on rates of
synthesis (the diet- and substrate-dependent component) but
also on utilization and catabolism, rates of intravascular-
extravascular exchange and the degree of hydration. It is the
balance between these processes that determines whether the
concentration of a specific protein reflects the degree of
protein-energy malnutrition. However, three plasma proteins
have consistently attracted attention: these are transferrin,
thyroxine-binding prealbumin (TBPA) and retinol-binding pro-
tein (RBP).
McFarlane et al. (1969), McFarlane et al. (1970) and Gabr et
al. (1971) showed that low transferrin concentrations were
associated with a poor prognosis in children with kwashiorkor,
and Reeds & Laditan (1976) extended this observation to
include those with marasmus. Furthermore, the latter workers
showed that serum transferrin concentrations were linearly
related to deficits in weight- and length-for-age in under-
nourished children although albumin concentrations were not
Others have also advocated the use of plasma transferrin
concentration as a most sensitive index of protein-energy
malnutrition because of its rapid response to refeeding in
malnourished children, and sensitivity to reduced protein intake
in experimental animals (Olusi et al. 1975). However, the
frequency with which iron-deficiency anaemia2 occurs in
malnourished children can complicate the situation to the extent
that a decrease in transferrin concentration caused by mal-
nutrition can be masked by an increase due to a lack of iron
(Ismadi et al. 1971; Ingenbleek et al. 1975; Delpeuch et al.
1980), and in these circumstances other indices of malnutrition
are likely to be less ambiguous.
Plasma RBP and TBPA have also been proposed as sensitive
indicators of nutritional status (Ingenbleek et al. 1972, 1975;
Delpeuch et al. 1980), because their concentrations are greatly
S Nirumg* Ro. PP- 23-30 of thiiBuBttm.ED.
Br. hied. Bull. 1981
 BIOCHEMISTRY AND PHYSIOLOGY OF KWASHIORKOR AND MARASMUS
reduced in malnourished children admitted to hospital and
rapidly return to normal with refeeding. Ogunshina & Hussain
(1980) have also shown that TBPA concentrations decrease
with increasing severity of malnutrition assessed anthropo-
metrically. Experimental studies on obese women (Shetty et al.
1979) indicate that TBPA and RBP concentrations are sensitive
to changes in either energy or protein intake and this finding
supports the observations that TBPA and RBP concentrations
are equally low in kwashiorkor, marasmic kwashiorkor and
marasmus (Smith et al. 1975). However, Large et al. (1980)
have recently investigated RBP and TBPA in children suffering
the combined effects of vitamin A deficiency and protein-energy
malnutrition and have shown that, following intramuscular
injection with vitamin A, plasma levels of holo-RBP (native
protein with the ligand retinol attached) increased, peaking at 3
hours after treatment. The peak levels were lowest in kwashi-
orkor and highest in marasmus; children with marasmic
kwashiorkor had intermediate values. The values achieved are
related to the accumulated surplus of native RBP in the liver
before dosing, since vitamin A deficiency inhibits the release of
RBP from the liver, so the authors considered that the peak
concentrations provided some measure of the liver's ability to
synthesize RBP from the outset. This result therefore indicates
that RBP synthesis is less affected in marasmus than in
kwashiorkor.
In reviewing the relationship between diet and plasma protein
concentrations, Olson (1975) found it possible to distinguish
groups of proteins on the basis of the responsiveness to dietary
therapy. The immunoglobulins (IgA, IgG and IgM) were
identified as diet-independent plasma proteins; diet-dependent
proteins were subdivided into those that increased in concentra-
tion when only 1 g protein/kg body weight per day was fed
(prothrombin, proconvertin, RBP and TBPA) and those
requiring larger protein intakes (albumin, transferrin, (3-
lipoprotein and complement). It was not possible convincingly
to relate these differences in responsiveness to normal fractional
or absolute rates of synthesis, or to their sites of synthesis, but
the differences illustrate the difficulties that exist when the
usefulness of an index for malnutrition is defined only in terms of
sensitivity to a dietary change. It would be wrong to suggest
that RBP and TBPA are better indices than albumin concentra-
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WA Coward & P G Lunn
tion and more appropriate to suggest instead that they are
different indices from the dietary and metabolic points of view.
Another group of proteins that has recently attracted
attention are the plasma proteinase inhibitors. Workers in
Thailand (Schelp et al. 1977, 1978, 1979) attach crucial
metabolic importance to changes in the plasma concentration of
a1-antitrypsin and a1-antichymotrypsin in the development of
malnutrition. The theory, most concisely outlined by Schelp et
al. (1978), recognizes that kwashiorkor and marasmus are
metabolically distinct diseases, but suggests that proteinase
inhibitor levels determine the extent to which a malnourished
child can mobilize endogenous proteins to provide amino acids
for the synthesis of proteins (e.g. albumin) essential for
homoeostasis. When proteinase inhibitor levels are high as a
result of infection, it is possible that a balanced relationship
between proteinases and their inhibitors is destroyed; this leads
to disturbances in homoeostasis such as those found in
kwashiorkor. This is an intriguing, novel idea, but it needs
experimental investigation and further studies on malnourished
children in other developing countries.
We recognize that marasmus, rather than kwashiorkor, is the
nutritional problem most frequently encountered by doctors
working in developing countries. In this respect, we accept the
view (McLaren, 1974) that in a universal context it is necessary
to appreciate that a lack of nutrients in general, with an energy
gap rather than a protein gap, is most important. However,
although we may have an adequate knowledge of how and why
marasmus appears, many aspects of the biochemistry and
physiology of kwashiorkor have not yet been explained. For
this reason we have biased our discussions towards re-
awakening an interest in the latter disease, even though only a
minority of the world's malnourished children are likely to suffer
from it. Elucidation of the mechanisms involved will not only
lead to improvements in the prevention and treatment of
nutritional disease, but will also provide a more complete
understanding of how nutritional and other environmental
stresses interact to produce the diseases identified as kwashi-
orkor, marasmus and marasmic kwashiorkor.
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