The incidence of malnutrition in hospitalised patients is often underestimated.
However, many studies have demonstrated the relation between malnutrition
and morbidity and mortality in hospital populations. Furthermore, fasting,
stress and disease are also potentially life-threatening conditions.
In order to better understand the metabolic and physiological consequences
of these phenomena, a compact refresher of protein, carbohydrate and
lipid metabolism has been included.
Malnutrition is induced by inadequate nutrient intake, excessive nutrient
losses or increased metabolic requirements. However, malnutrition and
its consequences can be prevented or treated by adequate nutritional
support.
Fasting and stress have different effects on the human organism. Fasting
leads to an conservation of the available energy stores, thus reducing
protein and nitrogen losses. In contrast, stress and disease metabolism
significantly increase energy expenditure, induced by a catabolic state.
Here also, the principal goal of nutritional support is to reduce morbidity
and mortality, which all too often accompany fasting and stress.
These subjects will be further developed and discussed in the first part
of this paper.
Surveys in the 1970s showed that 30 - 50% of the hospitalised
medical patients had anthropometric or biochemical evidence of malnutrition
(Bistrian et al., 1974; Bistrian et al., 1976; Hill et al., 1977). Malnutrition
affected many disease categories, including infection, gastrointestinal
and respiratory diseases. Malnutrition was also present in surgical patients,
as shown by a reduction in body weight in up to 40% of the patients entering
major surgery.
The relation between malnutrition and an increased morbidity and mortality,
especially in the case of critically ill patients, has become clear (Buzby
et al., 1980; von Meyenfeldt et al., 1992). Hence, weight loss still
represents a risk factor for postoperative complications, especially
when it is associated with clinically relevant organ dysfunction; it
is the loss of physiological function as a result of cellular protein
loss that places the patient at risk. When more than 20% of body protein
has been lost, most physiologic functions are significantly impaired.
Such patients have more complications and a longer hospital stay as a
consequence (Windsor and Hill, Ann Surg 1988; 207; Windsor and Hill,
Ann Surg 1988; 208). Furthermore, malnutrition affects wound healing
(Haydock and Hill, 1986), suggesting a delay of the wound healing in
malnourished surgical patients. Patients who are protein depleted are
at greater risk for postoperative complications than patients in whom
protein depletion is not present; they are at greater risk not to survive
complications after surgery than are non-depleted patients (Chandra,
1983; Dempsey et al., 1988; Windsor and Hill, Ann Surg 1988; 207; Windsor
and Hill, Ann Surg 1988; 208; Windsor and Hill, Aust N Z J Surg 1988;
Hirsch et al., 1992).
Tab. 1: Nutritional status as predictor of postoperative
sepsis and mortality in adults undergoing major surgery
Malnutrition is characterised by an impairment of a number of physiological
functions. Strength is reduced and fatigue occurs much earlier. Respiratory
muscle function is deteriorated, as are other bodily functions, such
as cardiac, sexual and immune function as well as thermoregulation. Malnutrition
leads to depression, irritability, anxiety, reduced ability to maintain
concentration and reduced sexual drive. In children, malnutrition impairs
growth and delays sexual maturation. The importance of feeding on neurodevelopment
in preterm infants has been shown by the influence of the type of feeding
(preterm formula vs term formula) on the IQ eight years later (Morley
and Lucas, 1993).
Hence, in the hospitalised patient, malnutrition combined with weight
loss affects the ability to recover and facilitates the supervention
of infectious complications with consequences on the duration of hospitalisation.
Prevention and treatment of malnutrition therefore often justify recourse
to artificial nutritional support.
The crucial issue in the definition of malnutrition is a decreased protein
store, as a consequence of an insufficient metabolism. This can be caused
by both insufficient food uptake and chronic catabolic illness. The lack
of minerals, vitamins or trace elements resulting from insufficient feeding
is beyond the scope of this definition, because these shortages can be
supplemented relatively easily. Especially in the feeding of the acutely
ill patient, manipulation of the protein mass, however, forms the major
problem.
Two main types of malnutrition can be discerned. Malnutrition may take
the form of a protein-energy deficiency (marasmus-type) or of a protein
deficiency (kwashiorkor-type). Besides these two types, marasmic kwashiorkor
is defined as a combination of these two clinical states. Marasmus (or
simple starvation) is diagnosed relatively easily and is characterised
by a gradual loss of lean body mass and adipose tissue, due to a chronic
imbalance between protein and energy intake and requirements. The patient
utilises his endogenous energy reserves, including adipose and somatic
muscle tissue with subsequent weight loss, muscle wasting and loss of
fat depots. Marasmic malnutrition develops over a relatively long time
period and patients are underweight and more or less cachectic.
The diagnosis of kwashiorkor is often more difficult, since body protein
is reduced but fat stores are normal. This type of malnutrition is caused
by an unbalanced feeding pattern and is characterised by hypoalbuminemia.
Other symptoms are hepatomegaly and hair and skin changes. Extracellular
water spaces are expanded, with salt retention, oedema and occasionally
ascites. Marasmic kwashiorkor, an intermediate form characterised by
wasting and hypoalbuminemia, with or without oedema, is also relatively
common in hospital patients. These patients are often overweight and
at first sight do not necessarily appear malnourished.
Malnourished hospitalised patients have a diminished immune response
and are at greater risk of developing postoperative complications or
infection.
Tab. 2:Description of types of malnutrition
It is especially the kwashiorkor type of malnutrition, characterised
by protein and muscle wasting, that represents a potential risk to the
hospitalised patient under stress. Detection and characterisation of
malnutrition is therefore of utmost importance.
The first step in the detection and assessment of malnutrition lies in
the definition and description of the patients at risk. The clinical
impression of the patient forms the basis. This clinical impression is
based on the patient´s history and disease, its effect on body weight
over the 3 last months, the palpation of the subcutaneous adipose tissue
(abdominal, triceps, subscapular), the power of the limbs and the condition
of the hair. These parameters are probably at least as important as the
parameters in Table IV, to gain an accurate picture. A meticulous clinical
examination can provide a good estimation of the patient´s risk for complications.
The physical examination should focus on the signs listed in Tab. 3.
These will be dealt with in more detail in the rest of this chapter.
Tab. 3:Clinical evaluation in the assessment of
malnutrition
In addition to the clinical impression, anthropometric and biochemical
parameters for the assessment of nutritional status have been defined.
In Tab. 4, simple anthropometric and biochemical parameters for the evaluation
of malnutrition are summarized.
Tab. 4: Parameters for the assessment of
malnutrition
A decrease in food consumption is, in most cases, secondary to the disease.
However, chronic undernutrition, occasionally in a marginal form may
undoubtedly aggravate the severity of the acute disorder, as seen in
certain groups at risk such as the economically underprivileged, alcoholics
and the elderly.
Anorexia may occasionally be attributable, in part, to a depressive state,
but is frequently indicative of latent organic disease. Sensory deprivation,
diminution or impairment of the sense of taste or smell, secondary to
the disease, may play a major role. Certain patients complain of an unpleasant
taste or even an aversion to specific foods. In others, therapy induces
nausea and anorexia. Once malnutrition has set in, atrophy of the gustatory
papillae or nutritional deficiencies may maintain lack or impairment
in the sense of taste.
Food consumption may also be reduced due to lack of teeth, poorly fitting
dentures and salivary gland disorders. Problems of deglutition are common
in cases of diseases of the oral cavity, pharynx and oesophagus. Diseases
of the digestive tract often induce abdominal pain and vomiting, which
reduce the intake even if appetite is unaffected.
In a hospital context, food intake will be restricted by a sequence of
daily events, particularly tests which necessitate prolonged fasting.
Other iatrogenic causes include restrictive diets and hypocaloric glucose
infusions.
The physiology of digestion and absorption is such that normal protein
and energy losses are minimal. In a diseased state, by contrast, losses
secondary to malabsorption may increase to a significant extent. Losses
may also occur through the skin in certain dermatological diseases characterised
by desquamation and exudation of fluids rich in electrolytes and proteins
as well as in severe burn cases.
Many diseases entail malabsorption of specific nutrients such as vitamins,
minerals and trace elements. The steatorrhea observed in diffuse diseases
of the small intestine, pancreatic insufficiency and cholestatic diseases
result in high energy losses, as well as malabsorption of fat-soluble
vitamins.
Consequently, vitamin deficiency syndromes, such as osteomalacia and
disturbances of coagulation factors may arise. The loss of minerals,
particularly calcium, magnesium and zinc, also occurs in this context.
Intestinal fistulas, in inflammatory diseases of the digestive tract
or as a result of surgery, entail high losses of nutrients, water and
electrolytes.
Hypermetabolic states are characterized by an acceleration of the metabolic
processes caused by the disease. Fever increases the basal metabolism
by a little more than 10% for each degree temperature rise. Disorders
associated with very severe or prolonged conditions, such as extensive
burns, sepsis, trauma and injury lead to a hypermetabolic stress response
from the body, thus altering metabolism and fuel utilisation. The extent
of alteration depends on the severity and the type of the stress insultus.
Furthermore, the alterations are characterised by an increased energy
expenditure and body temperature. Elective operations increase resting
energy expenditure by up to 10%; multiple fractures, stab wounds or gunshot
wounds cause an increase to 30%; severe sepsis up to 60%. Extensive third-degree
burns can even cause more than a doubling of the energy expenditure (Kinney
et al., 1970).
In a hospital population, the prevalence of malnutrition is variable,
but is probably underestimated because of the difficulties involved in
recording accurately the patients nutritional status. Surveys in the
mid-seventies showed that up to 50% of the patients admitted to the hospital
had evidence of malnutrition, a situation which remains the case today.
A recent survey of 500 patients admitted to the hospital showed that
40% of the patients were undernourished (McWrither
and Pennington, 1994). Undernutrition was found in all
medical and surgical specialities investigated. In this group, 44% of
the patients were regarded as having moderate undernutrition (body mass
index (BMI) < 18) and 24% as having severe undernutrition (BMI < 16).
Furthermore, 75% of the patients continued to lose weight in the hospital.
Even more worrying was the fact that in 55 of the patients that were
followed, only 10 received nutritional support in the hospital; 7 of
these 10 patients (70%) gained weight. In contrast, of the patients who
received no specialised nutritional support, only 11% gained weight.
These findings indicate that routine screening for undernutrition is
still not performed and that undernutrition remains a severe problem
in hospitalized patients.
Bistrian BR, Blackburn GL, Hallowell E, Heddle R.:
Protein status of general surgical patients.
JAMA 1974;230:858 - 60.
Bistrian BR, Blackburn GL, Vitale J, Cochran D, Naylor J.:
Prevalence of malnutrition in general medical patients.
JAMA 1976; 235:1567 - 70.
Bozetti F.:
Nutritional assessment from the perspective of a clinician.
JPEN 1987;11(suppl):115S - 21S.
Butterworth CE Jr, Weinsier RL.:
Malnutrition in hospital patients: assessment and treatment. In: Goodhart
RS, Shils ME, eds. Modern nutrition in health and disease, 2nd ed.
Philadelphia:
Lea & Febiger, 1980:667 - 84.
Buzby GP, Mullen JL, Matthews DC, Hobbs CL, Rosato EF.:
Prognostic nutritional index in gastrointestinal surgery.
Am J Surg 1980;139:160 - 7.
McCarnish MA.:
Malnutrition and nutrition support interventions: cost, benefits, and
outcomes.
Nutrition 1993;9:556 - 7.
Chandra RK.:
Nutrition, immunity, and infection: present knowledge and future directions.
Lancet 1983;1:688 - 91.
Dempsey DT, Mullen JL, Buzby GP.:
The link between nutritional status and clinical outcome: can nutritional
intervention modify it?
Am J Clin Nutr 1988;47:352 - 6.
Farthing MJG.:
Malnutrition in the wards of the world.
Nutrition 1994; 10: 424 - 5.
Haydock DA, Hill GL.:
Impaired wound healing in surgical patients with varying degrees of malnutrition.
JPEN 1986;10:550 - 4.
Hill GL.:
Body composition research: implications for the practice of clinical
nutrition.
JPEN 1992;16:197 - 218.
Hill GL, Pickford I, Young GA et al.:
Malnutrition in surgical patients: an unrecognised problem.
Lancet 1977; 1: 689 - 92.
Hirsch S, de Osbaldia N, Petermann M et al.:
Nutritional status of surgical patients and the relationship of nutrition
to postoperative outcome.
J Am Coll Nutr 1992; 11: 21 - 4.
Kinney JM, Duke JH Jr, Long CL, Gump F.:
Tissue fuel and weight loss after injury.
J Clin Path 1970;23(suppl 4):65 - 72.
Energy metabolism or intermediate metabolism is characterized by an
intimate interrelation between the metabolism of protein, lipid and carbohydrate.
The body´s energy requirements are basically covered by carbohydrates
and lipids. Proteins play a specific functional role in normal circumstances
and are used only slightly, if at all, as an energy substrate.
The estimated basal requirement of an adult is 25 - 30 kcal/kg/day,
i.e. 1750 - 2100 kcal/day for a body weight of 70 kg. Physical
activity and disease may increase the requirement to about 40 - 45
kcal/kg/day and higher in certain hypermetabolic conditions such as sepsis,
extensive burns, multiple organ failure, etc.
Protein stores are in the order of 30.000 kcal (Bistrian,
1977). Only muscle proteins can be regarded as potential
energy reserve in case of energy deprivation. As muscular tissue
contains approximately 75% water, the loss of 1 kg of protein corresponds
to a total loss of approximately 4 kg of body weight. On average,
1 kg of muscle contains 180 g of proteins, 750 g of water, 70 g of
fat and 7 g of glycogen. The most abundant amino acids in muscular
tissue are glutamine and alanine. They constitute more than 50% of
the amino acids released from skeletal muscle tissue.
No intact proteins enter the body, so that all proteins must be synthesized
anew from amino acids. Amino acids from the bloodstream are rapidly taken
up by the tissue, where they, together with the amino acids from the
endogenous protein degradation, form the "labile amino acid pool". This
pool is relatively constant in size and increased outward flux (due to
increased protein synthesis, excretion or catabolism) must be met by
increased influx from dietary sources or protein breakdown.
Fig. 1: Schematic flux of the free amino acid
(From: Stein, 1981)
Although this pool contains only one percent of total body amino acids,
it provides a mechanism for movement of amino acids between various organs,
thereby determining in large part the state of the nitrogen balance of
the organism (Stein, 1981). The amino acids from the labile pool may
enter one of two metabolic pathways. In the anabolic pathway, specific
proteins are synthesized. In the catabolic pathway, amino acids can undergo
specific metabolic interactions like transamination, thereby transferring
an amino group, decarboxylation or desamination.
In the body, each protein has a specific functional role and no visceral
protein reserves exist as such. The utilisation of protein for energy
purposes results in an obligatory functional insultus, a luxury which
only the muscular compartment can afford. As protein store can only be
used to a limited degree. The body must modify its utilisation of nitrogen
(N) stores, thereby reducing gluconeogenesis and urinary nitrogen excretion
by shifting to a fuel system of fat utilisation and ketone body production
as starvation progresses.
Amino acid catabolism involves a transamination reaction in which the
amino group is removed. The carbon residue is then either oxidized to
CO2 or used in the liver as a substrate for gluconeogenesis. The amino
groups resulting from protein catabolism are transported from muscle
to the liver by alanine. The amino acid thus undergoes a cycle transporting
the amino groups to the liver where urea is synthesized, and then returning
to the periphery in the form of glucose synthesized from the carbon residue.
It is estimated that when 40% of the protein pool is destroyed, the state
of malnutrition is incompatible with survival.
Protein in the body is not static; protein synthesis and breakdown is
constantly taking place. However, the total body protein pool in a healthy
adult is constant. Synthesis of protein from endogenous and exogenous
amino acids is equal to degradation and external losses. Some proteins
have a long lifetime, such as muscle protein and plasma albumin, while
others have a high turnover rate. Muscle protein constitutes up to approximately
50% of total body protein, but contributes only approximately 30% of
the protein turnover in the body, because in visceral and other organs,
protein turnover rates are several times higher than in muscle tissue.
Protein metabolism is dependent on a vast number of endogenous mediators.
These mediators define the balance between anabolic and catabolic processes.
Insulin is the major anabolic hormone and also has an important role
in amino acid and protein homeostasis. During injury and stress two major
alterations in insulin are noted: a catecholamine-mediated suppression
of insulin release and an insulin resistance, leading to a release of
skeletal muscle amino acid for gluconeogenesis and, at the same time,
a decreased utilisation of glucose by insulin-dependent tissues. This
mechanism provides glucose to the insulin-dependent tissues that are
important for survival and the healing of injury, such as the central
nervous system (CNS), immune system and red blood cells. Other hormones,
like glucagon and the catecholamines, control or counteract the effects
of insulin and are more or less proteolytic; the exact role of catecholamines
is still under discussion, however.
Fig. 2: Amino acid and protein metabolism
(Modified from: Matthews and Fong, 1993)
In order to define protein requirements, an overview of protein metabolism
is necessary. By determining the renewal of proteins susceptible to measurement,
such as plasma, muscle and digestive secretion proteins, it has been
possible to estimate the daily turnover in proteins. Considerable recycling
of endogenous amino acids seems to occur, the quantity amounting to twice
the daily intake. Hence, normal protein metabolism incorporates about
100 g of dietary amino acids and over 200 g of endogenous amino acids
daily. Allowance must therefore be made for increased losses of endogenous
proteins when assessing patients´ protein intake.
The minimal protein requirement is about 0.50 g/kg/24 h and the recommended
quantity for the normal state is 1 g/kg/24 h. Given that 1 g of nitrogen
is equivalent to 6.25 g of protein, the normal nitrogen requirement is
0.16 g of nitrogen/kg/24 h. Depending on circumstances, the protein requirement
may increase to about 2 g/kg in the adult .
Tab. 5: Recommended amounts of nitrogen and
energy for normometabolic subjects and for injured, septic and malnourished
patients. Very approximate.
Glucose is the most important carbohydrate involved in the metabolism.
It is the obligate energy source for the brain, renal medulla and erythrocytes.
Besides this, glucose forms the fuel for the muscular tissue, liver,
heart, kidneys and intestinal tissue.
In normal diets, carbohydrates account for an average of 45 to 55% of
the caloric intake. Glucose has a calorific value of about 4 kcal/g.
It is stored as glycogen, a branched-chain polymer of glucose, mainly
in the liver and the muscle tissue. Energy reserves in the form of glycogen
are nevertheless very limited, in total about 900 kcal (Cahill,
1970).
Physiologic control mechanisms ensure a close matching of the uptake
of glucose by tissues and the appearance of glucose in the bloodstream.
The glucose production is of primary importance in the regulation of
the plasma glucose concentration. During fasting, endogenous glucose
production replaces the glucose taken up and catabolised by glucose dependent
tissue. Glycogenolysis in the liver and gluconeogenesis in liver and
kidneys are the two primary processes of glucose production. However,
the kidneys may significantly contribute to gluconeogenesis in cases
of starvation only.
The major hormone inhibiting gluconeogenesis is insulin. Although the
concentration of glucose in the blood is regulated within narrow limits,
the rate of glucose uptake and oxidation in various tissues can vary
greatly. The glucose dependent tissues have a relatively constant rate
of glucose uptake. The liver plays the dominant role in the disposal
of glucose loads and much of the glucose is converted to glycogen here.
It is further the muscle mass that exerts a profound influence on the
overall rate of glucose utilisation and this can vary greatly, depending
on the physical activity.
Gluconeogenesis refers to the de novo formation of glucose from non-carbohydrate
precursors. The process of gluconeogenesis comprises a complex reaction
sequence and may arise from various precursors such as lactate, glycerol
and amino acids. Lactate is an important glucose precursor in resting
humans and in some circumstances represents the primary gluconeogenic
precursor. As lactate is derived from plasma glucose in glycogenolysis,
the resynthesis of glucose from lactate is a cyclic reaction (Cori cycle).
Gluconeogenesis from amino acids, especially alanine, has a limited role
in rest.
When energy is required, the glycogen, present in the liver and muscular
tissue, is mobilized rapidly and liver glycogen therefore plays a key
role in the regulation of fasting glycemia. The synthesis of glycogen
is under the control of glucose, stimulated by excess glucose in the
blood and under hormonal control. Insulin decreases the breakdown of
glycogen and stimulates the uptake of glucose in the tissue. Hormones
released in response to hypoglycaemia or stress stimulate glycogenolysis
and tend to inhibit glycogen synthesis. These hormones that stimulate
glycogenolysis are glucagon, (nor)epinephrine, vasopressin and angiotensin
II.
Lipids are the major organic constituents of all body tissues. They
have two essential functions. Firstly, they represent a major source
of energy in the form of triglycerides stored in the adipose tissue.
In the normal adult, adipose triglycerides account for a substantial
reserve of 140.000 to 160.000 kcal (Bistrian,
1977; Cahill, 1970). The energy value of lipids (9 kcal/g)
is more than twice that of carbohydrate and protein. As the storage of
lipids requires much less water, they have the additional advantage of
a higher ratio of energy to stored volume.
Secondly, lipids have several important structural functions: they are
an essential component of cell membranes, surround critical organs and
protect against physical injury and heat loss. Furthermore, lipids serve
as precursors for the synthesis of eicosanoids, such as prostaglandins,
which serve as important regulatory compounds.
Essential fatty acids (EFA) are called "essential", because the human
body is not able to synthesize them. Linoleic acid is regarded as the
classic EFA. According to the literature, normal daily requirements are
estimated between 0.5 and 7% of the daily energy intake (Rivers
and Frankel, 1981). These values are influenced by age,
physical condition and the criteria by which they are measured. There
is now increasing evidence that ?-linolenic acid is also an EFA,
with functions which can be distinguished from those of linoleic acid.
The first case of ?-linolenic acid deficiency was reported in 1982 (Holman
et al.); the minimal daily requirement was estimated to
be about 0.54% of caloric intake. Essentiality of ?-linolenic acid
is claimed for the development and function of the retina and brain,
with 1% of total calories as an advisable intake (Neuringer
et al., 1988). The essential fatty acids are liberated
at night, in the postabsorptive phase and hence it is almost impossible
to demonstrate EFA-deficiency (EFAD) in normal circumstances. In the
case of artificial nutrition, continuous provision of carbohydrate and
protein increases insulin concentration, thus decreasing lipase activity
in adipose tissue, with a suppression of essential fatty acid release
as a result. A provision of 7.7 g/day to patients receiving total parenteral
nutrition can adequately prevent EFAD (Barr
et al., 1981).
The major classes of lipids found in the plasma include triacylglycerols,
phospholipids, unesterified and esterified cholesterol and free fatty
acids (FFA). In the plasma, lipids are hydrolyzed by lipoprotein lipase
(LPL) into glycerol and the free fatty acids. These fatty acids are the
metabolically active components and are readily used as an energy source.
In the cell, fatty acids are activated in the cytosol by the formation
of long chain acylcoenzyme A (acyl-coA) and then transported into the
mitochondria in association with carnitine. After entering the mitochondrion,
carnitine is cleavaged from the acylcarnitine and the resulting acyl-coA
is oxidized via ?-oxidation.
In ß-oxidation, acetylcoenzyme A (acetyl-coA) units are formed
from the acyl-chain, which are completely oxidized to water and carbondioxide
in the citric acid cycle. The ß-oxidation is controlled by the
availability of the substrate acyl-coA and oxidizing factors. An excess
of acetyl-coA over the oxidation capacity in the citric acid cycle can
be converted into ketone bodies in the liver or be resynthesized in the
plasma as short-chain carnitine esters.
Increased lipolysis, as occurs in starvation or with limited glucose
availability, leads to an increased conversion of fatty acids to ketone
bodies in the liver and to a decreased oxidation in the citric acid cycle.
After their release from the liver, these ketone bodies are readily taken
up by the tissues, especially muscular tissue, and oxidized in the citric
acid cycle, after being converted back to acetyl-coA.
Ketone bodies have an energy density of 4.2 kcal/g (17.9 kJ/g). Because
ketone bodies cross the mitochondrial membrane independently from carnitine,
they are more readily used in muscular tissue than are fatty acids. In
case of starvation, ketone body formation represents the mechanism for
energy supply for the Central Nervous System (CNS), that is not capable
of oxidizing fatty acids (Rich, 1990).
Intermediate between the metabolism of glucose and lipids are the medium-chain
triglycerides (MCT), which are rapidly oxidized and form a readily available
energy source for all tissues because of their rapid and complete oxidation,
thus also rendering ketone bodies. In this way, the available energy
is delivered to the whole body (Bach and Babayan, 1982).
Until recently, it was thought that medium-chain fatty acids (MCFA)
do not require carnitine to cross the mitochondrial membrane, but some
data would indicate that oxidation of MCFA is, to some extent, carnitine
dependent (Rössle et al., 1990)
Insulin is the hormone of major importance in lipid metabolism. During
th efed state, insulin increases lipoprotein lipase (LPL) activity, thereby
promoting the availability of fatty acids of triglyceride synthesis;
besides that, insulin promotes the glucose availability for triglyceride
synthesis adipose tissue. The inhibitory action of insuline on hormone-sensitive
lipase is counteracted in the catabolic hormones glucagon, (nor)adrenaline,
adrenocorticotrope hormone (ACTH), thyroid stimulating hormone (TSH)
and growth hormone (GH), which stimulate the ctivity of the lipase, thereby
accelerating the release of FFA from adipose tissue for use as an energy
source.
In stress and acute illness, endogenous fat is used as a major energy
source. In these states, mobilisation of fatty acids from fat stores
is increased; the hypersecretion of the catabolic stress hormone overrides
the inhibitory stimulus of promoting fat mobilisation.
As can be learned from the previous sections, two types of metabolic
reactions can be discerned: those that lead to the storage of energy
(anabolic reactions) and those that lead to the liberation of energy
(catabolic reactions).
Anabolic reactions are biochemical reactions leading to a net gain of
lean body mass and adipose tissue. These reactions are aimed at the preservation
of the body energy store. The major hormone regulating the process of
anabolism is insulin. Insulin promotes glucose uptake into cells (for
metabolism and glycogen storage), protein synthesis and liponeogenesis
and reduces glycogenolysis, lipolysis and proteolysis. Insulin maintains
and repairs lean tissue and stores excess energy.
Catabolic reactions are biochemical reactions leading to a net loss
of lean body mass and adipose tissue. These reactions lead to the liberation
of energy, thereby depleting the body energy store. The main hormone
of catabolism is glucagon. Other hormones promoting catabolism are (nor)adrenalin,
ACTH, TSH and GH. These hormones are collectively called counterregulatory
hormones because their effects are opposite to insulin. In catabolic
reactions, body reserves are liberated with the purpose of generating
energy. Catabolic reactions lead to the generation of glucose and fatty
acids, substrates that can easily be oxidized. Body stores of glycogen,
protein and fat are diminished in catabolic reactions.
Fig. 5: Major catabolic reactions
Fig. 6: Basic scheme of catabolic reactions
As can be learned from the above, energy and protein metabolism are
interrelated. The major role in this metabolism is for glucose, which
plays the key role in the metabolism and is the intermediate between
anabolic and catabolic reactions.
Bach AC, Babayan VK.:
Medium-chain triglycerides: an update.
Am J Clin Nutr 1982;36:950 - 62.
Barr LH, Dewey Dunn G, Brennan MF.:
Essential fatty acid deficiency during total parenteral nutrition.
Ann Surg 1981;193:304 - 11.
Bengoa JM:
Fondements de la nutrition parentérale dans le traitement de support
des affections médico-chirurgicales aigu´s.
Méd Hyg 1984;42:3234 - 42.
Bistrian BR.:
Nutritional assessment and therapy of protein-calorie malnutrition in
hospital.
J Am Diet Assoc 1977;71:393 - 7.
Cahill GF Jr.:
Starvation in man.
N Engl J Med 1970;282:668 - 75.
Carpentier YA, Van Gossum A, Dubois DY, Deckelbaum RJ.:
Lipid metabolism in parenteral nutrition. In: Rombeau JL, Caldwell MD
eds. Clinical nutrition: parenteral nutrition, 2nd ed. Philadelphia:
WB Saunders Company, 1993: 35 - 74.
Elwyn DH.:
Protein and energy requirements: effect of clinical state.
Clin Nutr 1993;12(suppl):44S - 51S.
Holman RT, Johnson SB, Hatch TF.:
A case of human linolenic acid deficiency involving neurological abnormalities.
Am J Clin Nutr 1982;35:617 - 23.
Matthews DE, Fong Y.:
Amino acids and protein metabolism. In: Rombeau JL, Caldwell MD eds.
Clinical nutrition: parenteral nutrition, 2nd ed. Philadelphia:
WB Saunders Company, 1993:75 - 122.
Neuringer M, Anderson GJ, Connor WE.:
The essentiality of n-3 fatty acids for the development and function
of the retina and the brain.
Annu Rev Nutr 1988;8:517 - 41.
Fasting and stress have opposite influences on the energy expenditure
of the human organism. The healthy human body is capable of passing from
a state involving three regular food intakes to a state of short-term
fasting and even prolonged fasting, as a result of precise metabolic
regulation. In these cases, the organism will save as much energy as
possible, thus reducing energy expenditure.
However, in stress conditions, energy expenditure is markedly increased.
As a result, the body´s metabolism will be converted into a catabolic
state, the gravity of which is determined by the nature and degree of
the injury and type and severity of underlying disease.
These and other processes will be developed in the following chapters.
In theory, if a person having 15 kg of adipose triglycerides — i.e.
140.000 kcal of reserves in the form of fats (Cahill,
1970)— and energy requirements of 1800 kcal/day, begins
to fast, he should be capable of withstanding 75 days of total fasting.
In practice, an abstinence from feeding leads to death after about 50
days of total fasting. In other words, the theoretical value of the energy
reserves can not be used in its entirety, because death intervenes beforehand
due to partial depletion of functional tissue proteins.
In the case of abstinence or fasting, endogenous energy stores are used
for metabolic processes. Fat, stored in indifferent fat tissue, is the
major source of energy. Energy can also be derived from protein; however,
there is no indifferent protein tissue and as a consequence the loss
of protein always leads to a loss of organ function.
Hence, in the case of fasting in healthy persons, the metabolism is aimed
at keeping the loss of protein as low as possible by lowering the metabolism
and the gluconeogenesis. The loss of nitrogen is reduced in the case
of complete fasting from 10 g per day to 4 - 5 g a day after
3 weeks. Fat stores are depleted faster with the purpose of providing
energy.
Many organs including the heart, kidneys and muscles, can use either
fatty acids or ketone bodies, derived from partial oxidation of fatty
acids, directly as energy substrates. The central nervous system, on
the other hand, and the red blood cells can only use glucose as an energy
substrate. For example, during a 24 hour fast, the brain will consume
150 g of glucose and the other organs about 36 g, i.e. a total of 186
g of glucose per day. Since the body is incapable of synthesizing glucose
from fat, it uses other substrates for gluconeogenesis. In fact, the
glycogen reserves are insufficient to cover the requirements for more
than 1 day. The most important substrate for gluconeogenesis is provided
by amino acids and, to a minor extent, by glycerol derived from the triglycerides.
Fig. 8: Metabolism of short-term fasting
In short-term fasting, some of the glucose required by the brain is
provided by liver glycogen, the reserve being exhausted within 48 hours.
If the human body is to withstand fasting, it must mobilize 1800 kcal/day
and produce 186 g of glucose mainly for the central nervous system. Eighty
percent of the energy requirements are provided by lipolysis of adipose
tissue where 160 g of triglycerides are split into fatty acids and glycerol.
Approximately 75 g of muscle proteins, i.e. nearly 300 g of muscle, per
day are mobilized to provide the substrate for gluconeogenesis. If protein
breakdown were to continue at the initial rate, roughly one-third of
the total body proteins would be exhausted in 3 weeks, which is incompatible
with survival.
So, if fasting is prolonged, a major metabolic adaptation occurs. The
central nervous system begins to use ketone bodies as an energy substrate,
thereby reducing glucose requirements. Therefore, in prolonged fasting,
there is a shift from the use of protein as an energy source towards
the use of fats (in the form of ketone bodies). This adaptation permits
protein sparing and preserves the proteins' functional role. Nevertheless,
obligatory proteolysis always persists, amounting in the foregoing example
to at least 20 g of protein daily.
Fig. 9: Metabolism of prolonged fasting
Metabolic processes respond to internal signals. During fasting, blood
glucose levels fall with a consequent reduction in the secretion of insulin
and an increase in glucagon, two hormones with antagonistic actions on
energy metabolism. As a result of the decrease in the circulating insulin
level, triglyceride catabolism increases, causing the release of free
fatty acids and glycerol. The raised glucagon levels lead initially to
a distinct increase in liver glycogenolysis. Further, gluconeogenesis
is stimulated by glucagon, which inhibits protein synthesis and stimulates
muscular proteolysis, thereby furnishing the amino acid substrate.
There is therefore a metabolic adaptation to prolonged fasting, resulting
in a reduction of energy expenditure of up to 40% (Goldstein and Elwyn,
1989; Kinney, 1970). These mechanisms, which tend to limit proteolysis
in the healthy person, are defective or non-operative in cases of severe
disease or stress, as will be discussed in the next chapter.
Metabolic responses to disease and stress depend on a sequence of events
under the control of the central nervous system, the purpose of which
is to mobilize endogenous energy substrates. The nature and magnitude
of these neurohumoral signals emitted by the brain depend on the degree
of stress, which in turn is a function of the extent of the lesions of
the tissue. These responses may be modulated by the patient´s age, physiological
reserves, nutritional status and latent diseases. The complexity of the
metabolic regulation which culminates in the hypermetabolism induced
by certain disorders is illustrated by the example of severe acute trauma.
The metabolic response to injury has been intensively studied by Cuthbertson
(1969, 1978, 1979). In the course of post-traumatic metabolism, two phases
may be distinguished in the stress response: the ebb and the flow phase.
The ebb or shock phase is transitory and generally completed in 24 hours,
but may continue for a few days. This phase is immediate and characterized
by a general depression of the body´s physiological functions. There
is a progressive fall in blood flow, in body temperature and oxygen utilisation.
A series of cardiovascular readjustments takes place, the cardiac output
falls, the peripheral resistance increases and the blood is redistributed
to the vital organs. The circulating levels of the so-called stress hormones,
catecholamines, ACTH, growth hormone and glucocorticoids increase significantly.
At the site of the injury, there is an accumulation of water, plasma
protein and sodium, thus helping the organism to retain sodium and conserve
body water.
If these initial adjustments enable the traumatized patient to survive,
a second phase of stress response follows. This is the flow phase which
is mainly characterized by a hypermetabolic state associated with increased
losses of nitrogen and other body constituents. It is possible to divide
the flow phase into a catabolic and an anabolic stage. The latter then
heralds the final recovery of the patient. However, the flow phase is
dominated by the catabolic stage, which is in fact an inflammatory response,
a kind of defence reaction in order to initiate repair of the damaged
tissue.
There is also a rise in urinary excretion of nitrogen, sulphur, phosphorus,
potassium, magnesium and creatinine. This goes together with an increased
basal oxygen consumption. Usually, the catabolic processes reach a maximum
4 - 8 days after stress induction. In general, the more severe
the injury is, the longer the catabolic response lasts and the more rigorous
it is. With burns, for example, the time course can be extended to a
few weeks. There is a net protein catabolism with urinary nitrogen loss,
increased substrate cycling of lipids, carbohydrates and proteins, accounting
for much of the increase in energy expenditure. The increase in amino
acid turnover results in a negative nitrogen balance. However, there
is a qualitative predominance of proteolysis over protein synthesis.
Both processes are stimulated: proteolysis can increase by as much as
45%, while the maximum augmentation of protein synthesis can be about
35 - 36%. As a result, the losses can even be higher than 20
g of nitrogen per day, which corresponds to a loss of 600 to 800 g of
muscle per day (Cohen, 1993). The main goal of clinical nutrition is
to support protein synthesis rather than to suppress proteolysis. This
will help to initiate the anabolic stage of the flow phase, leading to
the patient´s convalescence.
Tab. 6: Metabolic physiology
The central nervous system processes the information received during
stress and dictates the responses, which are transmitted on the one hand
by the autonomic nervous system and on the other hand by the hypothalamopituitary
axis. Hormones and cytokines are the mediators of these processes.
The role of the autonomic nervous system is to exercise the control
of the central nervous system on internal homeostasis. Under normal conditions,
numerous functions such as cardiac rate, vascular tonus, gastrointestinal
motility and the majority of the endocrine functions are under the tonic
influence of one or another of the two divisions of the autonomic nervous
system. The sympathetic system is primarily responsible for mediating
the stress response. The clinical characteristics of the stress response,
such as sweating, acceleration of the heart rate, peripheral vasoconstriction
and increase in intestinal motility are governed by the sympathetic nervous
system. Catecholamine levels appear to be correlated with the severity
of stress while elevated levels reflect its duration. On the one hand,
catecholamines modulate the cardiovascular response. On the other hand,
these mediators raise blood glucose concentration by promoting glycogenolysis
in the liver and muscle as well as increasing the release of free fatty
acids from the adipose tissue. The combined effect of adrenaline-induced
insulin suppression and glucagon stimulation increases gluconeogenesis
in the liver and accounts for the hyperglycaemic conditions encountered
during stress.
In the responses to stress, all the hormones secreted by the hypophysis
(ACTH, GH, luteinic hormone (LH) and prolactin (PRL)) may play a role
but only the effect of ACTH is well documented. Increased secretion of
ACTH and glucocorticoids is observed in trauma, extensive burns, infections
and after surgery. To some extent, the physiological effects of the glucocorticoids
on metabolism are basically opposed to the effect of insulin. They affect
the regulation of carbohydrate, protein, lipid and nucleic acid metabolism.
Glucocorticoids increase gluconeogenesis. As regards protein metabolism,
corticosteroids favour the breakdown of muscle proteins, thereby furnishing
the precursors for gluconeogenesis. Also, the permissive effect of glucocorticoids
on the action of catecholamines is necessary for the mobilisation of
triglycerides. As regards body composition, the overall effect of corticosteroids
is a loss in lean body mass, while the adipose tissue may be preserved.
The retention of extracellular water may also be promoted. Corticosteroids,
in conjunction with catecholamines, have a catabolic effect, transferring
energy substrates from the muscular carcass and adipose tissue to the
viscera as a matter of biological priority.
Cytokines are immune-derived endogenous polypeptide mediators, which
initiate immune, haematological and metabolic alterations that are integral
to the response of the organism to stress conditions. Cytokines are products
of immunocompetent cells and act at very low concentrations to regulate
the biological functions of other cells and organs. These mediators participate
in the development of both the beneficial and injurious sequelae of immune
system activation. They are essential to the recovery process, but lethal
in high doses. Their beneficial properties are for example, the stimulation
of antimicrobial function, wound healing, myelostimulation and mobilisation
of fuel stores. On the other hand, cytokines are capable of triggering
a state of chronic cachexia or acute septic shock, followed by tissue
injury, multiple organ failure and eventually even death of the patient.
Through a cascade system, different cytokines can stimulate each other´s
production. (Fong et al., 1990; Grimble,
1990; Tracey, 1992).
One cytokine in particular seems to occupy a pivotal role in the development
of the metabolic and pathological consequences of the stress response:
tumour necrosis factor (TNF), also known as cachectin. TNF is probably
the most potent mediator of septic shock. It has been detected in the
serum of patients experiencing various diseases, such as parasitic or
bacterial infections, tumour-bearing disease, burns and acute hepatic
failure. TNF also exerts influences on the metabolism of the organism.
It increases degradation of protein in skeletal muscle but also stimulates
the production of acute phase proteins in the liver. TNF also induces
changes in lipid metabolism. There is further a loss of triglycerides
from the adipocytes and an increase of cellular lipolysis.
These phenomena together account for hypertriglyceridemia and loss of
body fat. Overall, the beneficial effects of TNF predominate at low tissue
levels, while higher concentrations contribute to the development of
cachexia and septic shock syndrome.
Other important cytokines are interleukin-1 (IL-1) and interleukin-6
(IL-6). Both mediators are induced by the presence of TNF. IL-1 has been
shown to stimulate the proliferation of T-cells and to promote myelopoiesis.
Furthermore, it is able to induce fever and anorexia. Like TNF, IL-1
exerts beneficial influences during injury, but chronic IL-1 release
has also been implicated in the pathogenesis of different degenerative
diseases. In patients developing sepsis in the intensive care unit, high
TNF serum levels were found in patients with septic shock. There was
a correlation between TNF level and sepsis severity score and mortality;
no correlation, however, was found with IL-1 values (Damas
et al., 1989).
IL-6 is also rapidly released into the circulation in response to injury.
It is the main promoter of hepatic acute phase protein synthesis. IL-6
is also an endogenous pyrogen. Like TNF and IL-1, IL-6 is an early responder
in the cascade of host mediators after injury. Its influence is rather
beneficial to the host by enhancing immune function.
Nutritional factors may have an influence on cytokine synthesis and release.
Furthermore, nutrition can affect the direct and indirect actions on
target tissues. Especially lipids exert an influence on cytokine production
and inflammation. Lipids are known to be able to modify cell membrane
structure and to alter eicosanoid metabolism. Protein-energy malnutrition
probably also influences cytokines in such a way that their levels are
lowered. Preliminary data seem to indicate that overnutrition might increase
cytokine production.
Basically, the stress response due to an infection is the same as the
response after injury, trauma or severe disease. As a matter of fact,
the same mechanisms and mediators intervene.
Hence, a catabolic response occurs with all infections, even when they
are subclinical and not accompanied by symptoms.
The biological response is amplified by the production of chemical mediators
(histamine, prostaglandins, serotonin, cytokines, etc.) and inflammatory
processes. Cell-mediated immunity is depressed in malnutrition; delayed
hypersensitivity skin responses to antigen are reduced. Malnutrition
has differential effects on cytokine production. Production of interferon,
prostaglandin E2 and interleukin-2 and interactions with T-lymphocytes
appear to be compromised in severe malnutrition. In contrast, production
of other cytokines are apparently unaffected by protein-energy malnutrition.
For each degree centigrade above the normal value, an increase in energy
expenditure of 12 - 13% is observed (Scrimshaw,
1991). Microbial infections frequently complicate the clinical
profile of an ill, traumatized or surgical patient. Apart from local
tissue destruction, the systemic effects of infections may have a pronounced
effect on metabolic responses. Measurements of energy expenditure have
shown that the development of an infection intensifies the metabolic
response to stress. If the energy expenditure is measured before and
after elective, uncomplicated surgery, the post-operative value is found
to be some 10% higher. If, on the other hand, peritonitis supervenes,
the post-operative increase will be 20 - 50% higher than the
expected value. This observation may be confirmed by measuring the excretion
of urinary nitrogen, the level of which is much higher in the presence
of post-operative infection. The increase in nutrient requirements depends
on the nature, duration and severity of the infection. Moreover, the
type of infection, chronic or acute, and the nutritional state of the
patient both influence the recovery. Improvement of the nutritional status
reduces morbidity and mortality from infection.
Basically, nutritional support must be effective in reversing protein-energy
malnutrition, thereby decreasing morbidity and mortality to the level
of the well-nourished hospital patient, or producing an increased response
rate to treatment. It is aimed at reducing the rate of weight loss and
protein breakdown and at stabilizing or increasing the body weight and
protein mass.
In acute illness and stress, the hypermetabolic responses override the
physiological adaptations and prolong the catabolic state, which may
have an influence on the length of time for which a patient lacking nutritional
support can survive. In disease-induced conditions of stress, a fundamental
requirement is the provision of energy and protein intakes sufficient
to maintain normal bodily functions, to meet the increased needs due
to the underlying disorder and to furnish the necessary substrates for
the reparative processes. Hence, initially the aim of nutritional support
is to limit the consequences of protein catabolism by permitting protein
sparing and then to promote anabolism. The final goal is to improve the
patient´s outcome by reducing the high morbidity and mortality associated
with severe malnutrition.
In protein and energy depleted patients, nutritional repletion can lead
to rapid responses on many physiological functions after 3 - 4
days, long before there is a demonstrable gain in total body protein.
Improvements in wound healing response are reported after one week of
nutritional support, before there is a measurable improvement in nutritional
status (Haydock and Hill, 1986).
In patients with malnutrition, an adequate nutritional support may lead
to an improvement of cellular chemistry and thus of organ, skeletal muscle,
respiratory and immune functions. (Windsor
and Hill, Ann Surg 1988; 207,208)
Furthermore, psychological function also responds to early nutritional
support.
Despite the fact that the need for nutrition is generally accepted as
an indispensable part of modern surgical treatment, it has proven difficult
to determine the effect of feeding on postoperative outcome and mortality
rate and the overall resource utilisation, because of the ethical problems
of withholding nutritional support in the control group. Furthermore,
the improvement of surgical techniques and the further development of
life-saving treatments and methods for post-operative care tend to mask
the impact of perioperative nutrition support.
However, comprehensive data are available which illustrate that nutritional
support improves biochemical and physiological parameters that define
malnutrition. These parameters include a positive nitrogen balance, reflecting
an improved protein status, normalization of delayed hypersensitivity
skin responses, indicating improved immunological status, and improved
biochemical markers of nutritional status. Preoperative malnutrition
is obviously associated with poor postoperative outcome. The many reports
evaluating the effect of perioperative nutritional support on postoperative
outcome vary widely in number of patients studied, primary diagnosis
and duration and quality of nutritional support. Hence, there is no clear-cut
consensus about the efficacy of perioperative nutritional support in
improving postoperative outcome, but critical analyses of published reports
more and more confirm the existence of such a correlation.
Preoperative parenteral nutrition administered in adequate amounts for
7 - 15 days, especially in the high risk surgical patient with a poor
or abnormal preoperative nutritional status, has been shown to reduce
postoperative morbidity, mortality and septic complication rate and to
improve nutritional status (Bellantone et al, 1988; Campos and Meguid,
1992; Starker et al., 1986; The Veterans Affairs Total Parenteral Nutrition
Co-operative Study Group, 1991). Other studies have evaluated the efficacy
of postoperative nutritional support. The influence of such a support
on outcome seems to be correlated with an increase of the serum albumin
level of the patients (Ching et al., 1980). Postoperative parenteral
nutrition for a period of 15 days, in comparison with only a glucose
treatment, has been demonstrated to improve mortality and complications
rates and to diminish functional disturbances, the need for additional
medical support and abnormalities in nutritional state. Postoperative
TPN is potentially life-saving in 20% of unselected patients undergoing
major surgical procedures, although these patients can not be identified
by preoperative criteria (Sandström, 1993). A group of nutritionally
depleted patients who did not receive nutritional support was characterized
by an increased rate of postoperative infectious complications (von Meyenfeldt
et al., 1992).
Another study on perioperative parenteral nutrition support for patients
undergoing hepatectomy has demonstrated a reduction in overall postoperative
morbidity rate with fewer septic complications, less postoperative weight
loss and less deterioration of the liver function in the perioperative
nutrition group as compared with the control group, which only received
an usual oral diet preoperatively. These benefits were more pronounced
in those patients with underlying cirrhosis and who underwent major hepatectomy
(Fan et al., 1994).
However, it remains relatively complicated to adequately select the
kind of patients who would maximally benefit from such a treatment in
terms of life-supporting therapy. Hence, perioperative nutritional support
should be considered for patients requiring a major operative procedure
who are not able to consume an adequate oral diet and for patients who
are candidates for immediate operation but who have significant nutritional
deficits.
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